1
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Ai D, Arrey EN, Postlewait LM, Gao Y, Li X. The prevalence and clinical significance of residual occult breast cancer after neoadjuvant chemotherapy: reassessing surgical pathology in cases initially described as pathological complete response. Histopathology 2025; 86:1112-1120. [PMID: 39904575 DOI: 10.1111/his.15417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 12/30/2024] [Accepted: 01/15/2025] [Indexed: 02/06/2025]
Abstract
AIMS Evaluation of pathological complete response (pCR) [no residual invasive carcinoma in the breast (RIC) or lymph node metastases (LNM) in surgical specimens following therapy] is typically based on evaluation of one level of haematoxylin and eosin (H&E) section. Not achieving pCR is associated with worse outcomes, and additional therapy may ensue. This study of patients with triple-negative (TNBC) or human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer who underwent neoadjuvant therapy aims to assess whether occult residual disease (ORD) can be identified in deeper sections of tumour beds and lymph nodes in cases originally reported as pCR and whether ORD is associated with worse outcomes. METHODS AND RESULTS In 84 cases of pCR (2009-17) at our institution, deeper-level recuts were assessed for ORD. Oncological and survival outcomes were compared. ORD was identified in seven of 40 TNBC (17.5%; five RIC; one LMN; one RIC and LMN) and four of 44 HER2+ (9.1%; three RIC; one LMN) cases (all residual cancer burden I). Median follow-up was 46.7 months for TNBC (one local recurrence, four distant metastases and two deaths) and 86.8 months for HER2+ (no local recurrence, three distant metastases and two deaths). All recurrence and death events occurred in patients with pCR without ORD, with no recurrence events in patients with ORD. CONCLUSIONS In patients with TNBC and HER2+ breast cancer with pCR by standard pathological assessment, occult residual disease is not uncommon. Occult disease was not associated with worse oncological or survival outcomes, suggesting standard pathological assessment is sufficient to identify clinically meaningful disease.
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Affiliation(s)
- Di Ai
- Department of Pathology and Laboratory Medicine, McGovern School of Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Eliel N Arrey
- Department of Surgery, Morehouse School of Medicine, Atlanta, GA, USA
| | - Lauren M Postlewait
- Division of Surgical Oncology, Department of Surgery, Grady Memorial Hospital, Emory University, Atlanta, GA, USA
| | - Yuan Gao
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
| | - Xiaoxian Li
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
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2
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Wu G, Chen X, Luo R, Koh YX, Lim TKH, Chew V, Zhou J, Fan J, Gao Q, Zhu K, Shi R. Histopathologic Grading of Residual Tumor Predicts Survival of Intrahepatic Cholangiocarcinoma Patients Treated With Neoadjuvant Therapy: Major Pathologic Response and Its Clinical Significance. Am J Surg Pathol 2025; 49:578-587. [PMID: 40103370 PMCID: PMC12068548 DOI: 10.1097/pas.0000000000002359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
Neoadjuvant therapy (NAT) is increasingly used to treat patients with initially unresectable intrahepatic cholangiocarcinoma (iCCA). A histopathologic grading system for residual tumors that can predict patient survival is lacking in the literature. This retrospective study enrolled 151 iCCA patients who received NAT. The percentage of residual viable tumor (%RVT) extent was calculated by RVT surface area/total tumor bed area ×100 and scored in 5% increments. Kaplan-Meier and Cox regression analyses were used to investigate its correlations with recurrence-free survival (RFS) and overall survival (OS). Tumor regression grading by the College of American Pathologists (CAP) and MD Anderson (MDA) methodologies were also validated. A 10% RVT-based tumor regression score (TRS) showed a significant correlation with both OS and RFS. TRS and major pathologic response (mPR) were therefore defined as follows: TRS 1/mPR, tumor with 0 to 10% RVT; TRS 2, more than 10% RVT. Patients graded as TRS 1/mPR had superior OS ( P =0.006) and RFS ( P <0.001) compared with those with TRS 2 in univariate analysis. In a multivariate analysis including ypTNM stages, lymphovascular invasion, and perineural invasion, TRS 1/mPR was also found to be an independent prognostic factor for both OS (hazard ratio [HR]: 0.226; 95% CI: 0.053-0.966, P =0.045) and RFS (HR: 0.474; 95% CI: 0.231-0.974, P =0.042). As for the CAP and MDA grading methodologies, they were found to correlate with RFS (CAP: P =0.002; MDA: P =0.001), but not with OS (CAP: P =0.181; MDA: P =0.09). Our study revealed that a TRS of ≤10% RVT significantly correlates with longer OS and RFS and can be suggested as an mPR in iCCA. This indicator is easily applicable, prognostically relevant, and could be further validated in future prospective clinical trials.
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Affiliation(s)
- Gaohua Wu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute
| | - Xiufen Chen
- Department of Anatomical Pathology, Singapore General Hospital
| | - Rongkui Luo
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ye Xin Koh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre
| | | | - Valerie Chew
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute
| | - Kai Zhu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute
| | - Ruoyu Shi
- Department of Pathology and Laboratory Medicine, Kandang Kerbau Women’s and Children’s Hospital, Singapore
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3
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López-Velazco JI, Manzano S, Elorriaga K, Otaño M, Lahuerta A, Álvarez L, Etxabe I, Huarte M, Buch E, Gimenez J, Quiroga V, Fernandez M, Aragón S, Paré L, Prat A, Álvarez-López I, Caffarel MM, Urruticoechea A. Molecular characterisation of the residual disease after neoadjuvant endocrine therapy in ER+/HER2- breast cancer uncovers biomarkers of tumour response. Transl Oncol 2025; 57:102407. [PMID: 40349505 DOI: 10.1016/j.tranon.2025.102407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2025] [Accepted: 05/04/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Neoadjuvant endocrine therapy (NET) in oestrogen receptor-positive /HER2-negative breast cancer (ER+/HER2- BC) allows real-time evaluation of treatment sensitivity by monitoring tumour response and offers the opportunity of personalised therapy. However, the lack of reproducible biomarkers to assess response and long-term prognosis after NET is a significant barrier to increase its indications. METHODS In this study we searched for clinically relevant molecular reporters of response to NET in a multicentre population of ER+/HER2- BC patients (n = 87) by using: PAM50 gene expression panel and immunohistochemical evaluation of key proteins involved in tumorigenesis. RESULTS Our PAM50 analyses show that tumours changing from luminal A to normal-like subtype after NET presented better radiological and pathological tumour responses, a significant larger decrease in Ki67 at surgery, lower preoperative endocrine prognostic index score (PEPI) and lower tumour cellularity size (TCS) than those with persistent luminal A status. Patients with the highest response to NET showed the largest decrease in PAM50-derived risk of recurrence (ROR) following NET. In addition, the percentage of p53 positive cells was associated with decreased response to NET. CONCLUSIONS Our findings highlight the change of intrinsic subtype from luminal A to normal-like after NET as a putative biomarker characterising the patient population that obtains the highest benefit from NET. Our study also suggests that changes in PAM50-derived ROR score and p53 evaluation could also help to identify those patients. Thus, this study uncovers potential biomarkers of response to NET and prognosis, which should be validated in independent cohorts, helping to the implementation of NET in the clinical practice.
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Affiliation(s)
- Joanna I López-Velazco
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, San Sebastián, Spain
| | - Sara Manzano
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, San Sebastián, Spain
| | - Kepa Elorriaga
- Gipuzkoa Pathology Unit, OSI Donostialdea - Onkologikoa, San Sebastián, Spain
| | - Maria Otaño
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, San Sebastián, Spain; Gipuzkoa Cancer Unit/OSI Donostialdea - Onkologikoa, San Sebastián, Spain
| | - Ainhara Lahuerta
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, San Sebastián, Spain; Gipuzkoa Cancer Unit/OSI Donostialdea - Onkologikoa, San Sebastián, Spain
| | - Luis Álvarez
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, San Sebastián, Spain; Gynecology and General Surgery Departments - Breast Unit, Onkologikoa, San Sebastián, Spain
| | - Inge Etxabe
- Gynecology and General Surgery Departments - Breast Unit, Onkologikoa, San Sebastián, Spain
| | - Miren Huarte
- Gynecology and General Surgery Departments - Breast Unit, Onkologikoa, San Sebastián, Spain
| | - Elvira Buch
- Hospital Clínico Universitario de Valencia, Spain
| | | | | | - Marta Fernandez
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, San Sebastián, Spain; Gynecology Department - Breast Unit, OSI Donostialdea, San Sebastián, Spain
| | | | - Laia Paré
- Hospital Clinic, Barcelona - IDIBAPS, Barcelona, Spain
| | - Aleix Prat
- Hospital Clinic, Barcelona - IDIBAPS, Barcelona, Spain
| | - Isabel Álvarez-López
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, San Sebastián, Spain; Gipuzkoa Cancer Unit/OSI Donostialdea - Onkologikoa, San Sebastián, Spain
| | - Maria M Caffarel
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, San Sebastián, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
| | - Ander Urruticoechea
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, San Sebastián, Spain; Gipuzkoa Cancer Unit/OSI Donostialdea - Onkologikoa, San Sebastián, Spain.
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4
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Fan L, Shao ZM. Camrelizumab vs Placebo in Patients With Triple-Negative Breast Cancer. JAMA 2025:2833138. [PMID: 40266589 DOI: 10.1001/jama.2025.1294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Affiliation(s)
- Lei Fan
- Department of Breast Surgery, Shanghai Cancer Center, Shanghai, China
| | - Zhi-Ming Shao
- Department of Breast Surgery, Shanghai Cancer Center, Shanghai, China
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5
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Lee SY, Yoo TK, Lee SB, Kim J, Chung IY, Ko BS, Kim HJ, Lee JW, Son BH. Prognostic value of residual cancer burden after neoadjuvant chemotherapy in breast cancer: a comprehensive subtype-specific analysis. Sci Rep 2025; 15:13977. [PMID: 40263332 PMCID: PMC12015579 DOI: 10.1038/s41598-025-98176-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 04/09/2025] [Indexed: 04/24/2025] Open
Abstract
This study evaluated the prognostic impact of residual cancer burden (RCB) on breast cancer subtypes following neoadjuvant chemotherapy (NAC). We retrospectively examined 2,416 breast cancer patients treated with NAC and surgery at Asan Medical Center (2015-2020). Baseline characteristics, clinicopathological parameters, recurrence, and survival outcomes were analyzed using Kaplan-Meier and Cox regression methods to assess RCB's prognostic significance across subtypes. Pathologic complete response (pCR) was achieved in 25.6% (619) of patients. RCB2 was the most common (44.0%, 1,063), followed by RCB3 (19.6%, 474) and RCB1 (10.8%, 260). Among HR-/HER2 + patients, 67% had RCB0/1, while 87% of HR+/HER2- patients had RCB2/3. Higher RCB was significantly associated with worse overall survival (OS) and disease-free survival (DFS) across all subtypes. Subtype-specific analysis revealed that HR-/HER2 + patients with RCB3 and HR-/HER2- patients with RCB2/3 had significantly worse OS and DFS. Multivariate analysis revealed that RCB2/3 (vs. RCB0), total mastectomy (vs. breast-conserving surgery), axillary lymph node dissection (ALND), lymphovascular invasion (LVI), high Ki-67 index (≥ 20), HR negativity, and HER2 negativity were linked to higher risks of recurrence and death (p < 0.05). Factors associated with higher RCB included ALND, LVI, higher Ki-67, and HR+/HER2- subtype. RCB classification is a strong prognostic indicator across all subtypes. Patients with RCB2/3 in the HR-/HER2- and RCB3 in the HR-/HER2 + subtypes had particularly poor outcomes, suggesting benefits from additional treatments beyond standard care.
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Affiliation(s)
- Soo-Young Lee
- Department of General Surgery, Inha University College of Medicine, Inha University Hospital, Incheon, Korea
| | - Tae-Kyung Yoo
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-Ro 43-gil, Songpa-Gu, Seoul, 05505, Korea
| | - Sae Byul Lee
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-Ro 43-gil, Songpa-Gu, Seoul, 05505, Korea
| | - Jisun Kim
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-Ro 43-gil, Songpa-Gu, Seoul, 05505, Korea
| | - Il Yong Chung
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-Ro 43-gil, Songpa-Gu, Seoul, 05505, Korea
| | - Beom Seok Ko
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-Ro 43-gil, Songpa-Gu, Seoul, 05505, Korea
| | - Hee Jeong Kim
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-Ro 43-gil, Songpa-Gu, Seoul, 05505, Korea
| | - Jong Won Lee
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-Ro 43-gil, Songpa-Gu, Seoul, 05505, Korea
| | - Byung Ho Son
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-Ro 43-gil, Songpa-Gu, Seoul, 05505, Korea.
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6
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Conforti F, Nekljudova V, Sala I, Ascari R, Solbach C, Untch M, Denkert C, Bagnardi V, Pala L, Fasching PA, Schneeweiss A, Lück HJ, Pagan E, De Pas T, van Mackelenbergh M, Huober J, Müller V, Link T, Karn T, Reinisch M, Marmé F, Bjelic-Radisic V, Schem C, Hartkopf A, Stickeler E, Hanusch C, Blohmer JU, Fehm T, Rhiem K, Holtschmidt J, Gelber RD, Loibl S. Surrogate End Points for Overall Survival in Neoadjuvant Randomized Clinical Trials for Early Breast Cancer. J Clin Oncol 2025; 43:1441-1452. [PMID: 39883887 DOI: 10.1200/jco-24-01360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 11/07/2024] [Accepted: 12/23/2024] [Indexed: 02/01/2025] Open
Abstract
PURPOSE To assess trial-level surrogacy value for overall survival (OS) of the pathologic complete response (pCR) and invasive disease-free survival (iDFS) in randomized clinical trials (RCTs) for early breast cancer (BC). METHODS Individual patient data of neoadjuvant RCTs with available data on pCR, iDFS, and OS were included in the analysis. We used the coefficient of determination R2 from weighted linear regression models to quantify the association between treatment effects on OS and on the surrogate end points. RESULTS Eleven RCTs, for a total of 15 treatment comparisons and 12,247 patients, were included in the analysis. There was a weak association between hazard ratios (HRs) for OS and odds ratio of pCR overall (R2, 0.07; 95% CI, 0.00 to 0.48), as well as in all the subgroups explored. Overall, the R2 for the association between HR OS and HR iDFS was 0.46 (95% CI, 0.08 to 0.71), which is just below the cutoff of 0.5 for moderate surrogacy. In the majority of subgroups explored, the R2 ranged from 0.5 to <0.7, while in hormone receptor-/human epidermal growth factor receptor 2- subtype, histologic grade 1-2 tumors, and lobular tumors, surrogacy was strong (ie, R2 ≥0.7). The surrogacy value of iDFS for OS was affected by follow-up (FUP) length: R2 substantially increased up to 36 months of FUP, with little further improvement after 48 months of FUP. CONCLUSION iDFS with sufficient FUP is an acceptable surrogate end point to confidently anticipate final OS results of neoadjuvant RCTs for early BC. This recommendation holds true across many subgroups, with the notable exception of HR+ disease. There is definite need to reassess whether OS is the optimal end point for treatment efficacy measurement in HR+ early BC.
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Affiliation(s)
- Fabio Conforti
- Medical Oncology Unit, Humanitas Gavazzeni, Bergamo, Italy
- Humanitas University, Rozzano, Italy
| | | | - Isabella Sala
- Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Roberto Ascari
- Department of Economics, Management and Statistics, University of Milano-Bicocca, Milan, Italy
| | | | | | - Carsten Denkert
- Institute of Pathology, Philipps-University Marburg, University Hospital UKGM Marburg, Marburg, Germany
| | - Vincenzo Bagnardi
- Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
| | - Laura Pala
- Medical Oncology Unit, Humanitas Gavazzeni, Bergamo, Italy
- Humanitas University, Rozzano, Italy
| | | | - Andreas Schneeweiss
- National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany
| | - Hans-Joachim Lück
- Gynäkologisch-onkologische Praxis Neumarkt, Neumarkt in der Oberpfalz, Germany
| | - Eleonora Pagan
- Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
| | - Tommaso De Pas
- Medical Oncology Unit, Humanitas Gavazzeni, Bergamo, Italy
| | - Marion van Mackelenbergh
- Universitätsklinikum Schleswig-Holstein, Klinik für Gynäkologie und Geburtshilfe, Schleswig-Holstein, Germany
| | - Jens Huober
- Departement Interdisziplinäre medizinische Dienste, Kantonsspital St Gallen, Brustzentrum, St Gallen, Switzerland
| | - Volkmar Müller
- Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | - Theresa Link
- Department of Gynecology and Obstetrics, Technische Universität Dresden, Dresden, Germany
| | - Thomas Karn
- Klinik für Frauenheilkunde und Geburtshilfe, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Mattea Reinisch
- Department of Gynecology with Breast Center, Evang. Kliniken Essen-Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Frederik Marmé
- Medizinische Fakultät Mannheim, Universität Heidelberg, Universitätsfrauenklinik Mannheim, Mannheim, Germany
| | - Vesna Bjelic-Radisic
- Breast Unit, University Hospital Helios, University Witten Herdecke, Wuppertal, Germany
| | | | - Andreas Hartkopf
- AGO Study Group and University Hospital Tübingen, Tübingen, Germany
| | - Elmar Stickeler
- Klinik für Gynäkologie und Geburtsmedizin, Uniklinik Aachen, Aachen, Germany
| | | | - Jens-Uwe Blohmer
- Gynakologie mit Brustzentrum, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Tanja Fehm
- Universitätsklinik Düsseldorf, Düsseldorf, Germany
| | - Kerstin Rhiem
- Center for Familial Breast and Ovarian Cancer, University of Cologne, Cologne, Germany
| | | | - Richard D Gelber
- Department of Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Harvard T.H. Chan School of Public Health, and Frontier Science & Technology Research Foundation, Boston, MA
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7
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Chen L, Wu W, Liang F, Liu G, Yu K, Wu J, Di G, Fan L, Wang Z, Li J, Shao Z. A prospective, phase II, neoadjuvant study based on chemotherapy sensitivity in HR+/HER2- breast cancer-FINEST study. Cancer Commun (Lond) 2025; 45:411-421. [PMID: 39754712 PMCID: PMC11999884 DOI: 10.1002/cac2.12649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 12/01/2024] [Accepted: 12/22/2024] [Indexed: 01/06/2025] Open
Abstract
BACKGROUND Hormone receptor-positive (HR+)/humaal growth factor receptor 2-negative (HER2-) breast cancer, the most common breast cancer type, has variable prognosis and high recurrence risk. Neoadjuvant therapy is recommended for median-high risk HR+/HER2- patients. This phase II, single-arm, prospective study aimed to explore appropriate neoadjuvant treatment strategies for HR+/HER2- breast cancer patients. METHODS Eligible female patients with newly diagnosed, untreated HR+/HER2- breast cancer received 2 cycles of nab-paclitaxel and carboplatin (nabPCb). Magnetic resonance imaging (MRI) was performed to assess tumor responses, and ≥ $ \ge $ 40% regression of the maximal tumor diameter was deemed chemo-sensitive. Chemo-sensitive patients continued nabPCb for 4 more cycles (group A). Chemo-insensitive patients were randomized to groups B, C, and D at a ratio of 1:3:1 to receive a new chemotherapy for 4 cycles or endocrine-immune-based therapy (dalpiciclib, letrozole and adebrelimab, with goserelin if patients were premenopausal) for 4 cycles or to undergo surgery. Peripheral blood and core-needle biopsy (CNB) samples were collected before treatment, followed by a next-generation sequencing (NGS) panel detection and similarity network fusion (SNF) typing through digital pathology data. The primary endpoint was the pathological complete response (pCR) rate, and the secondary endpoint was the clinical objective response rate (ORR). RESULTS A total of 121 patients were enrolled (67.8% with stage III disease), with 76, 9, 27, and 9 patients in groups A, B, C and D, respectively. The total pCR rate was 4.1%, and all patients who received pCR were in group A. Group C had a better ORR than Group B (81.5% vs. 66.7%). Exploratory analysis revealed that patients with the SNF4 subtype were the most sensitive to nabPCb (pCR rate of 21.1% vs. 1.8% in group A), whereas patients in group C with the SNF2 subtype were more sensitive to endocrine-immune-based therapy (Miller-Payne grade 4-5, 45.5% vs. 6.3%). CONCLUSIONS Converting to endocrine-immune-based therapy improved the ORR, but not the pCR rate in chemo-insensitive patients. Neoadjuvant chemotherapy and endocrine therapy are not mutually exclusive. The SNF4 subtype of HR+/HER2- breast cancer was more chemo-sensitive, whereas the SNF2 subtype might be more sensitive to immunotherapy.
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Affiliation(s)
- Li Chen
- Department of Breast SurgeryKey Laboratory of Breast Cancer in ShanghaiFudan University Shanghai Cancer CentreShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
| | - Wen‐Ya Wu
- Department of Breast SurgeryKey Laboratory of Breast Cancer in ShanghaiFudan University Shanghai Cancer CentreShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
| | - Fei Liang
- Department of BiostatisticsZhongshan HospitalFudan UniversityShanghaiP. R. China
- Clinical Research UnitInstitute of Clinical ScienceZhongshan HospitalFudan UniversityShanghaiP. R. China
| | - Guang‐Yu Liu
- Department of Breast SurgeryKey Laboratory of Breast Cancer in ShanghaiFudan University Shanghai Cancer CentreShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
| | - Ke‐Da Yu
- Department of Breast SurgeryKey Laboratory of Breast Cancer in ShanghaiFudan University Shanghai Cancer CentreShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
| | - Jiong Wu
- Department of Breast SurgeryKey Laboratory of Breast Cancer in ShanghaiFudan University Shanghai Cancer CentreShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
| | - Gen‐Hong Di
- Department of Breast SurgeryKey Laboratory of Breast Cancer in ShanghaiFudan University Shanghai Cancer CentreShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
| | - Lei Fan
- Department of Breast SurgeryKey Laboratory of Breast Cancer in ShanghaiFudan University Shanghai Cancer CentreShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
| | - Zhong‐Hua Wang
- Department of Breast SurgeryKey Laboratory of Breast Cancer in ShanghaiFudan University Shanghai Cancer CentreShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
| | - Jun‐Jie Li
- Department of Breast SurgeryKey Laboratory of Breast Cancer in ShanghaiFudan University Shanghai Cancer CentreShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
| | - Zhi‐Ming Shao
- Department of Breast SurgeryKey Laboratory of Breast Cancer in ShanghaiFudan University Shanghai Cancer CentreShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
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8
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Malhaire C, Umay O, Cockenpot V, Selhane F, Ramtohul T, Reyal F, Pierga JY, Romano E, Vincent-Salomon A, Kirova Y, Laas E, Brisse HJ, Frouin F. Predicting axillary residual disease after neoadjuvant therapy in breast cancer using baseline MRI and ultrasound. Eur Radiol 2025:10.1007/s00330-025-11408-4. [PMID: 39920303 DOI: 10.1007/s00330-025-11408-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 12/01/2024] [Accepted: 01/10/2025] [Indexed: 02/09/2025]
Abstract
OBJECTIVES To predict axillary node residual disease in women treated for node-positive breast cancer (BC) by neoadjuvant therapy (NAT), using breast BI-RADS MRI features and axillary ultrasound at baseline. MATERIAL AND METHODS In this single-center, retrospective study, women with node-positive BC who underwent NAT between 2016 and 2021 were included. Pre-treatment axillary US and breast MRIs were evaluated using the BI-RADS lexicon and T2 features, including Breast Edema Score. Univariate and multivariate logistic regression analyses were conducted for the prediction of axillary residual disease (ARD). A multivariable model based on logistic regression was trained and evaluated on randomly split train and test sets (7:3 ratio). RESULTS Out of the 141 women, 41% had post-NAT ARD. Axillary metastasis was independently associated with luminal subtype (odds ratio (OR), 25.5; p < 0.001), anterior tumor location (OR, 14.1; p = 0.008), and cortical thickening ≥ 7 mm (OR, 6.09; p = 0.002). Intratumoral T2 high signal intensity was protective (OR, 0.16; p = 0.006), while Ki67 had a marginal association (p = 0.064). In the training and test sets, the model, which is available online, achieved AUCs of 0.860 (95% CI: 0.783-0.936) and 0.843 (95% CI: 0.714-0.971), respectively. Anterior depth location and cortical thickening greater than 7 mm were also independently associated with post-NAT axillary burden. CONCLUSION Adjusting for BC subtype and KI-67 index, the anterior third location of BC, a cortical thickness greater than 7 mm, and the absence of intratumoral T2 hyperintensity is predictive of ARD after NAT. KEY POINTS Question What baseline imaging-based predictive models can identify patients at risk of persistent nodal disease after neoadjuvant therapy? Findings Baseline US cortical thickness superior to 7 mm, anterior tumor location, and absence of an intratumoral high signal on T2-weighted MRI predict residual axillary disease. Clinical relevance Our predictive model, available online at: litoic.shinyapps.io/LNPred_Apps , including breast cancer subtype, Ki-67 index level, breast cancer location, intratumoral signal intensity on T2WI, and initial lymph node thickness, could guide post-NAT axillary management.
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Affiliation(s)
- Caroline Malhaire
- Institut Curie, Department of Medical Imaging, PSL Research University, 26 rue d'Ulm, 75005, Paris, France.
- Institut Curie, LITO Laboratory, INSERM U1288, Paris-Saclay University, 91401, Orsay, France.
| | - Ozgun Umay
- Institut Curie, Department of Medical Imaging, PSL Research University, 26 rue d'Ulm, 75005, Paris, France
| | - Vincent Cockenpot
- Institut Curie, Department of Pathology, 26 rue d'Ulm, 75005, Paris, France
| | - Fatine Selhane
- Gustave Roussy, Department of Imaging, 94800, Villejuif, France
| | - Toulsie Ramtohul
- Institut Curie, Department of Medical Imaging, PSL Research University, 26 rue d'Ulm, 75005, Paris, France
| | - Fabien Reyal
- Institut Curie, Surgical Oncology Department, 26 rue d'Ulm, 75005, Paris, France
| | - Jean-Yves Pierga
- Institut Curie, Medical Oncology, 26 rue d'Ulm, 75005, Paris, France
| | - Emanuella Romano
- Institut Curie, Medical Oncology, 26 rue d'Ulm, 75005, Paris, France
- Institut Curie, Department of Immunology, INSERM U932, PSL Research University, 75005, Paris, France
| | | | - Youlia Kirova
- Institut Curie, Department of Radiotherapy, University Versailles St Quentin, 26 rue d'Ulm, 75005, Paris, France
| | - Enora Laas
- Institut Curie, Surgical Oncology Department, 26 rue d'Ulm, 75005, Paris, France
| | - Hervé J Brisse
- Institut Curie, Department of Medical Imaging, PSL Research University, 26 rue d'Ulm, 75005, Paris, France
- Institut Curie, LITO Laboratory, INSERM U1288, Paris-Saclay University, 91401, Orsay, France
| | - Frédérique Frouin
- Institut Curie, LITO Laboratory, INSERM U1288, Paris-Saclay University, 91401, Orsay, France
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9
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Niu S, Sun T, Wang M, Yao L, He T, Wang Y, Zhang H, Li X, Xu Y. Multiple time points for detecting circulating tumor DNA to monitor the response to neoadjuvant therapy in breast cancer: a meta-analysis. BMC Cancer 2025; 25:115. [PMID: 39844103 PMCID: PMC11752932 DOI: 10.1186/s12885-025-13526-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 01/15/2025] [Indexed: 01/24/2025] Open
Abstract
BACKGROUND Not all breast cancer (BC) patients can benefit from neoadjuvant therapy (NAT). A poor response may result in patients missing the best opportunity for treatment, ultimately leading to a poor prognosis. Thus, to identify an effective predictor that can assess and predict patient response at early time points, we focused on circulating tumor DNA (ctDNA), which is a vital noninvasive liquid biopsy biomarker. We performed a meta-analysis to explore the predictive value of response by monitoring ctDNA at four time points of NAT using pathologic complete response (pCR) and residual cancer burden (RCB). METHODS By searching Embase, PubMed, the Cochrane Library, and the Web of Science until December 24, 2023, we selected studies concerning the relationship between ctDNA and response or prognosis. We analysed the results at the following various time points: baseline (T0), first cycle of NAT (T1), mid-treatment (MT), and end of NAT (EOT). pCR and RCB were used to evaluate the response as the primary endpoint. The secondary endpoint was to investigate the relationship between ctDNA and prognosis. Odds ratios (ORs) and hazard ratios (HRs) were used as effect indicators. RESULTS Thirteen reports from twelve studies were eligible for inclusion in this meta-analysis. The results demonstrated that ctDNA negativity was associated with pCR at T1 (OR = 0.34; 95% CI: 0.21-0.57), MT (OR = 0.35; 95% CI: 0.20-0.60), and EOT (OR = 0.38; 95% CI: 0.22-0.66). When RCB was used to evaluate responses, ctDNA negativity was associated with RCB-0/I at the MT (OR = 0.34; 95% CI: 0.21-0.55) and EOT (OR = 0.26; 95% CI: 0.15-0.46). Furthermore, ctDNA positivity at T1 predicted a worse prognosis for patients (HR = 2.73; 95% CI: 1.29-5.75). We also performed a subgroup analysis to more accurately assess the predictive value of ctDNA for triple-negative breast cancer. CONCLUSIONS Our meta-analysis suggested that the ctDNA status at the early stage of NAT can predict patient response, which provides evidence for adjusting personalized treatment strategies and improving patient survival. PROSPERO REGISTRATION NUMBER CRD42024496465.
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Affiliation(s)
- Shuyi Niu
- Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Tie Sun
- The Third Department of General Surgery, People's Hospital of China Medical University (Liaoning Provincial People's Hospital), Shenyang, Liaoning, 110001, China
| | - Mozhi Wang
- Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Litong Yao
- Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Tianyi He
- Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Yusong Wang
- Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Hengjun Zhang
- Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Xiang Li
- Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning, 110001, China.
| | - Yingying Xu
- Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning, 110001, China.
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10
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Amylidi AL, Kontovinis L, Douganiotis G, Natsiopoulos I, Papazisis K. The Role of the NOLUS Score in Predicting pCR and iDFS in HR-positive HER2-negative Early Breast Cancer Patients who Received Neoadjuvant Chemotherapy. CANCER DIAGNOSIS & PROGNOSIS 2024; 4:775-782. [PMID: 39502621 PMCID: PMC11534053 DOI: 10.21873/cdp.10395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 08/29/2024] [Accepted: 08/30/2024] [Indexed: 11/08/2024]
Abstract
Background/Aim Breast cancer remains a significant health challenge, with neoadjuvant chemotherapy (NACT) improving clinical outcomes in certain subtypes. However, the role of NACT in hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer is unclear due to various outcomes and generally low rates of pathologic complete response (pCR). This study introduces the Non-Luminal Disease Score (NOLUS) as a potential predictive tool for assessing the response to NACT in these cases. Patients and Methods We retrospectively assessed patients diagnosed with locally advanced HR+/HER2- breast cancer who received NACT at our institution from 2009 to 2023. The study explored the association between NOLUS and pCR rates. NOLUS was calculated as positive or negative based on the percentage of estrogen receptor, progesterone receptor, and Ki-67 in tumor cells. We also investigated the correlation between pCR and invasive disease-free survival (iDFS), and examined NOLUS positivity across different age groups. Results A total of 149 patients met the inclusion criteria. NOLUS-positive patients exhibited a significantly higher pCR rate of 33.33% compared to 10.4% in NOLUS-negative patients (p=0.0031). With a median follow-up of 2.47 years, NOLUS-positive patients who achieved pCR had a 100% iDFS rate, mirroring the pCR versus residual disease patterns seen in triple-negative patients. NOLUS positivity was observed in 20.43% of patients aged 22-50, compared to 8.93% in those over 50, though this difference was not statistically significant. Conclusion NOLUS exhibits potential in predicting pCR in HR+/HER2- breast cancer, serving as a cost-effective substitute for genomic tests.
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Affiliation(s)
- Anna-Lea Amylidi
- Oncomedicare Oncology Group, Thessaloniki, Greece
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece
| | - Loukas Kontovinis
- Oncomedicare Oncology Group, Thessaloniki, Greece
- Medical Oncology Department, Euromedica General Clinic, Thessaloniki, Greece
| | | | | | - Konstantinos Papazisis
- Oncomedicare Oncology Group, Thessaloniki, Greece
- Medical Oncology Department, Euromedica General Clinic, Thessaloniki, Greece
- Interbalkan European Medical Center, Thessaloniki, Greece
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11
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Zumsteg ZS, Sheth S, Jabbour SK, Patel KR, Kimple RJ, Williams TM, Xu-Welliver M, Torres-Saavedra PA, Monjazeb AM, Mayadev J, Finkelstein SE, Buatti JM, Patel SP, Lin SH. Challenges and opportunities for early phase clinical trials of novel drug-radiotherapy combinations: recommendations from NRG Oncology, the American Society for Radiation Oncology (ASTRO), the American College of Radiology (ACR), the Sarah Cannon Research Institute, and the American College of Radiation Oncology (ACRO). Lancet Oncol 2024; 25:e489-e500. [PMID: 39362260 PMCID: PMC11778933 DOI: 10.1016/s1470-2045(24)00264-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 05/01/2024] [Accepted: 05/02/2024] [Indexed: 10/05/2024]
Abstract
NRG Oncology's Developmental Therapeutics and Radiation Therapy Subcommittee assembled an interdisciplinary group of investigators to address barriers to successful early phase clinical trials of novel combination therapies involving radiation. This Policy Review elucidates some of the many challenges associated with study design for early phase trials combining radiotherapy with novel systemic agents, which are distinct from drug-drug combination development and are often overlooked. We also advocate for potential solutions that could mitigate or eliminate some of these barriers, providing examples of specific clinical trial designs that could help facilitate efficient and effective evaluation of novel drug-radiotherapy combinations.
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Affiliation(s)
- Zachary S Zumsteg
- Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| | - Siddharth Sheth
- Division of Oncology, University of North Carolina, Chapel Hill, NC, USA
| | - Salma K Jabbour
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Krishnan R Patel
- Radiation Oncology Branch, National Cancer Institute, Bethesda, MD, USA
| | - Randall J Kimple
- Department of Human Oncology, Univeristy of Wisconsin, Madison, WI, USA
| | | | - Meng Xu-Welliver
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
| | - Pedro A Torres-Saavedra
- Division of Cancer Treatment and Diagnosis, Biometric Research Program, National Institutes of Health, Bethesda, MD, USA
| | - Arta M Monjazeb
- Department of Radiation Oncology, University of California, San Diego, CA, USA
| | - Jyoti Mayadev
- Department of Radiation Medicine and Applied Sciences, University of California, San Diego, CA, USA
| | - Steven E Finkelstein
- The US Oncology Network, Florida Cancer Affiliates, Panama City, FL, USA; Sarah Cannon Research Institute, Nashville, TN, USA; Associated Medical Professional of NY, US Urology Partners, Syracuse, NY, USA
| | - John M Buatti
- Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
| | - Sandip P Patel
- Division of Medical Oncology, University of California, San Diego, CA, USA
| | - Steven H Lin
- Department of Thoracic Radiation Oncology, Division of Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA
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12
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Hirmas N, Holtschmidt J, Loibl S. Shifting the Paradigm: The Transformative Role of Neoadjuvant Therapy in Early Breast Cancer. Cancers (Basel) 2024; 16:3236. [PMID: 39335206 PMCID: PMC11430607 DOI: 10.3390/cancers16183236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 09/20/2024] [Accepted: 09/20/2024] [Indexed: 09/30/2024] Open
Abstract
The use of neoadjuvant systemic therapy (NST) has become increasingly important in the treatment of breast cancer because of its various advantages. These include the ability to downstage tumors without compromising locoregional control and the potential to obtain valuable information about clinical and biological response to therapy with implications for individual prognoses. Surgical response assessment paves the way for response-adapted therapy, and pathological complete response (pCR; defined as ypT0/is ypN0) serves as an additional endpoint for drug development trials. Recommended NST regimens commonly consist of anthracyclines and taxane, with dose-dense anthracyclines and weekly paclitaxel often preferred, whenever feasible. For patients with human epidermal growth factor receptor-2 (HER2)-positive tumors, dual anti-HER2 therapy (trastuzumab and pertuzumab) is indicated together with NST in case of elevated risk of recurrence. For patients with triple-negative breast cancer (TNBC), adding carboplatin to NST correlates with improved pCR and survival rates, as does the addition of immune checkpoint inhibitors. For hormone receptor (HR)-positive/HER2-negative cancers, emerging data on NST including immune checkpoint inhibitors may elevate the significance of NST in high-risk luminal breast cancer. Here, we present a synthesis of the results from neoadjuvant clinical trials that aim at optimizing treatment options for patients with high-risk breast cancer.
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Affiliation(s)
- Nader Hirmas
- German Breast Group, 63263 Neu-Isenburg, Germany
| | | | - Sibylle Loibl
- German Breast Group, 63263 Neu-Isenburg, Germany
- Faculty of Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany
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13
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Lee JW, Won YK, Ahn H, Lee JE, Han SW, Kim SY, Jo IY, Lee SM. Peritumoral Adipose Tissue Features Derived from [ 18F]fluoro-2-deoxy-2-d-glucose Positron Emission Tomography/Computed Tomography as Predictors for Response to Neoadjuvant Chemotherapy in Breast Cancer Patients. J Pers Med 2024; 14:952. [PMID: 39338206 PMCID: PMC11432773 DOI: 10.3390/jpm14090952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 09/02/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
This study investigated whether the textural features of peritumoral adipose tissue (AT) on [18F]fluoro-2-deoxy-2-d-glucose (FDG) positron emission tomography/computed tomography (PET/CT) can predict the pathological response to neoadjuvant chemotherapy (NAC) and progression-free survival (PFS) in breast cancer patients. We retrospectively enrolled 147 female breast cancer patients who underwent staging FDG PET/CT and completed NAC and underwent curative surgery. We extracted 10 first-order features, 6 gray-level co-occurrence matrix (GLCM) features, and 3 neighborhood gray-level difference matrix (NGLDM) features of peritumoral AT and evaluated the predictive value of those imaging features for pathological complete response (pCR) and PFS. The results of our study demonstrated that GLCM homogeneity showed the highest predictability for pCR among the peritumoral AT imaging features in the receiver operating characteristic curve analysis. In multivariate logistic regression analysis, the mean standardized uptake value (SUV), 50th percentile SUV, 75th percentile SUV, SUV histogram entropy, GLCM entropy, and GLCM homogeneity of the peritumoral AT were independent predictors for pCR. In multivariate survival analysis, SUV histogram entropy and GLCM correlation of peritumoral AT were independent predictors of PFS. Textural features of peritumoral AT on FDG PET/CT could be potential imaging biomarkers for predicting the response to NAC and disease progression in breast cancer patients.
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Affiliation(s)
- Jeong Won Lee
- Department of Nuclear Medicine, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Republic of Korea
| | - Yong Kyun Won
- Department of Radiation Oncology, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Republic of Korea
| | - Hyein Ahn
- Department of Pathology, CHA Gangnam Medical Center, CHA University School of Medicine, 569 Nonhyon-ro, Gangnam-gu, Seoul 06135, Republic of Korea
| | - Jong Eun Lee
- Department of Surgery, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Republic of Korea
| | - Sun Wook Han
- Department of Surgery, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Republic of Korea
| | - Sung Yong Kim
- Department of Surgery, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Republic of Korea
| | - In Young Jo
- Department of Radiation Oncology, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Republic of Korea
| | - Sang Mi Lee
- Department of Nuclear Medicine, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Republic of Korea
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14
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Thomas N, Garaud S, Langouo M, Sofronii D, Boisson A, De Wind A, Duwel V, Craciun L, Larsimont D, Awada A, Willard-Gallo K. Tumor-Infiltrating Lymphocyte Scoring in Neoadjuvant-Treated Breast Cancer. Cancers (Basel) 2024; 16:2895. [PMID: 39199667 PMCID: PMC11352458 DOI: 10.3390/cancers16162895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 08/13/2024] [Accepted: 08/14/2024] [Indexed: 09/01/2024] Open
Abstract
Neoadjuvant chemotherapy (NAC) is now the standard of care for patients with locally advanced breast cancer (BC). TIL scoring is prognostic and adds predictive value to the residual cancer burden evaluation after NAC. However, NAC induces changes in the tumor, and the reliability of TIL scoring in post-NAC samples has not yet been studied. H&E- and dual CD3/CD20 chromogenic IHC-stained tissues were scored for stromal and intra-tumoral TIL by two experienced pathologists on pre- and post-treatment BC tissues. Digital TIL scoring was performed using the HALO® image analysis software (version 2.2). In patients with residual disease, we show a good inter-pathologist correlation for stromal TIL on H&E-stained tissues (CCC value 0.73). A good correlation for scoring with both staining methods (CCC 0.81) and the digital TIL scoring (CCC 0.77) was also observed. Overall concordance for TIL scoring in patients with a complete response was however poor. This study reveals there is good reliability for TIL scoring in patients with detectable residual tumors after NAC treatment, which is comparable to the scoring of untreated breast cancer patients. Based on the good consistency observed with digital TIL scoring, the development of a validated algorithm in the future might be advantageous.
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Affiliation(s)
- Noémie Thomas
- Molecular Immunology Unit, Institut Jules Bordet, 1070 Brussels, Belgium (A.B.)
| | - Soizic Garaud
- Molecular Immunology Unit, Institut Jules Bordet, 1070 Brussels, Belgium (A.B.)
| | - Mireille Langouo
- Molecular Immunology Unit, Institut Jules Bordet, 1070 Brussels, Belgium (A.B.)
| | - Doïna Sofronii
- Molecular Immunology Unit, Institut Jules Bordet, 1070 Brussels, Belgium (A.B.)
| | - Anaïs Boisson
- Molecular Immunology Unit, Institut Jules Bordet, 1070 Brussels, Belgium (A.B.)
| | - Alexandre De Wind
- Anantomical Pathology Department, Institut Jules Bordet, 1070 Brussels, Belgium
| | - Valérie Duwel
- Anatomical Pathology Department, AZ Klina, 2930 Brasschaat, Belgium;
| | - Ligia Craciun
- Anantomical Pathology Department, Institut Jules Bordet, 1070 Brussels, Belgium
- Tumor Bank, Institut Jules Bordet, 1070 Brussels, Belgium
| | - Dennis Larsimont
- Anantomical Pathology Department, Institut Jules Bordet, 1070 Brussels, Belgium
| | - Ahmad Awada
- Medical Oncology, Institut Jules Bordet, 1070 Brussels, Belgium
| | - Karen Willard-Gallo
- Molecular Immunology Unit, Institut Jules Bordet, 1070 Brussels, Belgium (A.B.)
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15
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Magbanua MJM, Li W, van ’t Veer LJ. Integrating Imaging and Circulating Tumor DNA Features for Predicting Patient Outcomes. Cancers (Basel) 2024; 16:1879. [PMID: 38791958 PMCID: PMC11120531 DOI: 10.3390/cancers16101879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 05/06/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
Biomarkers for evaluating tumor response to therapy and estimating the risk of disease relapse represent tremendous areas of clinical need. To evaluate treatment efficacy, tumor response is routinely assessed using different imaging modalities like positron emission tomography/computed tomography or magnetic resonance imaging. More recently, the development of circulating tumor DNA detection assays has provided a minimally invasive approach to evaluate tumor response and prognosis through a blood test (liquid biopsy). Integrating imaging- and circulating tumor DNA-based biomarkers may lead to improvements in the prediction of patient outcomes. For this mini-review, we searched the scientific literature to find original articles that combined quantitative imaging and circulating tumor DNA biomarkers to build prediction models. Seven studies reported building prognostic models to predict distant recurrence-free, progression-free, or overall survival. Three discussed building models to predict treatment response using tumor volume, pathologic complete response, or objective response as endpoints. The limited number of articles and the modest cohort sizes reported in these studies attest to the infancy of this field of study. Nonetheless, these studies demonstrate the feasibility of developing multivariable response-predictive and prognostic models using regression and machine learning approaches. Larger studies are warranted to facilitate the building of highly accurate response-predictive and prognostic models that are generalizable to other datasets and clinical settings.
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Affiliation(s)
- Mark Jesus M. Magbanua
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94115, USA;
| | - Wen Li
- Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94115, USA;
| | - Laura J. van ’t Veer
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94115, USA;
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16
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Dave S, Choudhury A, Alurkar SS, Shah AM. Is Ki-67 Really Useful as a Predictor for Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer? Indian J Surg Oncol 2024; 15:44-52. [PMID: 38511030 PMCID: PMC10948718 DOI: 10.1007/s13193-023-01822-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 09/21/2023] [Indexed: 03/22/2024] Open
Abstract
Neoadjuvant chemotherapy (NACT) is routinely offered to operable locally advanced breast cancer (LABC) patients desirous of breast conservation surgery and inoperable LABC patients. Pathological complete response (pCR) following chemotherapy is recognized as a surrogate for survival outcomes in high grade tumour subtypes. Many biological and tumor characters have been shown to predict pCR. The current study was performed with the aim of investigating the ability of Ki-67 in predicting pCR with NACT in breast cancer patients. A total of 105 patients with locally advanced breast cancer who completed NACT followed by surgery were included in this study from January 2020 till December 2022. Patients with advanced metastatic breast carcinoma, who did not give consent for NACT, who did not complete NACT and who did not undergo surgery were excluded. All patients were assessed for Ki-67 score on core-needle biopsy samples and response rate was assessed clinically and by histopathological examination of resected specimen. Quantitative variables were compared using unpaired t-test or Mann-Whitney 'U' test and for categorical variables Chi-square or Fisher's exact test were used. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive potential of Ki-67 expression levels in predicting pCR. To identify the predictive factors associated with pCR, univariate analysis was performed. The P value < 0.05 was considered as statistically significant. Mean age was 51.57 ± 10.8 years. 51 patients achieved clinical complete response (cCR) and 33 achieved pCR after NACT. Mean Ki-67 index in overall study population, in pCR group and no pCR group was 46.44 ± 22.92%, 51.60 ± 22.3% and 44.06 ± 22.7%, respectively. On univariate analysis, ER negativity, PR negativity and Her 2neu positivity were found predictive of pCR. On subgroup analysis, TNBC and Her 2neu positive sub groups were associated with higher cCR and pCR rate. We found no significant association between Ki-67 and pCR. This result may be confounded by the fact that a significant duration of the study was in the COVID-19 pandemic. Validation of this data is required in a large prospective study.
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Affiliation(s)
- Sukruti Dave
- Department of Medical Oncology, Apollo Hospitals International Limited: Apollo Hospitals Ahmedabad, Ahmedabad, Gujarat India
| | - Arpan Choudhury
- Department of Surgical Oncology, Apollo Hospitals International Limited: Apollo Hospitals Ahmedabad, Ahmedabad, Gujarat India
| | - Shirish S. Alurkar
- Department of Medical Oncology, Apollo Hospitals International Limited: Apollo Hospitals Ahmedabad, Ahmedabad, Gujarat India
| | - Akash M. Shah
- Department of Medical Oncology, Apollo Hospitals International Limited: Apollo Hospitals Ahmedabad, Ahmedabad, Gujarat India
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17
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Kim MJ, Eun NL, Ahn SG, Kim JH, Youk JH, Son EJ, Jeong J, Cha YJ, Bae SJ. Elasticity Values as a Predictive Modality for Response to Neoadjuvant Chemotherapy in Breast Cancer. Cancers (Basel) 2024; 16:377. [PMID: 38254866 PMCID: PMC10814692 DOI: 10.3390/cancers16020377] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 01/15/2024] [Accepted: 01/15/2024] [Indexed: 01/24/2024] Open
Abstract
Shear-wave elastography (SWE) is an effective tool in discriminating malignant lesions of breast and axillary lymph node metastasis in patients with breast cancer. However, the association between the baseline elasticity value of breast cancer and the treatment response of neoadjuvant chemotherapy is yet to be elucidated. Baseline SWE measured mean stiffness (E-mean) and maximum stiffness (E-max) in 830 patients who underwent neoadjuvant chemotherapy and surgery from January 2012 to December 2022. Association of elasticity values with breast pCR (defined as ypTis/T0), pCR (defined as ypTis/T0, N0), and tumor-infiltrating lymphocytes (TILs) was analyzed. Of 830 patients, 356 (42.9%) achieved breast pCR, and 324 (39.0%) achieved pCR. The patients with low elasticity values had higher breast pCR and pCR rates than those with high elasticity values. A low E-mean (adjusted odds ratio (OR): 0.620; 95% confidence interval (CI): 0.437 to 0.878; p = 0.007) and low E-max (adjusted OR: 0.701; 95% CI: 0.494 to 0.996; p = 0.047) were independent predictive factors for breast pCR. Low elasticity values were significantly correlated with high TILs. Pretreatment elasticity values measured using SWE were significantly associated with treatment response and inversely correlated with TILs, particularly in HR+HER2- breast cancer and TNBC.
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Affiliation(s)
- Min Ji Kim
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea; (M.J.K.); (S.G.A.); (J.J.)
- Institute for Breast Cancer Precision Medicine, Yonsei University College of Medicine, Seoul 06273, Republic of Korea;
| | - Na Lae Eun
- Department of Radiology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea; (N.L.E.); (J.H.Y.); (E.J.S.)
| | - Sung Gwe Ahn
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea; (M.J.K.); (S.G.A.); (J.J.)
- Institute for Breast Cancer Precision Medicine, Yonsei University College of Medicine, Seoul 06273, Republic of Korea;
| | - Jee Hung Kim
- Institute for Breast Cancer Precision Medicine, Yonsei University College of Medicine, Seoul 06273, Republic of Korea;
- Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea
| | - Ji Hyun Youk
- Department of Radiology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea; (N.L.E.); (J.H.Y.); (E.J.S.)
| | - Eun Ju Son
- Department of Radiology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea; (N.L.E.); (J.H.Y.); (E.J.S.)
| | - Joon Jeong
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea; (M.J.K.); (S.G.A.); (J.J.)
- Institute for Breast Cancer Precision Medicine, Yonsei University College of Medicine, Seoul 06273, Republic of Korea;
| | - Yoon Jin Cha
- Institute for Breast Cancer Precision Medicine, Yonsei University College of Medicine, Seoul 06273, Republic of Korea;
- Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea
| | - Soong June Bae
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea; (M.J.K.); (S.G.A.); (J.J.)
- Institute for Breast Cancer Precision Medicine, Yonsei University College of Medicine, Seoul 06273, Republic of Korea;
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18
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Litton JK, Regan MM, Pusztai L, Rugo HS, Tolaney SM, Garrett-Mayer E, Amiri-Kordestani L, Basho RK, Best AF, Boileau JF, Denkert C, Foster JC, Harbeck N, Jacene HA, King TA, Mason G, O'Sullivan CC, Prowell TM, Richardson AL, Sepulveda KA, Smith ML, Tjoe JA, Turashvili G, Woodward WA, Butler LP, Schwartz EI, Korde LA. Standardized Definitions for Efficacy End Points in Neoadjuvant Breast Cancer Clinical Trials: NeoSTEEP. J Clin Oncol 2023; 41:4433-4442. [PMID: 37433103 PMCID: PMC10522109 DOI: 10.1200/jco.23.00435] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/25/2023] [Accepted: 06/06/2023] [Indexed: 07/13/2023] Open
Abstract
PURPOSE The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points. METHODS The NeoSTEEP working group concentrated on neoadjuvant systemic therapy end points in clinical trials with efficacy outcomes-both pathologic and time-to-event survival end points-particularly for registrational intent. Special considerations for subtypes and therapeutic approaches, imaging, nodal staging at surgery, bilateral and multifocal diseases, correlative tissue collection, and US Food and Drug Administration regulatory considerations were contemplated. RESULTS The working group recommends a preferred definition of pathologic complete response (pCR) as the absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0 per AJCC staging). Residual cancer burden should be a secondary end point to facilitate future assessment of its utility. Alternative end points are needed for hormone receptor-positive disease. Time-to-event survival end point definitions should pay particular attention to the measurement starting point. Trials should include end points originating at random assignment (event-free survival and overall survival) to capture presurgery progression and deaths as events. Secondary end points adapted from STEEP 2.0, which are defined from starting at curative-intent surgery, may also be appropriate. Specification and standardization of biopsy protocols, imaging, and pathologic nodal evaluation are also crucial. CONCLUSION End points in addition to pCR should be selected on the basis of clinical and biologic aspects of the tumor and the therapeutic agent investigated. Consistent prespecified definitions and interventions are paramount for clinically meaningful trial results and cross-trial comparison.
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Affiliation(s)
- Jennifer K. Litton
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Meredith M. Regan
- Division of Biostatistics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Lajos Pusztai
- Breast Medical Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT
| | - Hope S. Rugo
- University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA
| | - Sara M. Tolaney
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | | | | | - Reva K. Basho
- The Lawrence J. Ellison Institute for Transformative Medicine, Los Angeles, CA
| | - Ana F. Best
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD
| | | | - Carsten Denkert
- Institute of Pathology, Philipps University Marburg and University Hospital Marburg (UKGM), Marburg, Germany
| | - Jared C. Foster
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD
| | - Nadia Harbeck
- The Breast Center, Department of Obstetrics and Gynecology and Comprehensive Cancer Center Munich, LMU University Hospital, Munich, Germany
| | | | - Tari A. King
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA
| | - Ginny Mason
- The Inflammatory Breast Cancer Research Foundation, Broadway, VA
| | | | - Tatiana M. Prowell
- US Food and Drug Administration, Silver Spring, MD
- Women's Malignancies Disease Group, Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore, MD
| | | | | | | | - Judy A. Tjoe
- Division of Breast Surgery, Department of Surgery, Novant Health, Greensboro, NC
| | - Gulisa Turashvili
- Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA
| | - Wendy A. Woodward
- Department of Breast Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - Elena I. Schwartz
- Coordinating Center for Clinical Trials, National Cancer Institute, Rockville, MD
| | - Larissa A. Korde
- Cancer Therapy and Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD
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19
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Ivanovic N, Bjelica D, Loboda B, Bogdanovski M, Colakovic N, Petricevic S, Gojgic M, Zecic O, Zecic K, Zdravkovic D. Changing the role of pCR in breast cancer treatment - an unjustifiable interpretation of a good prognostic factor as a "factor for a good prognosis". Front Oncol 2023; 13:1207948. [PMID: 37534241 PMCID: PMC10391828 DOI: 10.3389/fonc.2023.1207948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 07/03/2023] [Indexed: 08/04/2023] Open
Abstract
Pathologic complete response (pCR) after neoadjuvant systemic therapy (NAST) of early breast cancer (EBC) has been recognized as a good prognostic factor in the treatment of breast cancer because of its significant correlation with long-term disease outcome. Based on this correlation, pCR has been accepted by health authorities (FDA, EMA) as a surrogate endpoint in clinical trials for accelerated drug approval. Moreover, in recent years, we have observed a tendency to treat pCR in routine clinical practice as a primary therapeutic target rather than just one of the pieces of information obtained from clinical trials. These trends in routine clinical practice are the result of recommendations in treatment guidelines, such as the ESMO recommendation "…to deliver all planned (neoadjuvant) treatment without unnecessary breaks, i.e. without dividing it into preoperative and postoperative periods, irrespective of the magnitude of tumor response", because "…this will increase the probability of achieving pCR, which is a proven factor for a good prognosis…". We hypothesize that the above recommendations and trends in routine clinical practice are the consequences of misunderstanding regarding the concept of pCR, which has led to a shift in its importance from a prognostic factor to a desired treatment outcome. The origin of this misunderstanding could be a strong subconscious incentive to achieve pCR, as patients who achieved pCR after NAST had a better long-term outcome compared with those who did not. In this paper, we attempt to prove our hypothesis. We performed a comprehensive analysis of the therapeutic effects of NAST and adjuvant systemic therapy (AST) in EBC to determine whether pCR, as a phenomenon that can only be achieved at NAST, improves prognosis per se. We used published papers as a source of data, which had a decisive influence on the formation of the modern attitude towards EBC therapy. We were unable to find any evidence supporting the use of pCR as a desired therapeutic goal because NAST (reinforced by pCR) was never demonstrated to be superior to AST in any context.
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Affiliation(s)
- Nebojsa Ivanovic
- Department of Surgical Oncology, University Hospital Medical Center (UHMC) “Bezanijska kosa”, Belgrade, Serbia
- Department of Surgery, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Dragana Bjelica
- Department of Surgical Oncology, University Hospital Medical Center (UHMC) “Bezanijska kosa”, Belgrade, Serbia
| | - Barbara Loboda
- Department of Surgical Oncology, University Hospital Medical Center (UHMC) “Bezanijska kosa”, Belgrade, Serbia
| | - Masan Bogdanovski
- Faculty of Philosophy, Department of Philosophy, University of Belgrade, Belgrade, Serbia
| | - Natasa Colakovic
- Department of Surgical Oncology, University Hospital Medical Center (UHMC) “Bezanijska kosa”, Belgrade, Serbia
- Department of Surgery, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Simona Petricevic
- Department of Surgical Oncology, University Hospital Medical Center (UHMC) “Bezanijska kosa”, Belgrade, Serbia
| | - Milan Gojgic
- Department of Surgical Oncology, University Hospital Medical Center (UHMC) “Bezanijska kosa”, Belgrade, Serbia
| | - Ognjen Zecic
- Department of Surgical Oncology, University Hospital Medical Center (UHMC) “Bezanijska kosa”, Belgrade, Serbia
| | - Katarina Zecic
- Clinic for Gynecology and Obstetrics, University Clinical Centre of Serbia, Belgrade, Serbia
| | - Darko Zdravkovic
- Department of Surgical Oncology, University Hospital Medical Center (UHMC) “Bezanijska kosa”, Belgrade, Serbia
- Department of Surgery, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
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20
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Cohen SA, Liu MC, Aleshin A. Practical recommendations for using ctDNA in clinical decision making. Nature 2023; 619:259-268. [PMID: 37438589 DOI: 10.1038/s41586-023-06225-y] [Citation(s) in RCA: 73] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 05/16/2023] [Indexed: 07/14/2023]
Abstract
The continuous improvement in cancer care over the past decade has led to a gradual decrease in cancer-related deaths. This is largely attributed to improved treatment and disease management strategies. Early detection of recurrence using blood-based biomarkers such as circulating tumour DNA (ctDNA) is being increasingly used in clinical practice. Emerging real-world data shows the utility of ctDNA in detecting molecular residual disease and in treatment-response monitoring, helping clinicians to optimize treatment and surveillance strategies. Many studies have indicated ctDNA to be a sensitive and specific biomarker for recurrence. However, most of these studies are largely observational or anecdotal in nature, and peer-reviewed data regarding the use of ctDNA are mainly indication-specific. Here we provide general recommendations on the clinical utility of ctDNA and how to interpret ctDNA analysis in different treatment settings, especially in patients with solid tumours. Specifically, we provide an understanding around the implications, strengths and limitations of this novel biomarker and how to best apply the results in clinical practice.
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Affiliation(s)
- Stacey A Cohen
- Fred Hutchinson Cancer Center, Seattle, WA, USA.
- University of Washington, Seattle, WA, USA.
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21
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Miglietta F, Dieci MV. How can we refine the prognostic stratification of triple-negative breast cancer? Expert Rev Anticancer Ther 2023; 23:1045-1047. [PMID: 37581212 DOI: 10.1080/14737140.2023.2248387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 08/10/2023] [Indexed: 08/16/2023]
Affiliation(s)
- Federica Miglietta
- Oncology Unit 2, Istituto Oncologico Veneto, IOV-IRCCS, (Via Gattamelata 64, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Maria Vittoria Dieci
- Oncology Unit 2, Istituto Oncologico Veneto, IOV-IRCCS, (Via Gattamelata 64, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
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22
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Bilici A, Olmez OF, Kaplan MA, Oksuzoglu B, Sezer A, Karadurmus N, Cubukcu E, Sendur MAN, Aksoy S, Erdem D, Basaran G, Cakar B, Shbair ATM, Arslan C, Sumbul AT, Sezgin Goksu S, Karadag I, Cicin I, Gumus M, Selcukbiricik F, Harputluoglu H, Demirci U. Impact of adding pertuzumab to trastuzumab plus chemotherapy in neoadjuvant treatment of HER2 positive breast cancer patients: a multicenter real-life HER2PATH study. Acta Oncol 2023; 62:381-390. [PMID: 37083566 DOI: 10.1080/0284186x.2023.2202330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/22/2023]
Abstract
AIM To investigate the pathological complete response (pCR) achieved after neoadjuvant therapy with versus without adding pertuzumab (P) to trastuzumab (H) plus neoadjuvant chemotherapy (NCT) in HER2+ breast cancer (BC) patients in a real-life setting. METHODS A total of 1528 female HER2+ BC patients who received NCT plus H with or without P were included in this retrospective real-life study. Primary endpoint was pCR rate (ypT0/Tis ypN0). Clinicopathological characteristics, event-free survival (EFS) time, and relapse rates were evaluated with respect to HER2 blockade (NCT-H vs. NCT-HP) and pCR. RESULTS Overall, 62.2% of patients received NCT-H and 37.8% received NCT-HP. NCT-HP was associated with a significantly higher pCR rate (66.4 vs. 56.8%, p < 0.001) and lower relapse (4.5 vs. 12.2%, p < 0.001) in comparison to NCT-H. Patients with pCR had a significantly lower relapse (5.6 vs. 14.9%, p < 0.001) and longer EFS time (mean(SE) 111.2(1.9) vs. 93.9(2.7) months, p < 0.001) compared to patients with non-pCR. Patients in the NCT-HP group were more likely to receive docetaxel (75.0 vs. 40.6%, p < 0.001), while those with pCR were more likely to receive paclitaxel (50.2 vs. 40.7%, p < 0.001) and NCT-HP (41.5 vs. 32.1%, p < 0.001). Hormone receptor status and breast conservation rates were similar in NCT-HP vs. NCT-H groups and in patients with vs. without pCR. Invasive ductal carcinoma (OR, 2.669, 95% CI 1.596 to 4.464, p < 0.001), lower histological grade of the tumor (OR, 4.052, 95% CI 2.446 to 6.713, p < 0.001 for grade 2 and OR, 3.496, 95% CI 2.020 to 6.053, p < 0.001 for grade 3), lower T stage (OR, 1.959, 95% CI 1.411 to 2.720, p < 0.001) and paclitaxel (vs. docetaxel, OR, 1.571, 95% CI 1.127 to 2.190, p = 0.008) significantly predicted the pCR. CONCLUSIONS This real-life study indicates that adding P to NCT-H enables higher pCR than NCT-H in HER2+ BC, while pCR was associated with lower relapse and better EFS time.
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Affiliation(s)
- Ahmet Bilici
- Istanbul Medipol University Faculty of Medicine, Istanbul, Turkey
| | - Omer Fatih Olmez
- Istanbul Medipol University Faculty of Medicine, Istanbul, Turkey
| | | | - Berna Oksuzoglu
- University of Health Sciences Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey
| | - Ahmet Sezer
- Baskent University Adana Hospital, Adana, Turkey
| | - Nuri Karadurmus
- University of Health Sciences Gulhane Training and Research Hospital, Ankara, Turkey
| | - Erdem Cubukcu
- Uludag University Faculty of Medicine, Bursa, Turkey
| | | | - Sercan Aksoy
- Hacettepe University Cancer Institute, Ankara, Turkey
| | - Dilek Erdem
- Samsun Medical Park Hospital, Samsun, Turkey
| | - Gul Basaran
- School of Medicine, Acibadem University, Istanbul, Turkey
| | - Burcu Cakar
- Ege University Faculty of Medicine, Izmir, Turkey
| | | | | | | | | | | | - Irfan Cicin
- Trakya University Faculty of Medicine, Edirne, Turkey
| | - Mahmut Gumus
- Istanbul Medeniyet University Faculty of Medicine, Istanbul, Turkey
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23
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Lorenzo R, Meani F, Longhitano C, Carciotto R, Lanzafame K, Inzerilli N, Vigneri P. The optimal timing between neoadjuvant therapy and surgery of breast cancer: A brief systematic review of the literature. Crit Rev Oncol Hematol 2023; 183:103921. [PMID: 36746358 DOI: 10.1016/j.critrevonc.2023.103921] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 10/23/2022] [Accepted: 01/20/2023] [Indexed: 02/05/2023] Open
Abstract
Neoadjuvant therapy is a cornerstone of some early and locally advanced breast cancer treatment. The use of neoadjuvant chemotherapy, in fact, allows to obtain numerous advantages, including allowing a more conservative intervention, evaluating the in vivo response to therapy, modulating the intensity of subsequent treatments based on the degree of response to therapy and allowing to surgery with information on genetics. However, at the end of neoadjuvant cytotoxic therapy it is not possible to carry out surgery immediately, as a certain amount of time is required for recovery from toxicity, especially haematological, due to the systemic therapy itself. At the same time, it is intuitive that too much time must not pass between the end of neoadjuvant therapy and surgery. The goal of this systematic literature review is to summarize the most relevant literature data on this topic, selected and extracted according to the methodology of systematic reviews.
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Affiliation(s)
- Rossi Lorenzo
- EOC, Institute of Oncology of Southern Switzerland (IOSI), Bellinzona, Switzerland; EOC, Breast Unit of Southern Switzerland (CSSI), Lugano, Switzerland.
| | - Francesco Meani
- EOC, Breast Unit of Southern Switzerland (CSSI), Lugano, Switzerland
| | - Claudio Longhitano
- Division of Medical Oncology, Humanitas Catania Cancer Center, Catania, Italy
| | - Rosaria Carciotto
- Division of Medical Oncology, A.O.U. Policlinico-S. Marco, Catania, Italy
| | - Katia Lanzafame
- Division of Medical Oncology, A.O.U. Policlinico-S. Marco, Catania, Italy
| | - Nicola Inzerilli
- Division of Medical Oncology, A.O.U. Policlinico-S. Marco, Catania, Italy
| | - Paolo Vigneri
- Division of Medical Oncology, A.O.U. Policlinico-S. Marco, Catania, Italy
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24
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McAndrew NP, Hurvitz SA. Systemic Therapy for Early- and Late-Stage, Human Epidermal Growth Factor Receptor-2-Positive Breast Cancer. Hematol Oncol Clin North Am 2023; 37:103-115. [PMID: 36435604 DOI: 10.1016/j.hoc.2022.08.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Systemic therapy for both early-stage and metastatic human epidermal growth factor receptor-2-positive (HER2+) breast cancer has seen significant evolution over the last 20 or more years. Innovative trials leveraging the prognostic and predictive information that neoadjuvant chemotherapy provides has led to preoperative systemic therapy becoming the overwhelmingly favored sequencing in the early-stage setting. However, deintensification of therapy is important to consider for patients with good-risk disease or significant comorbidities. Finally, with the abundance of newly approved agents, drug sequencing in the second-line setting has become an important and individualized decision for patients with metastatic disease.
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Affiliation(s)
| | - Sara A Hurvitz
- Division of Hematology/Oncology, UCLA David Geffen School of Medicine
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25
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Gorry C, McCullagh L, O'Donnell H, Barrett S, Schmitz S, Barry M, Curtin K, Beausang E, Barry R, Coyne I. Neoadjuvant treatment for stage III and IV cutaneous melanoma. Cochrane Database Syst Rev 2023; 1:CD012974. [PMID: 36648215 PMCID: PMC9844053 DOI: 10.1002/14651858.cd012974.pub2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND Cutaneous melanoma is amongst the most aggressive of all skin cancers. Neoadjuvant treatment is a form of induction therapy, given to shrink a cancerous tumour prior to the main treatment (usually surgery). The purpose is to improve survival and surgical outcomes. This review systematically appraises the literature investigating the use of neoadjuvant treatment for stage III and IV cutaneous melanoma. OBJECTIVES To assess the effects of neoadjuvant treatment in adults with stage III or stage IV melanoma according to the seventh edition American Joint Committee on Cancer (AJCC) staging system. SEARCH METHODS We searched the following databases up to 10 August 2021 inclusive: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, LILACS and four trials registers, together with reference checking and contact with study authors to identify additional studies. We also handsearched proceedings from specific conferences from 2016 to 2020 inclusive. SELECTION CRITERIA Randomised controlled trials (RCTs) of people with stage III and IV melanoma, comparing neoadjuvant treatment strategies (using targeted treatments, immunotherapies, radiotherapy, topical treatments or chemotherapy) with any of these agents or current standard of care (SOC), were eligible for inclusion. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. Primary outcomes were overall survival (OS) and adverse effects (AEs). Secondary outcomes included time to recurrence (TTR), quality of life (QOL), and overall response rate (ORR). We used GRADE to evaluate the certainty of the evidence. MAIN RESULTS We included eight RCTs involving 402 participants. Studies enrolled adults, mostly with stage III melanoma, investigated immunotherapies, chemotherapy, or targeted treatments, and compared these with surgical excision with or without adjuvant treatment. Duration of follow-up and therapeutic regimens varied, which, combined with heterogeneity in the population and definitions of the endpoints, precluded meta-analysis of all identified studies. We performed a meta-analysis including three studies. We are very uncertain if neoadjuvant treatment increases OS when compared to no neoadjuvant treatment (hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.15 to 1.21; 2 studies, 171 participants; very low-certainty evidence). Neoadjuvant treatment may increase the rate of AEs, but the evidence is very uncertain (26% versus 16%, risk ratio (RR) 1.58, 95% CI 0.97 to 2.55; 2 studies, 162 participants; very low-certainty evidence). We are very uncertain if neoadjuvant treatment increases TTR (HR 0.51, 95% CI 0.22 to 1.17; 2 studies, 171 participants; very low-certainty evidence). Studies did not report ORR as a comparative outcome or measure QOL data. We are very uncertain whether neoadjuvant targeted treatment with dabrafenib and trametinib increases OS (HR 0.28, 95% CI 0.03 to 2.25; 1 study, 21 participants; very low-certainty evidence) or TTR (HR 0.02, 95% CI 0.00 to 0.22; 1 study, 21 participants; very low-certainty evidence) when compared to surgery. The study did not report comparative rates of AEs and overall response, and did not measure QOL. We are very uncertain if neoadjuvant immunotherapy with talimogene laherparepvec increases OS when compared to no neoadjuvant treatment (HR 0.49, 95% CI 0.15 to 1.64; 1 study, 150 participants, very low-certainty evidence). It may have a higher rate of AEs, but the evidence is very uncertain (16.5% versus 5.8%, RR 2.84, 95% CI 0.96 to 8.37; 1 study, 142 participants; very low-certainty evidence). We are very uncertain if it increases TTR (HR 0.75, 95% CI 0.31 to 1.79; 1 study, 150 participants; very low-certainty evidence). The study did not report comparative ORRs or measure QOL. OS was not reported for neoadjuvant immunotherapy (combined ipilimumab and nivolumab) when compared to the combination of ipilimumab and nivolumab as adjuvant treatment. There may be little or no difference in the rate of AEs between these treatments (9%, RR 1.0, 95% CI 0.75 to 1.34; 1 study, 20 participants; low-certainty evidence). The study did not report comparative ORRs or measure TTR and QOL. Neoadjuvant immunotherapy (combined ipilimumab and nivolumab) likely results in little to no difference in OS when compared to neoadjuvant nivolumab monotherapy (P = 0.18; 1 study, 23 participants; moderate-certainty evidence). It may increase the rate of AEs, but the certainty of this evidence is very low (72.8% versus 8.3%, RR 8.73, 95% CI 1.29 to 59; 1 study, 23 participants); this trial was halted early due to observation of disease progression preventing surgical resection in the monotherapy arm and the high rate of treatment-related AEs in the combination arm. Neoadjuvant combination treatment may lead to higher ORR, but the evidence is very uncertain (72.8% versus 25%, RR 2.91, 95% CI 1.02 to 8.27; 1 study, 23 participants; very low-certainty evidence). It likely results in little to no difference in TTR (P = 0.19; 1 study, 23 participants; low-certainty evidence). The study did not measure QOL. OS was not reported for neoadjuvant immunotherapy (combined ipilimumab and nivolumab) when compared to neoadjuvant sequential immunotherapy (ipilimumab then nivolumab). Only Grade 3 to 4 immune-related AEs were reported; fewer were reported with combination treatment, and the sequential treatment arm closed early due to a high incidence of severe AEs. The neoadjuvant combination likely results in a higher ORR compared to sequential neoadjuvant treatment (60.1% versus 42.3%, RR 1.42, 95% CI 0.87 to 2.32; 1 study, 86 participants; low-certainty evidence). The study did not measure TTR and QOL. No data were reported on OS, AEs, TTR, or QOL for the comparison of neoadjuvant interferon (HDI) plus chemotherapy versus neoadjuvant chemotherapy. Neoadjuvant HDI plus chemotherapy may have little to no effect on ORR, but the evidence is very uncertain (33% versus 22%, RR 1.75, 95% CI 0.62 to 4.95; 1 study, 36 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS We are uncertain if neoadjuvant treatment increases OS or TTR compared with no neoadjuvant treatment, and it may be associated with a slightly higher rate of AEs. There is insufficient evidence to support the use of neoadjuvant treatment in clinical practice. Priorities for research include the development of a core outcome set for neoadjuvant trials that are adequately powered, with validation of pathological and radiological responses as intermediate endpoints, to investigate the relative benefits of neoadjuvant treatment compared with adjuvant treatment with immunotherapies or targeted therapies.
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Affiliation(s)
- Claire Gorry
- National Centre for Pharmacoeconomics, St James's Hospital, Dublin, Ireland
| | - Laura McCullagh
- National Centre for Pharmacoeconomics, St James's Hospital, Dublin, Ireland
- Department of Pharmacology and Therapeutics, Trinity College Dublin, Dublin, Ireland
| | - Helen O'Donnell
- Department of Pharmacology and Therapeutics, Trinity College Dublin, Dublin, Ireland
| | - Sarah Barrett
- Applied Radiation Therapy Trinity, Discipline of Radiation Therapy, Trinity St James's Cancer Institute, Trinity College Dublin, Dublin, Ireland
| | - Susanne Schmitz
- Department of Pharmacology and Therapeutics, Trinity College Dublin, Dublin, Ireland
| | - Michael Barry
- Department of Pharmacology and Therapeutics, Trinity College Dublin, Dublin, Ireland
| | - Kay Curtin
- Melanoma Support Ireland, Dublin, Ireland
| | - Eamon Beausang
- Plastic and Reconstructive Surgery, St James's Hospital, Dublin, Ireland
| | - Rupert Barry
- Department of Dermatology, St James's Hospital, Dublin, Ireland
| | - Imelda Coyne
- School of Nursing & Midwifery, Trinity College Dublin, Dublin, Ireland
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26
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Liu X, Ye Y, Zhu L, Xiao X, Zhou B, Gu Y, Si H, Liang H, Liu M, Li J, Jiang Q, Li J, Yu S, Ma R, Su S, Liao JY, Zhao Q. Niche stiffness sustains cancer stemness via TAZ and NANOG phase separation. Nat Commun 2023; 14:238. [PMID: 36646707 PMCID: PMC9842735 DOI: 10.1038/s41467-023-35856-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 01/04/2023] [Indexed: 01/18/2023] Open
Abstract
Emerging evidence shows that the biomechanical environment is required to support cancer stem cells (CSCs), which play a crucial role in drug resistance. However, how mechanotransduction signals regulate CSCs and its clinical significance has remained unclear. Using clinical-practice ultrasound elastography for patients' lesions and atomic force microscopy for surgical samples, we reveal that increased matrix stiffness is associated with poor responses to neoadjuvant chemotherapy, worse prognosis, and CSC enrichment in patients with breast cancer. Mechanically, TAZ activated by biomechanics enhances CSC properties via phase separation with NANOG. TAZ-NANOG phase separation, which is dependent on acidic residues in the N-terminal activation domain of NANOG, promotes the transcription of SOX2 and OCT4. Therapeutically, targeting NANOG or TAZ reduces CSCs and enhances the chemosensitivity in vivo. Collectively, this study demonstrated that the phase separation of a pluripotency transcription factor links mechanical cues in the niche to the fate of CSCs.
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Affiliation(s)
- Xinwei Liu
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China.,Department of Breast Surgery, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450000, China.,Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Yingying Ye
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Liling Zhu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Xiaoyun Xiao
- Department of Ultrasound, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Boxuan Zhou
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Yuanting Gu
- Department of Breast Surgery, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450000, China
| | - Hang Si
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China.,Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Huixin Liang
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China.,Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Mingzhu Liu
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China.,Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Jiaqian Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Qiongchao Jiang
- Department of Ultrasound, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Jiang Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Shubin Yu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Ruiying Ma
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China.,Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Shicheng Su
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China. .,Department of Breast Surgery, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450000, China. .,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. .,Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. .,Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
| | - Jian-You Liao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
| | - Qiyi Zhao
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China. .,Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.
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27
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Yao L, Liu X, Wang M, Yu K, Xu S, Qiu P, Lv Z, Zhang X, Xu Y. Predicting Pathological Complete Response in Breast Cancer After Two Cycles of Neoadjuvant Chemotherapy by Tumor Reduction Rate: A Retrospective Case-Control Study. J Breast Cancer 2023; 26:136-151. [PMID: 37051647 PMCID: PMC10139844 DOI: 10.4048/jbc.2023.26.e12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 12/16/2022] [Accepted: 02/08/2023] [Indexed: 03/30/2023] Open
Abstract
PURPOSE We aimed to identify effectiveness-associated indicators and evaluate the optimal tumor reduction rate (TRR) after two cycles of neoadjuvant chemotherapy (NAC) in patients with invasive breast cancer. METHODS This retrospective case-control study included patients who underwent at least four cycles of NAC at the Department of Breast Surgery between February 2013 and February 2020. A regression nomogram model for predicting pathological responses was constructed based on potential indicators. RESULTS A total of 784 patients were included, of whom 170 (21.68%) reported pathological complete response (pCR) after NAC and 614 (78.32%) had residual invasive tumors. The clinical T stage, clinical N stage, molecular subtype, and TRR were identified as independent predictors of pCR. Patients with a TRR > 35% were more likely to achieve pCR (odds ratio, 5.396; 95% confidence interval [CI], 3.299-8.825). The receiver operating characteristic (ROC) curve was plotted using the probability value, and the area under the ROC curve was 0.892 (95% CI, 0.863-0.922). CONCLUSION TRR > 35% is predictive of pCR after two cycles of NAC, and an early evaluation model using a nomogram based on five indicators, age, clinical T stage, clinical N stage, molecular subtype, and TRR, is applicable in patients with invasive breast cancer.
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28
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Trapani D, Ferraro E, Giugliano F, Boscolo Bielo L, Curigliano G, Burstein HJ. Postneoadjuvant treatment for triple-negative breast cancer. Curr Opin Oncol 2022; 34:623-634. [PMID: 35993306 DOI: 10.1097/cco.0000000000000893] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Triple-negative breast cancer (TNBC) has been conventionally associated with poor prognosis, as a result of limited therapeutic options. In the early setting, prognosis is informed by clinical-pathological factors; for patients receiving neoadjuvant treatments, pathological complete response (pCR) is the strongest factor. In this review, we mapped the landscape of clinical trials in the postneoadjuvant space, and identified three patterns of clinical trial design. RECENT FINDINGS For patients at higher risk, effective postneoadjuvant treatments are of paramount importance to address a high clinical need. Postneoadjuvant risk-adapted treatments have demonstrated to improve survival in patients at high of recurrence. SUMMARY Patients at high risk have indication for adjuvant treatment intensification, informed by baseline clinical, pathological or molecular factors (type 1 approach), on the presence, extent and molecular characteristics of the residual disease at the time of surgery (type 2) or on risk factors assessed in the postsurgical setting (type 3), for example, circulating tumour DNA. Most of the past trials were based on type 2 approaches, for example, with capecitabine and Olaparib. Few trials were based on a type 1 approach, notably pembrolizumab for early TNBC. The clinical validity of type 3 approaches is under investigation in several ongoing trials.
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Affiliation(s)
- Dario Trapani
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Harvard Medical School, Boston, Massachusetts
| | - Emanuela Ferraro
- Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Federica Giugliano
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Luca Boscolo Bielo
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Giuseppe Curigliano
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Harold J Burstein
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Harvard Medical School, Boston, Massachusetts
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29
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Conforti F, Pala L, Bagnardi V, De Pas T, Colleoni M, Buyse M, Hortobagyi G, Gianni L, Winer E, Loibl S, Cortes J, Piccart M, Wolff AC, Viale G, Gelber RD. Surrogacy of Pathologic Complete Response in Trials of Neoadjuvant Therapy for Early Breast Cancer: Critical Analysis of Strengths, Weaknesses, and Misinterpretations. JAMA Oncol 2022; 8:1668-1675. [PMID: 36201176 DOI: 10.1001/jamaoncol.2022.3755] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Importance The pathologic complete response (pCR) is supported by regulatory agencies as a surrogate end point for long-term patients' clinical outcomes in the accelerated approval process of new drugs tested in neoadjuvant randomized clinical trials (RCTs) for early breast cancer (BC). However, a meaningful association between pCR and patients' survival has been proven only at the patient level (ie, significantly better survival of patients who achieved pCR compared with those who did not), but not at trial level (ie, poor association between degree of improvement in pCR rate and survival reported across trials). Observations We critically discuss the potential reasons of such discrepancy between pCR surrogacy value at the patient and trial level, as well as the relevant implications for both clinical research and drug regulatory policy. We also describe alternative surrogate end points, including combined end points that jointly analyzed pathological response and event-free survival data, or the assessment of circulating tumor DNA (ctDNA). Such proposed surrogate end points could overcome limits of pCR and provide a reasonable trade-off between the 2 conflicting needs to have access to effective therapies rapidly, and to reliably assess patients' clinical benefit. Conclusions and Relevance Using surrogate end points to grant drug approvals is justified only when they can provide accurate prediction of a drug's effect on the long-term patient outcomes. Evidence currently available does not support pCR used alone as a reliable surrogate end point in regulatory neoadjuvant RCTs for BC. The surrogacy value at trial level of potentially more robust surrogate end points needs to be urgently tested.
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Affiliation(s)
- Fabio Conforti
- European Institute of Oncology, Milan, Italy.,Department of Medical Oncology, Cliniche, Humanitas Gavazzeni, Bergamo, Italy
| | - Laura Pala
- European Institute of Oncology, Milan, Italy
| | - Vincenzo Bagnardi
- Department of Medical Oncology, Cliniche, Humanitas Gavazzeni, Bergamo, Italy.,Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy
| | - Tommaso De Pas
- European Institute of Oncology, Milan, Italy.,Harvard T.H. Chan School of Public Health, and Frontier Science & Technology Research Foundation, Boston, Massachusetts
| | - Marco Colleoni
- Division of Medical Senology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Marc Buyse
- International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium
| | - Gabriel Hortobagyi
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Eric Winer
- Yale Cancer Center, New Haven, Connecticut
| | - Sibylle Loibl
- Center for Hematology and Oncology Bethanien, Frankfurt, Germany
| | - Javier Cortes
- International Breast Cancer Center, Pangaea Oncology, Quiron Group, Madrid and Barcelona, Spain.,Universidad Europea de Madrid, Faculty of Biomedical and Health Sciences, Department of Medicine, Madrid, Spain
| | - Martine Piccart
- Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | | | - Giuseppe Viale
- Department of Pathology, European Institute of Oncology, Milan, Italy.,University of Milan, Milan, Italy
| | - Richard D Gelber
- Department of Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.,Harvard T.H. Chan School of Public Health, and Frontier Science & Technology Research Foundation, Boston, Massachusetts
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30
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Wang RX, Ji P, Gong Y, Shao ZM, Chen S. SDF-1 expression and tumor-infiltrating lymphocytes identify clinical subtypes of triple-negative breast cancer with different responses to neoadjuvant chemotherapy and survival. Front Immunol 2022; 13:940635. [PMID: 36341391 PMCID: PMC9630559 DOI: 10.3389/fimmu.2022.940635] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 10/05/2022] [Indexed: 11/25/2022] Open
Abstract
Background In this study, we investigated the prediction and prognostic value of SDF-1 for triple-negative breast cancer (TNBC) patients who underwent neoadjuvant chemotherapy (NAC) following standard radical surgery. Methods A total of 303 TNBC patients were included in this study. The NAC regimen was weekly paclitaxel plus carboplatin (PC) for all patients. SDF-1 and CXCR4 expression were measured at baseline and surgery via enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC), respectively. Correlations between variables and treatment response were studied, and Cox proportional hazards regression analysis was implemented for prognostic evaluation. Results Of the 303 patients, 103 (34.0%) experienced pathological complete response (pCR) after completion of NAC. Serum SDF-1 expression before NAC was significantly correlated with the abundance of TILs. A higher pCR rate was more likely to be observed in patients with lower serum SDF-1 levels before NAC (P=0.001, OR=0.997, 95% CI: 0.996-0.999) and higher levels of TILs (P=0.005). In the multivariate survival model for nonpCR patients, serum SDF-1 expression at surgery served as an independent prognostic value for survival (high level, HR=1.980, 95% CI: 1.170-3.350, low level was used as a reference; P=0.011). Additionally, the predictive and prognostic value of serum SDF-1 expression was significant in patients with high abundance of TILs but not in patients with low abundance of TILs. Conclusions This study contributes to the clarification of the value of serum SDF-1 to predict pCR and survival for TNBC patients who underwent NAC. This new serum marker, together with TILs, might help identify clinical subtypes of TNBC with different treatment responses and survival and play an important role in tailoring and modifying the NAC strategy for advanced TNBCs in the future.
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Affiliation(s)
- Ruo-Xi Wang
- Department of Breast Surgery, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Peng Ji
- Department of Breast Surgery, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yue Gong
- Department of Breast Surgery, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhi-Ming Shao
- Department of Breast Surgery, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institutes of Biomedical Science, Fudan University, Shanghai, China
| | - Sheng Chen
- Department of Breast Surgery, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- *Correspondence: Sheng Chen,
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31
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Guan D, Jie Q, Wu Y, Xu Y, Hong W, Meng X. Real-world data on breast pathologic complete response and disease-free survival after neoadjuvant chemotherapy for hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer: a multicenter, retrospective study in China. World J Surg Oncol 2022; 20:326. [PMID: 36175898 PMCID: PMC9520808 DOI: 10.1186/s12957-022-02787-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 07/16/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The data in the real-world setting on breast pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) for hormone receptor-positive, human epidermal growth factor receptor-2-negative (HR+, HER2-) breast cancer (BC) is limited. The present study aims to screen for some predictors and investigate the prognostic significance of breast pCR after NAC in HR+, HER2- BC in China. METHODS This was a multicenter, retrospective study. In this study, three hundred eighty-four HR+, HER2- BC patients who received NAC were enrolled between 2010 and 2016 from Shanghai Jiaotong University Breast Cancer Database (SJTU-BCDB). These patients were dichotomized according to the presence of breast pCR after NAC. Logistic analysis was used to screen for predictors associated with breast pCR. Kaplan-Meier (K-M) curve and a propensity score matching (PSM) analysis were performed to compare the disease-free survival (DFS) between the two groups. Cox regression was used to analyze the prognostic significance of breast pCR on DFS in HR+, HER2- BC. A nomogram model was established to predict the probability of DFS at 1, 3, and 5 years after NAC. RESULTS Fifty-seven patients (14.8%) achieved breast pCR. Univariate analysis showed that tumor size, estrogen receptor (ER), progesterone receptor (PR), and Ki67 were associated with breast pCR. Further, multivariate analysis showed that tumor size, PR, and Ki67 remained statistically significant. K-M curves showed a statistical difference between the breast pCR and non-pCR groups before PSM (p = 0.047), and a more significant difference was shown after PSM (p = 0.033). Cox regression after PSM suggested that breast pCR, adjuvant ET, clinical T stage, and Ki67 status were the significant predictive factors for DFS in HR+, HER2- BC patients. The adjusted hazards ratio (aHR) for breast pCR was 0.228 (95% CI, 0.070~0.739; p = 0.014), for adjuvant endocrine therapy was 0.217 (95% CI, 0.059~0.801; p = 0.022), for Ki67 was 1.027 (95% CI, 1.003~1.052; p = 0.027), for cT stages 2 and 3 compared with 1, the values were 1.331 (95% CI, 0.170~10.389), and 4.699 (95% CI, 0.537~41.142), respectively (p = 0.043). A nomogram was built based on these significant predictors, providing an integrated probability of DFS at 1, 3, and 5 years. The values of area under the receiver operating characteristic (ROC) curve (AUC) were 0.967, 0.991, and 0.787, at 1 year, 3 years, and 5 years, respectively, demonstrating the ability of the nomogram to predict the DFS. CONCLUSIONS This real-world study demonstrates that tumor size, PR, and Ki67 were independent predictive factors for breast pCR in HR+, HER2- BC. Breast pCR after NAC was an independent predictor for DFS in HR+, HER2- patients, regardless of a change in nodes. Furthermore, the nomogram built in our study could predict the probability of individualized DFS in HR+, HER2- BC patients.
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Affiliation(s)
- Dandan Guan
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Shangtang Road No. 158, Hangzhou, 310014, Zhejiang, China
| | - Qiu Jie
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yihao Wu
- Zhejiang University of Technology, Hangzhou, Zhejiang, China
| | - Yuhao Xu
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Weimin Hong
- Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Xuli Meng
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Shangtang Road No. 158, Hangzhou, 310014, Zhejiang, China.
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32
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Khoury T, Aljabab S, Yao S, Ambrosone C, Omilian A, Attwood K, Ji W, Gandhi S. Tumor-associated mononuclear cells in the tumor bed of triple-negative breast cancer associate with clinical outcomes in the post-neoadjuvant chemotherapy setting. Breast Cancer Res Treat 2022; 194:531-540. [PMID: 35716216 DOI: 10.1007/s10549-022-06641-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 05/26/2022] [Indexed: 11/02/2022]
Abstract
PURPOSE To evaluate the clinical role of tumor-associated macrophages, including foamy (FM) and hemosiderin-laden macrophages (HLM) in the tumor bed (TB) of triple-negative breast cancer (TNBC) post-neoadjuvant chemotherapy (NACT). METHODS We conducted a pathologic review of 129 women, diagnosed with TNBC between 2002 and 2016 at our institute. The residual cancer burden (RCB) was calculated. We estimated the percentage of tumor-infiltrating lymphocytes (TILs) in the core needle biopsy (CNB), and FM, HLM, and TILs (in TB) [the combined cells are designated as tumor-associated mononuclear cells (TAMNC)]. The information on patient demographics, chemotherapy regimen, recurrence-free survival (RFS), and overall survival (OS) was extracted from the medical records. RESULTS Pathologic complete response (pCR) was achieved in 34.1% of the women. TILs (10% increment in CNB) only were associated with pCR in the multivariable analysis [odds ratio 1.04 (1.02, 1.06) (p = 0.0003)]. Immune cells associated with better OS included TAMNC (≤ 30%) [hazard ratio (HR) 4.32 (1.93, 9.66) (p = 0.0004)], and FM (0%) [HR 2.30 (1.06, 4.98) (p = 0.036)]. While increased HLM (10% increment) was statistically significant with HR 0.93 and 95% CI (0.88 to 0.98) (p = 0.0061), using a cutoff of 0%, HLM (0%: negative vs. ≥ 1%: positive) achieved only borderline significance with HR 2.05 (0.98, 4.31) (p = 0.058). Similarly, these immune cells were also associated with better RFS: TAMNC (≤ 30%) [HR 4.57 (2.04, 10.21) (p = 0.0002)], FM (0%) [HR 2.80 (1.23, 6.35) (p = 0.014)], and HLM (0%) [HR 2.34 (1.07, 5.11) (p = 0.03)]. TILs (in TB) were not associated with any clinical outcomes. CONCLUSIONS Although TILs may play a role in the response to NACT, they may not be critical to the prognosis after NACT. Instead, FM and HLM may assume this role. More studies are warranted.
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Affiliation(s)
- Thaer Khoury
- Department of Pathology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY, 14263, USA.
| | - Saif Aljabab
- Department of Radiation Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Song Yao
- Department of Epidemiology and Population Science, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Christine Ambrosone
- Department of Epidemiology and Population Science, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Angela Omilian
- Department of Epidemiology and Population Science, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Kristopher Attwood
- Department of Biostatistics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Wenyan Ji
- Department of Biostatistics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Shipra Gandhi
- Department of Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
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Liu J, Lei B, Yu X, Li Y, Deng Y, Yang G, Li Z, Liu T, Ye L. Combining Immune-Related Genes For Delineating the Extracellular Matrix and Predicting Hormone Therapy and Neoadjuvant Chemotherapy Benefits In Breast Cancer. Front Immunol 2022; 13:888339. [PMID: 35911730 PMCID: PMC9331652 DOI: 10.3389/fimmu.2022.888339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 06/20/2022] [Indexed: 11/23/2022] Open
Abstract
Breast cancer (BC) is the most prevalent cancer in women worldwide. A systematic approach to BC treatment, comprising adjuvant and neoadjuvant chemotherapy (NAC), as well as hormone therapy, forms the foundation of the disease’s therapeutic strategy. The extracellular matrix (ECM) is a dynamic network that exerts a robust biological effect on the tumor microenvironment (TME), and it is highly regulated by several immunological components, such as chemokines and cytokines. It has been established that the ECM promotes the development of an immunosuppressive TME. Therefore, while analyzing the ECM of BC, immune-related genes must be considered. In this study, we used bioinformatic approaches to identify the most valuable ECM-related immune genes. We used weighted gene co-expression network analysis to identify the immune-related genes that potentially regulate the ECM and then combined them with the original ECM-related gene set for further analysis. Least absolute shrinkage and selection operator (LASSO) regression and SurvivalRandomForest were used to narrow our ECM-related gene list and establish an ECM index (ECMI) to better delineate the ECM signature. We stratified BC patients into ECMI high and low groups and evaluated their clinical, biological, and genomic characteristics. We found that the ECMI is highly correlated with long-term BC survival. In terms of the biological process, this index is positively associated with the cell cycle, DNA damage repair, and homologous recombination but negatively with processes involved in angiogenesis and epithelial–mesenchymal transition. Furthermore, the tumor mutational burden, copy number variation, and DNA methylation levels were found to be related to the ECMI. In the Metabric cohort, we demonstrated that hormone therapy is more effective in patients with a low ECMI. Additionally, differentially expressed genes from the ECM-related gene list were extracted from patients with a pathologic complete response (pCR) to NAC and with residual disease (RD) to construct a neural network model for predicting the chance of achieving pCR individually. Finally, we performed qRT-PCR to validate our findings and demonstrate the important role of the gene OGN in predicting the pCR rate. In conclusion, delineation of the ECM signature with immune-related genes is anticipated to aid in the prediction of the prognosis of patients with BC and the benefits of hormone therapy and NAC in BC patients.
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Affiliation(s)
- Jianyu Liu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Bo Lei
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xin Yu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yingpu Li
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yuhan Deng
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Guang Yang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Zhigao Li
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
- *Correspondence: Tong Liu, ; Zhigao Li, ; Leiguang Ye,
| | - Tong Liu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
- *Correspondence: Tong Liu, ; Zhigao Li, ; Leiguang Ye,
| | - Leiguang Ye
- Department of Oncology, Harbin Medical University, Harbin, China
- *Correspondence: Tong Liu, ; Zhigao Li, ; Leiguang Ye,
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Feng J, Yi J, Zouxu X, Li J, Xiong Z, Huang X, Zhong W, Huang W, Ye F, Wang X. Peripheral blood lymphocytes subtypes as new predictors for neoadjuvant therapy efficacy in breast cancer. Cancer Med 2022; 11:2923-2933. [PMID: 35411609 PMCID: PMC9359876 DOI: 10.1002/cam4.4666] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 01/24/2022] [Accepted: 02/02/2022] [Indexed: 12/02/2022] Open
Abstract
Background Host immunity plays an important role in tumor development and treatment. Tumor‐infiltrating lymphocytes (TILs) have been proven to predict the efficacy of neoadjuvant therapy (NAT) in breast cancer (BC) patients, but their application is limited due to various reasons. This study aims to explore the relationship between peripheral blood lymphocytes (PBLs) subsets distribution and the efficacy of NAT. Methods Between December 2017 and March 2021, a total of 116 BC patients appropriate for NAT in Sun Yat‐Sen University cancer center were enrolled, pre‐NAC baseline blood samples were taken for further flow cytometry analysis to quantitatively evaluate the PBLs subsets distribution, and corresponding clinical information including pathological complete response (pCR) rate of NAT response were recorded. Results Baseline CD3+ T cells(OR 1.11, 1.03–1.21, p = 0.011), CD8+ T cells (OR 1.09, 1.02–1.18, p = 0.015), and NK cells (OR 0.91, 0.83–0.98, p = 0.028) in PBLs subgroup distribution were independent predictors of pCR in BC patients receiving NAT, in which CD8+ T cells had the highest predictive ability (AUC = 0.76). Compared with some previous prediction indicators, its prediction ability has been improved to some extent. Conclusion Peripheral baseline CD3+ T cells, CD8+ T cells, and NK cells were independent predictors of pCR in BC patients receiving NAT, in which CD8+ T cells had the highest predictive ability. Therefore, it can provide newly non‐invasive, relatively accurate and easily accessible predictors for corresponding patients, and help clinicians better understand tumor immunity.
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Affiliation(s)
- Jikun Feng
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Jiarong Yi
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Xiazi Zouxu
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Jianxia Li
- Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, China
| | - Zhenchong Xiong
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Xinjian Huang
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Wenjing Zhong
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Weiling Huang
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Feng Ye
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Xi Wang
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
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Arora S, Narayan P, Osgood CL, Wedam S, Prowell TM, Gao JJ, Shah M, Krol D, Wahby S, Royce M, Ghosh S, Philip R, Ison G, Berman T, Brus C, Bloomquist EW, Fiero MH, Tang S, Pazdur R, Ibrahim A, Amiri-Kordestani L, Beaver JA. U.S. FDA Drug Approvals for Breast Cancer: A Decade in Review. Clin Cancer Res 2022; 28:1072-1086. [PMID: 34711632 PMCID: PMC8923912 DOI: 10.1158/1078-0432.ccr-21-2600] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 10/01/2021] [Accepted: 10/19/2021] [Indexed: 11/16/2022]
Abstract
Over the last decade, the treatment of patients with breast cancer has been greatly impacted by the approval of multiple drugs and indications. This summary describes 30 FDA approvals of treatments for breast cancer from 2010 to 2020. The trial design endpoints, results, and regulatory considerations are described for each approved indication. Of the 30 indications, 23 (76.6%) received regular and 7 (23.3%) received accelerated approval. Twenty-six approvals were granted in metastatic breast cancer (MBC) and four in early breast cancer. Approval decisions for the 26 MBC indications were initially supported by progression-free survival (PFS) in 21 (80.8%), overall survival (OS) or a combination of OS and PFS in two (7.7%), and objective response rate (ORR) in three (11.5%). The four approvals in early breast cancer utilized pathologic complete response (pCR) in one (25%) and invasive disease-free survival (iDFS) in three (75%) trials. Among the 30 indications, 22 received priority review, seven were granted Breakthrough Therapy Designation, and 10 applications participated in one or more pilot Oncology Center of Excellence regulatory review initiatives, including Real Time Oncology Review, Assessment Aid, and Project Orbis. FDA initiatives to advance breast cancer drug development are also described.
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Affiliation(s)
- Shaily Arora
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Preeti Narayan
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Christy L. Osgood
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Suparna Wedam
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Tatiana M. Prowell
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Jennifer J. Gao
- Oncology Center of Excellence, U.S. Food and Drug Administration
| | - Mirat Shah
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Danielle Krol
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Sakar Wahby
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Melanie Royce
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Soma Ghosh
- Center for Devices and Radiological Health, U.S. Food and Drug Administration
| | - Reena Philip
- Center for Devices and Radiological Health, U.S. Food and Drug Administration
| | - Gwynn Ison
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Tara Berman
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Christina Brus
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Erik W. Bloomquist
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Mallorie H. Fiero
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Shenghui Tang
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Richard Pazdur
- Oncology Center of Excellence, U.S. Food and Drug Administration
| | - Amna Ibrahim
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | | | - Julia A. Beaver
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
- Oncology Center of Excellence, U.S. Food and Drug Administration
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Prognostic Impact of High Baseline Stromal Tumor-Infiltrating Lymphocytes in the Absence of Pathologic Complete Response in Early-Stage Triple-Negative Breast Cancer. Cancers (Basel) 2022; 14:cancers14051323. [PMID: 35267631 PMCID: PMC8909018 DOI: 10.3390/cancers14051323] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/28/2022] [Accepted: 03/01/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary High stromal tumor-infiltrating lymphocytes (sTILs) are associated with an improved pathologic complete response (pCR) and survival in triple-negative breast cancer (TNBC). We hypothesized that high baseline sTILs would have a favorable prognostic impact in TNBC patients without a pCR. In this study of 318 early-stage TNBC patients in a prospective clinical trial, event-free survival (EFS) in patients without a pCR was not significantly different between those with high sTILs and those with low sTILs (p = 0.7). Therefore, high baseline sTILs do not confer a benefit in EFS in the absence of a pCR. RNA-seq analysis predicted more CD8+ T cells in the high-sTIL group with favorable EFS compared with the high-sTIL group with unfavorable EFS, suggesting the type of lymphocytes within the TIL fraction may be an important parameter to consider for de-escalation strategies. The implications of our findings in the setting of immune checkpoint inhibitor therapy remain to be investigated. Abstract High stromal tumor-infiltrating lymphocytes (sTILs) are associated with an improved pathologic complete response (pCR) and survival in triple-negative breast cancer (TNBC). We hypothesized that high baseline sTILs would have a favorable prognostic impact in TNBC patients without a pCR after neoadjuvant chemotherapy (NACT). In this prospective NACT study, pretreatment biopsies from 318 patients with early-stage TNBC were evaluated for sTILs. Recursive partitioning analysis (RPA) was applied to search for the sTIL cutoff best associated with a pCR. With ≥20% sTILs identified as the optimal cutoff, 33% patients had high sTILs (pCR rate 64%) and 67% had low sTILs (pCR rate 29%). Patients were stratified according to the sTIL cutoff (low vs. high) and response to NACT (pCR vs. residual disease (RD)). The primary endpoint was event-free survival (EFS), with hazard ratios calculated using the Cox proportional hazards regression model and the 3-year restricted mean survival time (RMST) as primary measures. Within the high-sTIL group, EFS was better in patients with a pCR compared with those with RD (HR 0.05; 95% CI 0.01–0.39; p = 0.004). The difference in the 3-year RMST for EFS between the two groups was 5.6 months (95% CI 2.3–8.8; p = 0.001). However, among patients with RD, EFS was not significantly different between those with high sTILs and those with low sTILs (p = 0.7). RNA-seq analysis predicted more CD8+ T cells in the high-sTIL group with favorable EFS compared with the high-sTIL group with unfavorable EFS. This study did not demonstrate that high baseline sTILs confer a benefit in EFS in the absence of a pCR.
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Zhou Q, Gampenrieder SP, Frantal S, Rinnerthaler G, Singer CF, Egle D, Pfeiler G, Bartsch R, Wette V, Pichler A, Petru E, Dubsky PC, Bago-Horvath Z, Fesl C, Rudas M, Ståhlberg A, Graf R, Weber S, Dandachi N, Filipits M, Gnant M, Balic M, Heitzer E. Persistence of ctDNA in Patients with Breast Cancer During Neoadjuvant Treatment Is a Significant Predictor of Poor Tumor Response. Clin Cancer Res 2022; 28:697-707. [PMID: 34862246 PMCID: PMC9377752 DOI: 10.1158/1078-0432.ccr-21-3231] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/27/2021] [Accepted: 11/29/2021] [Indexed: 01/07/2023]
Abstract
PURPOSE Accurate response assessment during neoadjuvant systemic treatment (NST) poses a clinical challenge. Therefore, a minimally invasive assessment of tumor response based on cell-free circulating tumor DNA (ctDNA) may be beneficial to guide treatment decisions. EXPERIMENTAL DESIGN We profiled 93 genes in tissue from 193 patients with early breast cancer. Patient-specific assays were designed for 145 patients to track ctDNA during NST in plasma. ctDNA presence and levels were correlated with complete pathological response (pCR) and residual cancer burden (RCB) as well as clinicopathologic characteristics of the tumor to identify potential proxies for ctDNA release. RESULTS At baseline, ctDNA could be detected in 63/145 (43.4%) patients and persisted in 25/63 (39.7%) patients at mid-therapy (MT) and 15/63 (23.8%) patients at the end of treatment. ctDNA detection at MT was significantly associated with higher RCB (OR = 0.062; 95% CI, 0.01-0.48; P = 0.0077). Of 31 patients with detectable ctDNA at MT, 30 patients (96.8%) were nonresponders (RCB II, n = 8; RCB III, n = 22) and only one patient responded to the treatment (RCB I). Considering all 145 patients with baseline (BL) plasma, none of the patients with RCB 0 and only 6.7% of patients with RCB I had ctDNA detectable at MT, whereas 30.6% and 29.6% of patients with RCB II/III, respectively, had a positive ctDNA result. CONCLUSIONS Overall, our results demonstrate that the detection and persistence of ctDNA at MT may have the potential to negatively predict response to neoadjuvant treatment and identify patients who will not achieve pCR or be classified with RCB II/III.
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Affiliation(s)
- Qing Zhou
- Institute of Human Genetics, Diagnostic & Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria
- Christian Doppler Laboratory for Liquid Biopsies for Early Detection of Cancer, Medical University of Graz, Graz, Austria
| | - Simon P. Gampenrieder
- IIIrd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria
- Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research (LIMCR) and Center for Clinical Cancer and Immunology Trials (CCCIT), Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Sophie Frantal
- Department of Statistics, Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria
| | - Gabriel Rinnerthaler
- IIIrd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria
- Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research (LIMCR) and Center for Clinical Cancer and Immunology Trials (CCCIT), Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Christian F. Singer
- Department of Gynecology and Gynecological Oncology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Daniel Egle
- Department of Obstetrics and Gynecology, Medical University Innsbruck, Innsbruck, Austria
| | - Georg Pfeiler
- Department of Gynecology and Gynecological Oncology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Rupert Bartsch
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Viktor Wette
- Breast Center, Brustzentrum Kaernten, St. Veit, Austria
| | - Angelika Pichler
- Department of Hemato-Oncology, LKH Hochsteiermark-Leoben, Leoben, Austria
| | - Edgar Petru
- Department of Gynaecology and Obstetrics, Medical University Graz, Graz, Austria
| | - Peter C. Dubsky
- Department of Surgery and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- Breast Center St. Anna, Lucerne, Switzerland
| | - Zsuzsanna Bago-Horvath
- Department of Surgery and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Christian Fesl
- Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research (LIMCR) and Center for Clinical Cancer and Immunology Trials (CCCIT), Salzburg, Austria
| | - Margaretha Rudas
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Anders Ståhlberg
- Department of Laboratory Medicine, Sahlgrenska Center for Cancer Research, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenberg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Genetics and Genomics, Gothenburg, Sweden
| | - Ricarda Graf
- Institute of Human Genetics, Diagnostic & Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria
| | - Sabrina Weber
- Institute of Human Genetics, Diagnostic & Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria
| | - Nadia Dandachi
- Division of Oncology, Department of Internal Medicine, Medical University Graz, Graz, Austria
| | - Martin Filipits
- Department of Medicine I, Comprehensive Cancer Center, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Michael Gnant
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Marija Balic
- Division of Oncology, Department of Internal Medicine, Medical University Graz, Graz, Austria
| | - Ellen Heitzer
- Institute of Human Genetics, Diagnostic & Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria
- Christian Doppler Laboratory for Liquid Biopsies for Early Detection of Cancer, Medical University of Graz, Graz, Austria
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Abuhadra N, Stecklein S, Sharma P, Moulder S. Early-stage Triple-negative Breast Cancer: Time to Optimize Personalized Strategies. Oncologist 2022; 27:30-39. [PMID: 35305094 PMCID: PMC8842325 DOI: 10.1093/oncolo/oyab003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 11/16/2021] [Indexed: 11/15/2022] Open
Abstract
Triple-negative breast cancer (TNBC) accounts for approximately 15%-20% of breast cancers diagnosed worldwide, which amounts to almost 200 000 cases each year. Although historically TNBC is considered difficult to treat with a poor prognosis, there is emerging evidence showing excellent response rates in a subset of TNBC patients. Attempts to de-escalate chemotherapy in hormone-receptor-positive (HR+) and HER2-neu amplified breast cancer subtypes have been successful. At present, robust strategies to personalize therapy in early-stage TNBC do not exist, and despite excellent response rates in a subset of patients, all patients are exposed to the same several cycles of cytotoxic chemotherapy. Personalizing therapy in TNBC represents a challenge due to the scarcity of treatment options outside of cytotoxic chemotherapy and limited predictive and prognostic biomarkers to tailor treatment. Recent developments in understanding TNBC biology have sparked interest in exploring treatment optimization and personalization with the goal of achieving excellent response rates and long-term clinical outcomes, while simultaneously reducing physical, psychological, and financial toxicities for select patients. Here, we provide an update on the current evidence to support future studies examining de-escalating chemotherapy in patients with low-risk TNBC and adjuvant intensification strategies to improve outcomes for patients who are at high risk for systemic failure despite current standard-of-care treatments.
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Affiliation(s)
- Nour Abuhadra
- Breast Medicine Service, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Shane Stecklein
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Priyanka Sharma
- Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Stacy Moulder
- Eli Lilly and Company. Lilly Corporate Center, Indianapolis, IN, USA
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McAndrew NP. Updates on targeting human epidermal growth factor receptor 2-positive breast cancer: what's to know in 2021. Curr Opin Obstet Gynecol 2022; 34:41-45. [PMID: 34967814 DOI: 10.1097/gco.0000000000000762] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW To highlight recent practice changing clinical trials, focusing on those leading to new drug approvals, in human epidermal growth factor receptor 2-positive (HER2+) breast cancer. RECENT FINDINGS The improved disease-free survival of adjuvant trastuzumab emtansine (T-DM1) over trastuzumab in patients with residual disease has made neoadjuvant sequencing of therapy standard for most patients with early stage disease. In patients with metastatic HER2+ breast cancer, trastuzumab deruxtecan has recently shown dramatically improved efficacy over T-DM1. Tucatinib is an oral tyrosine kinase inhibitor with best in class blood-brain barrier penetration. Margetuximab, a novel HER2-targeted chimeric monoclonal antibody with an engineered Fc receptor designed to activate local immune response, was recently approved in heavily pretreated patients based on modest but significant improvement in progression-free survival. SUMMARY Patients with HER2+ breast cancer have a variety of therapeutic options in the early stage and metastatic setting. Optimal sequencing of therapy will depend on patient-specific factors such as site of tumor progression and underlying comorbidities. De-escalation of the first-line metastatic regimen may be considered in select patients with hormone positive/HER2+ breast cancer, by using endocrine therapy instead of chemotherapy in combination with HER2-targeted therapy, which may improve side effects without sacrificing efficacy.
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Santisteban M, Solans BP, Hato L, Urrizola A, Mejías LD, Salgado E, Sánchez-Bayona R, Toledo E, Rodríguez-Spiteri N, Olartecoechea B, Idoate MA, López-Díaz de Cerio A, Inogés S. Final results regarding the addition of dendritic cell vaccines to neoadjuvant chemotherapy in early HER2-negative breast cancer patients: clinical and translational analysis. Ther Adv Med Oncol 2021; 13:17588359211064653. [PMID: 34987618 PMCID: PMC8721381 DOI: 10.1177/17588359211064653] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 11/16/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Primary breast cancer (BC) has shown a higher immune infiltration than the metastatic disease, justifying the optimal scenario for immunotherapy. Recently, neoadjuvant chemotherapy (NAC) combined with immune checkpoint inhibitors has demonstrated a gain in pathological complete responses (tpCR) in patients with BC. The aim of our study is to evaluate the safety, feasibility, and efficacy of the addition of dendritic cell vaccines (DCV) to NAC in HER2-negative BC patients. METHODS Thirty-nine patients with early BC received DCV together with NAC conforming the vaccinated group (VG) and compared with 44 patients as the control group (CG). All patients received anthracyclines and taxanes-based NAC (ddECx4→Dx4) followed by surgery ± radiotherapy ± hormonotherapy. RESULTS The tpCR rate was 28.9% in the VG and 9.09% in the CG (p = 0.03). Pathological CR in the triple negative (TN) BC were 50.0% versus 30.7% (p = 0.25), 16.6% versus 0% in luminal B (p = 0.15), and none among luminal A patients in VG versus CG, respectively. Impact of DCV was significantly higher in the programmed cell death ligand 1 (PD-L1) negative population (p < 0.001). PD-L1 expression was increased in patients with residual disease in the VG as compared with the CG (p < 0.01). No grade ⩾3 vaccine-related adverse events occurred. With a median follow-up of 8 years, no changes were seen in event-free survival or overall survival. Phenotypic changes post DCV in peripheral blood were observed in myeloid-derived suppressor cells (MDSC), NK, and T cells. Increase in blood cell proliferation and interferon (IFN)-γ production was detected in 69% and 74% in the VG, respectively. Humoral response was also found. Clonality changes in TCR-β repertoire were detected in 67% of the patients with a drop in diversity index after treatment. CONCLUSION The combination of DCV plus NAC is safe and increases tpCR, with a significant benefit among PD-L1-negative tumors. DCV modify tumor milieu and perform cellular and humoral responses in peripheral blood with no impact in outcome. TRIAL REGISTRATION ClinicalTrials.gov number: NCT01431196. EudraCT 2009-017402-36.
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Affiliation(s)
- Marta Santisteban
- Department of Medical Oncology, Clínica Universidad de Navarra, Avda. Pío XII 36, 31008 Pamplona, Spain
- Breast Cancer Unit, Clínica Universidad de Navarra, Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Belén Pérez Solans
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- Pharmacometrics and Systems Pharmacology, Universidad de Navarra, Pamplona, Spain
| | - Laura Hato
- Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain
| | - Amaia Urrizola
- Medical Oncology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Luis Daniel Mejías
- Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Esteban Salgado
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; Medical Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain
| | | | - Estefanía Toledo
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; Department of Preventive Medicine and Public Health, Universidad de Navarra, Pamplona, Spain
| | | | | | | | - Ascensión López-Díaz de Cerio
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain
- Cell Therapy Unit, Clínica Universidad de Navarra, Pamplona, Spain
- Clínica Universidad de Navarra, Universidad de Navarra, Complejo Hospitalario de Navarra and IdisNA, Pamplona, Spain
| | - Susana Inogés
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain
- Cell Therapy Unit, Clínica Universidad de Navarra, Pamplona, Spain
- Clínica Universidad de Navarra, Universidad de Navarra, Complejo Hospitalario de Navarra and IdisNA, Pamplona, Spain
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Gion M, Pérez-García JM, Llombart-Cussac A, Sampayo-Cordero M, Cortés J, Malfettone A. Surrogate endpoints for early-stage breast cancer: a review of the state of the art, controversies, and future prospects. Ther Adv Med Oncol 2021; 13:17588359211059587. [PMID: 34868353 PMCID: PMC8640314 DOI: 10.1177/17588359211059587] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 10/25/2021] [Indexed: 01/07/2023] Open
Abstract
Drug approval for early-stage breast cancer (EBC) has been historically granted in the context of registration trials based on adequate outcomes such as disease-free survival and overall survival. Improvements in long-term outcomes have made it more difficult to demonstrate the clinical benefit of a new cancer drug in large, randomized, comparative clinical trials. Therefore, the use of surrogate endpoints rather than traditional measures allows for cancer drug trials to proceed with smaller sample sizes and shorter follow-up periods, which reduces drug development time. Among surrogate endpoints for breast cancer, the increase in pathological complete response (pCR) rates was considered appropriate for accelerated drug approval. The association between pCR and long-term outcomes was strongest in patients with aggressive tumor subtypes, such as triple-negative and human epidermal growth factor receptor 2 (HER2)-positive/hormone receptor-negative breast cancers. Whereas in hormone receptor-positive/HER2-negative EBC, the most accepted surrogate markers for endocrine therapy-based trials include changes in Ki67 and the preoperative endocrine prognostic index. Beyond the classic endpoints, further prognostic tools are required to provide EBC patients with individualized and effective therapies, and the neoadjuvant setting provides an excellent platform for drug development and biomarker discovery. Nowadays, the availability of multigene signatures is offering a standardized quantitative and reproducible tool to potentiate the efficacy of standard treatment for high-risk patients and develop de-escalated treatments for patients at lower risk of relapse. In this article, we first evaluate the surrogacies used for long-term outcomes and the underlying evidence supporting the use of each surrogate endpoint for the accelerated or regular drug approval process in EBC. Next, we provide an overview of the most recent studies and innovative strategies in a (neo)adjuvant setting as a platform to accelerate new drug approval. Finally, we highlight some clinical trials aimed at tailoring systemic treatment of EBC using prognosis-related factors or early biomarkers of drug sensitivity or resistance.
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Affiliation(s)
- María Gion
- University Hospital Ramon y Cajal, Madrid, Spain
| | - José Manuel Pérez-García
- International Breast Cancer Center (IBCC), Quironsalud Group, Barcelona, Spain
- Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain
- Medica Scientia Innovation Research (MEDSIR), Ridgewood, NJ, USA
| | - Antonio Llombart-Cussac
- Hospital Arnau de Vilanova, Valencia, Spain
- Universidad Catolica de Valencia San Vicente Martir, Valencia, Spain
- Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain
- Medica Scientia Innovation Research (MEDSIR), Ridgewood, NJ, USA
| | - Miguel Sampayo-Cordero
- Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain
- Medica Scientia Innovation Research (MEDSIR), Ridgewood, NJ, USA
| | - Javier Cortés
- International Breast Cancer Center (IBCC), Quironsalud Group, Carrer de Vilana, 12, 08022 Barcelona, SpainVall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain
- Medica Scientia Innovation Research (MEDSIR), Ridgewood, NJ, USA
- Department of Medicine, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid, Spain
| | - Andrea Malfettone
- Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain
- Medica Scientia Innovation Research (MEDSIR), Ridgewood, NJ, USA
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Nakamoto S, Ikeda M, Kubo S, Yamamoto M, Yamashita T, Kuwahara C. The Systemic Immune Markers at Diagnosis Can Predict the Survival Benefit in Advanced Breast Cancer. CANCER DIAGNOSIS & PROGNOSIS 2021; 1:471-478. [PMID: 35403159 PMCID: PMC8962865 DOI: 10.21873/cdp.10063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/07/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND/AIM It has been difficult to establish prognostic markers for overall survival (OS) in patients with advanced breast cancer (ABC). Although systemic immune markers were reported as prognostic markers in several cancers, their utility in ABC remains unclear. PATIENTS AND METHODS We retrospectively analyzed 331 ABC patients, who received treatment at Fukuyama City Hospital between April 2009 and December 2020. RESULTS Patients with high absolute lymphocyte count (ALC), low neutrophil-to-lymphocyte ratio (NLR), and high lymphocyte-to-monocyte ratio (LMR) had significantly longer OS (p=0.025, p=0.010, and p<0.001, respectively). High ALC and high LMR were independently associated with longer OS (p=0.020 and p=0.015, respectively). High ALC was also independently associated with longer time to treatment failure (p=0.014). CONCLUSION These systemic immune markers at diagnosis can predict not only a better OS but also a better TTF after first-line treatment.
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Affiliation(s)
- Shogo Nakamoto
- Division of Breast and Thyroid Gland Surgery, Fukuyama City Hospital, Hiroshima, Japan
| | - Masahiko Ikeda
- Division of Breast and Thyroid Gland Surgery, Fukuyama City Hospital, Hiroshima, Japan
| | - Shinichiro Kubo
- Division of Breast and Thyroid Gland Surgery, Fukuyama City Hospital, Hiroshima, Japan
| | - Mari Yamamoto
- Division of Breast and Thyroid Gland Surgery, Fukuyama City Hospital, Hiroshima, Japan
| | - Tetsumasa Yamashita
- Division of Breast and Thyroid Gland Surgery, Fukuyama City Hospital, Hiroshima, Japan
| | - Chihiro Kuwahara
- Division of Breast and Thyroid Gland Surgery, Fukuyama City Hospital, Hiroshima, Japan
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Burstein HJ, Curigliano G, Thürlimann B, Weber WP, Poortmans P, Regan MM, Senn HJ, Winer EP, Gnant M. Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. Ann Oncol 2021; 32:1216-1235. [PMID: 34242744 PMCID: PMC9906308 DOI: 10.1016/j.annonc.2021.06.023] [Citation(s) in RCA: 475] [Impact Index Per Article: 118.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/22/2021] [Accepted: 06/27/2021] [Indexed: 12/12/2022] Open
Abstract
The 17th St Gallen International Breast Cancer Consensus Conference in 2021 was held virtually, owing to the global COVID-19 pandemic. More than 3300 participants took part in this important bi-annual critical review of the 'state of the art' in the multidisciplinary care of early-stage breast cancer. Seventy-four expert panelists (see Appendix 1) from all continents discussed and commented on the previously elaborated consensus questions, as well as many key questions on early breast cancer diagnosis and treatment asked by the audience. The theme of this year's conference was 'Customizing local and systemic therapies.' A well-organized program of pre-recorded symposia, live panel discussions and real-time panel voting results drew a worldwide audience of thousands, reflecting the far-reaching impact of breast cancer on every continent. The interactive technology platform allowed, for the first time, audience members to ask direct questions to panelists, and to weigh in with their own vote on several key panel questions. A hallmark of this meeting was to focus on customized recommendations for treatment of early-stage breast cancer. There is increasing recognition that the care of a breast cancer patient depends on highly individualized clinical features, including the stage at presentation, the biological subset of breast cancer, the genetic factors that may underlie breast cancer risk, the genomic signatures that inform treatment recommendations, the extent of response before surgery in patients who receive neoadjuvant therapy, and patient preferences. This customized approach to treatment requires integration of clinical care between patients and radiology, pathology, genetics, and surgical, medical and radiation oncology providers. It also requires a dynamic response from clinicians as they encounter accumulating clinical information at the time of diagnosis and then serially with each step in the treatment plan and follow-up, reflecting patient experiences and treatment response.
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Affiliation(s)
- H J Burstein
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA.
| | - G Curigliano
- European Institute of Oncology, University of Milan, Milan, Italy.
| | | | - W P Weber
- University of Basel, Basel, Switzerland
| | | | - M M Regan
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
| | - H J Senn
- St. Gallen Oncology Conferences (Foundation SONK), St. Gallen, Switzerland
| | - E P Winer
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
| | - M Gnant
- Medical University of Vienna, Vienna, Austria
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Zhou Q, Dong J, Sun Q, Lu N, Pan Y, Han X. Role of neutrophil-to-lymphocyte ratio as a prognostic biomarker in patients with breast cancer receiving neoadjuvant chemotherapy: a meta-analysis. BMJ Open 2021; 11:e047957. [PMID: 34561257 PMCID: PMC8475153 DOI: 10.1136/bmjopen-2020-047957] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 09/06/2021] [Indexed: 01/04/2023] Open
Abstract
OBJECTIVE The neutrophil-to-lymphocyte ratio (NLR) is recognised as a suitable prognostic biomarker in patients with breast cancer. Nevertheless, the efficacy of this biomarker in predicting the pathological complete response (pCR) and survival in patients with breast cancer receiving neoadjuvant chemotherapy (NACT) is still controversial. This meta-analysis aimed to identify the association between baseline NLR and the prognosis of patients with breast cancer treated with NACT. DESIGN Meta-analysis. DATA SOURCES Relevant literature published before 1 May 2021 was searched using the Cochrane Library, Embase, PubMed and the Web of Science databases. ELIGIBILITY CRITERIA All studies involving patients with breast cancer treated with NACT and peripheral blood pretreatment NLR recorded as a dichotomous variable were included. DATA EXTRACTION AND SYNTHESIS Two researchers independently extracted and evaluated OR/HR and its 95% CIs of survival outcomes and clinicopathological parameters. RESULTS A total of 19 studies were identified. From each study, the impact of NLR on the pCR, OR and HR, with their 95% CIs were extracted and combined using either a random or fixed-effects model. The results indicate that a higher pCR in patients with a low NLR (OR 1.620, 95% CI 1.209 to 2.169, p<0.001). In addition, an elevated NLR predicted lower disease-free survival (HR 2.269, 95% CI 1.557 to 3.307, p<0.001) and overall survival (HR 1.691, 95% CI 1.365 to 2.096, p<0.001) in patients with breast cancer treated with NACT. CONCLUSIONS NLR is a suitable biomarker for predicting pCR and survival in patients with breast cancer receiving NACT.
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Affiliation(s)
- Qiong Zhou
- Department of Oncology, Provincial Hospital Affiliated to Anhui Medical University, Hefei, China
| | - Jie Dong
- Department of Oncology, Provincial Hospital Affiliated to Anhui Medical University, Hefei, China
| | - Qingqing Sun
- Department of Oncology, Provincial Hospital Affiliated to Anhui Medical University, Hefei, China
| | - Nannan Lu
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, Hefei, Anhui, China
| | - Yueyin Pan
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, Hefei, Anhui, China
| | - Xinghua Han
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, Hefei, Anhui, China
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Chen J, Colosimo M, Lim E. The management of HER2-positive early breast cancer: Current and future therapies. Asia Pac J Clin Oncol 2021; 17 Suppl 6:3-12. [PMID: 34490737 DOI: 10.1111/ajco.13655] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Advances in human epidermal growth factor receptor 2 (HER2)-directed therapies have revolutionised the care of patients with HER2-positive breast cancer. While adjuvant trastuzumab in combination with chemotherapy has dramatically improved the prognosis for patients with early-stage disease, up to a quarter of patients will develop recurrent disease. The standard-of-care treatment paradigm has evolved with the introduction of newer HER2-directed therapies and increasing use of neoadjuvant systemic therapy, the latter providing us with important functional data to HER2-directed therapies and impacting subsequent adjuvant therapy decisions. However, these new strategies come at a cost of increased toxicity and economic burden, and only a subset of patients benefit from such approaches. Thus, ongoing work is required to identify predictive biomarkers of response, to de-escalate treatment in patients who may do just as well with less therapy, and new therapeutic approaches for patients who do not respond to currently used therapies. In this review, we will examine the current therapeutic landscape, summarise the latest evidence, and list the current treatment algorithms for early stage HER2-positive breast cancer.
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Affiliation(s)
- Julia Chen
- Garvan Institute of Medical Research, Sydney, Australia.,St Vincent's Clinical School, University of New South Wales, Sydney, Australia
| | - Maree Colosimo
- St Vincent's Private Hospital, Chermside, Queensland, Australia
| | - Elgene Lim
- Garvan Institute of Medical Research, Sydney, Australia.,St Vincent's Clinical School, University of New South Wales, Sydney, Australia
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Zhang Y, Liu M, Yang H, Wang S. Physicians’ Perception of the Evidence in Relation to Primary Endpoints of Clinical Trials on Breast Cancer. Breast Care (Basel) 2021; 17:180-187. [DOI: 10.1159/000518260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 06/21/2021] [Indexed: 11/19/2022] Open
Abstract
<b><i>Objective:</i></b> To investigate physicians’ perception of the evidence of clinical trials on breast cancer. <b><i>Methods:</i></b> A survey was conducted by the Chinese Society of Breast Surgeons. We investigated the physicians’ perception of meaningful endpoints, appropriate follow-up duration, and clinically acceptable benefit through online questionnaires. <b><i>Results:</i></b> Among 278 validated questionnaires, the majority of the questions had no consistent answer. For local treatment, 30.6, 28.8, and 28.4% of participants regarded locoregional recurrence (LRR), disease-free survival (DFS), and overall survival (OS) as the most meaningful endpoint, respectively, 47.5% believed that 5-year follow-up can alter clinical practice, and 34.5% thought it should be >10 years. In the adjuvant setting, 45.7, 38.5, and 12.9% regarded DFS, OS, and LRR as the most meaningful endpoint, respectively, 52.5% thought that 10-year follow-up was solid, while 37.4% thought that 5-year follow-up was enough. In the advanced setting, 49.6, 24.1, and 23.7% considered progression-free survival, quality of life, and OS the most meaningful endpoint, respectively, and 39.6 and 28.8% considered that a follow-up of 1 year and 3 years, respectively, was meaningful. Similarly, the clinically acceptable absolute difference was inconsistent. <b><i>Conclusion:</i></b> Most Chinese oncologists advocated that surrogate endpoints could be used in certain circumstances, though OS was the most reliable one in breast cancer studies. Doctors’ perceptions of follow-up time and magnitude of benefit vary widely, reflecting the fact that there are many unanswered questions about supporting the use of new cancer treatments; a common understanding needs to be reached, such as a very consensual surrogate endpoint and a meaningful sufficiently large therapeutic benefit.
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Sardesai SD, Thomas A, Gallagher C, Lynce F, Ottaviano YL, Ballinger TJ, Schneider BP, Storniolo AM, Bauchle A, Althouse SK, Perkins SM, Masters AR, Stratford RE, Dong Z, Liu JY, Zhang JT, Miller KD. Inhibiting Fatty Acid Synthase with Omeprazole to Improve Efficacy of Neoadjuvant Chemotherapy in patients with Operable TNBC. Clin Cancer Res 2021; 27:5810-5817. [PMID: 34400413 DOI: 10.1158/1078-0432.ccr-21-0493] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/26/2021] [Accepted: 08/11/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Fatty acid synthase (FASN) is overexpressed in 70% of operable triple negative breast cancer (TNBC) and is associated with poor prognosis. Proton pump inhibitors selectively inhibit FASN activity and induce apoptosis in TNBC cell lines. EXPERIMENTAL DESIGN Patients with operable TNBC were enrolled in this single arm Phase II study. Patients began omeprazole (OMP) 80 mg PO BID for 4-7 days prior to neoadjuvant anthracycline- taxane based chemotherapy (AC-T) and continued until surgery. The primary endpoint was pathologic complete response (pCR) in patients with baseline FASN overexpression (FASN+). Secondary endpoints included pCR in all surgery patients, change in FASN expression, enzyme activity, and downstream protein expression after OMP monotherapy; safety, and limited OMP pharmacokinetics. RESULTS Forty-two patients were recruited with a median age of 51y (28-72). Most patients had {greater than or equal to}cT2 (33, 79%) and {greater than or equal to}N1 (22, 52%) disease. FASN overexpression prior to AC-T was identified in 29/34 (85%) evaluable samples. The pCR rate was 72.4% (95% CI 52.8, 87.3) in FASN+ patients and 74.4% (95% CI 57.9, 87.0) in all surgery patients. Peak OMP concentration was significantly higher than the IC50 for FASN inhibition observed in preclinical testing; FASN expression decreased with OMP monotherapy (mean change 0.12 (SD 0.25) ; p = 0.02). OMP was well tolerated with no {greater than or equal to} grade 3 toxicities. CONCLUSIONS FASN is commonly expressed in early TNBC. OMP can be safely administered in doses that inhibit FASN. The addition of OMP to neoadjuvant AC-T yields a promising pCR rate that needs further confirmation in randomized studies.
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Affiliation(s)
| | | | | | | | | | | | | | - Anna Maria Storniolo
- Susan G. Komen Tissue Bank at the IU Simon Cancer Center, Indiana University School of Medicine
| | - Amber Bauchle
- Clinical Trials Office- School of Medicine, Indiana University Health
| | - Sandra K Althouse
- Hematology and Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | | | - Andrea R Masters
- Clinical Pharmacology Analytical Core, Indiana University Simon Cancer Center
| | | | - Zizheng Dong
- Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences
| | - Jing-Yuan Liu
- Department of Medicine, University of Toledo College of Medicine and Life Sciences
| | - Jian-Ting Zhang
- Departments of Cancer Biology, University of Toledo College of Medicine and Life Sciences
| | - Kathy D Miller
- Hematology and Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Karakas C, Francis AM, Ha MJ, Wingate HF, Meena RA, Yi M, Rasaputra KS, Barrera AMG, Arun B, Do KA, Sahin A, Keyomarsi K, Hunt KK. Cytoplasmic Cyclin E Expression Predicts for Response to Neoadjuvant Chemotherapy in Breast Cancer. Ann Surg 2021; 274:e150-e159. [PMID: 31436549 PMCID: PMC7031042 DOI: 10.1097/sla.0000000000003551] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Pathologic complete response (pCR) has been shown to be associated with favorable outcomes in breast cancer. Predictors of pCR could be useful in guiding treatment decisions regarding neoadjuvant therapy. The objective of this study was to evaluate cyclin E as a predictor of response to neoadjuvant chemotherapy in breast cancer. METHODS Patients (n = 285) with stage II-III breast cancer were enrolled in a prospective study and received neoadjuvant chemotherapy with anthracyclines, taxanes, or combination of the two. Pretreatment biopsies from 190 patients and surgical specimens following chemotherapy from 192 patients were available for immunohistochemical analysis. Clinical and pathologic responses were recorded and associated with presence of tumor infiltrating lymphocytes, cyclin E, adipophilin, programmed cell death-ligand 1, and elastase staining and other patient, tumor and treatment characteristics. RESULTS The pCR rate was significantly lower in patients with cytoplasmic cyclin E staining compared with those who had no cyclin E expression (16.1% vs 38.9%, P = 0.0005). In multivariable logistic regression analysis, the odds of pCR for patients who had cytoplasmic negative tumors was 9.35 times (P value < 0.0001) that compared with patients with cytoplasmic positive tumors after adjusting for ER, PR, and HER2 status. Cytoplasmic cyclin E expression also predicts long-term outcome and is associated with reduced disease free, recurrence free, and overall survival rates, independent of increased pretreatment tumor infiltrating lymphocytes. CONCLUSIONS Cyclin E independently predicted response to neoadjuvant chemotherapy. Hence, its routine immunohistochemical analysis could be used clinically to identify those breast cancer patients expected to have a poor response to anthracycline/taxane-based chemotherapy.
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Affiliation(s)
- Cansu Karakas
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Ashleigh M Francis
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Min Jin Ha
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Hannah F Wingate
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Richard A Meena
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Min Yi
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Komal S Rasaputra
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - Banu Arun
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kim-Anh Do
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Aysegul Sahin
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Khandan Keyomarsi
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kelly K Hunt
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
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Connolly RM, Leal JP, Solnes L, Huang CY, Carpenter A, Gaffney K, Abramson V, Carey LA, Liu MC, Rimawi M, Specht J, Storniolo AM, Valero V, Vaklavas C, Krop IE, Winer EP, Camp M, Miller RS, Wolff AC, Cimino-Mathews A, Park BH, Wahl RL, Stearns V. Updated Results of TBCRC026: Phase II Trial Correlating Standardized Uptake Value With Pathological Complete Response to Pertuzumab and Trastuzumab in Breast Cancer. J Clin Oncol 2021; 39:2247-2256. [PMID: 33999652 PMCID: PMC8260904 DOI: 10.1200/jco.21.00280] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 02/09/2021] [Accepted: 03/22/2021] [Indexed: 01/09/2023] Open
Abstract
PURPOSE Predictive biomarkers to identify patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who may benefit from targeted therapy alone are required. We hypothesized that early measurements of tumor maximum standardized uptake value corrected for lean body mass (SULmax) on 18F-labeled fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) would predict pathologic complete response (pCR) to pertuzumab and trastuzumab (PT). PATIENTS AND METHODS Patients with stage II or III, estrogen receptor-negative, HER2-positive breast cancer received four cycles of neoadjuvant PT. 18F-labeled fluorodeoxyglucose positron emission tomography-computed tomography was performed at baseline and 15 days after PT initiation (C1D15). Eighty evaluable patients were required to test the null hypothesis that the area under the curve of percent change in SULmax by C1D15 predicting pCR is ≤ 0.65, with a one-sided type I error rate of 10%. RESULTS Eighty-eight women were enrolled (83 evaluable), and 85% (75 of 88) completed all four cycles of PT. pCR after PT alone was 22%. Receiver operator characteristic analysis of percent change in SULmax by C1D15 yielded an area under the curve of 0.72 (80% CI, 0.64 to 0.80; one-sided P = .12), which did not reject the null hypothesis. However, between patients who obtained pCR and who did not, a significant difference in median percent reduction in SULmax by C1D15 was observed (63.8% v 41.8%; P = .004) and SULmax reduction ≥ 40% was more prevalent (83% v 52%; P = .03; positive predictive value, 31%). Participants not obtaining a 40% reduction in SULmax by C1D15 were unlikely to obtain pCR (negative predictive value, 91%). CONCLUSION Although the primary objective was not met, early changes in SULmax predict response to PT in estrogen receptor-negative and HER2-positive breast cancer. Once optimized, this quantitative imaging strategy may facilitate tailoring of therapy in this setting.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antineoplastic Agents, Immunological/adverse effects
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Breast Neoplasms/diagnostic imaging
- Breast Neoplasms/drug therapy
- Breast Neoplasms/metabolism
- Chemotherapy, Adjuvant
- Female
- Fluorodeoxyglucose F18
- Humans
- Middle Aged
- Neoadjuvant Therapy/adverse effects
- Positron Emission Tomography Computed Tomography
- Predictive Value of Tests
- Radiopharmaceuticals
- Receptor, ErbB-2/antagonists & inhibitors
- Receptor, ErbB-2/metabolism
- Time Factors
- Trastuzumab/adverse effects
- Trastuzumab/therapeutic use
- Treatment Outcome
- United States
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Affiliation(s)
- Roisin M. Connolly
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Jeffrey P. Leal
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Lilja Solnes
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Chiung-Yu Huang
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ashley Carpenter
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Katy Gaffney
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | | | | | | | | | | | | | - Vicente Valero
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | | | | | - Melissa Camp
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Robert S. Miller
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Antonio C. Wolff
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ashley Cimino-Mathews
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ben H. Park
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | | | - Vered Stearns
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
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Pretreatment systemic inflammation response index is predictive of pathological complete response in patients with breast cancer receiving neoadjuvant chemotherapy. BMC Cancer 2021; 21:700. [PMID: 34126950 PMCID: PMC8204500 DOI: 10.1186/s12885-021-08458-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 06/07/2021] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Inflammation plays an important role in tumor proliferation, metastasis, and resistance to chemotherapy. The systemic inflammation response index (SIRI), has been reported to be closely related to prognosis in many tumors, such as breast and gastric cancers. However, the predictive value of pretreatment SIRI on pathological complete response (pCR) rates in patients with breast cancer treated with neoadjuvant chemotherapy (NAC) is unknown. This study examined the correlation between SIRI and pCR in patients with breast cancer receiving NAC and identified convenient and accurate predictive indicators for pCR. METHODS We retrospectively analyzed the clinicopathological parameters and pretreatment peripheral blood characteristics of the 241 patients with breast cancer who received NAC between June 2015 and June 2020. Receiver operating characteristic (ROC) curves were used to determine the optimal cutoff of SIRI. ROC curves were also plotted to verify the accuracy of inflammatory markers for pCR prediction. The chi-squared test was used to explore the relationships of SIRI with pCR and other clinicopathological parameters. Multivariate analyses were performed using a logistic regression model. RESULTS Among the 241 patients, 48 (19.92%) achieved pCR. pCR was significantly related to SIRI, the neutrophil-lymphocyte ratio (NLR), the lymphocyte-monocyte ratio (LMR), molecular subtypes and other clinicopathological parameters, such as BMI, clinical T and N staging, and histological grade. Multivariate analyses indicated that the clinical T and N staging, SIRI, and NLR were independent prognostic factors for pCR in patients with breast cancer. The area under the ROC curve for SIRI was larger than that for NLR. Compared to patients with SIRI ≥0.72, patients with SIRI < 0.72 had a nearly 5-fold higher chance of obtaining pCR (odds ratio = 4.999, 95% confidence interval = 1.510-16.551, p = 0.000). CONCLUSIONS Pretreatment SIRI is predictive of pCR in patients with breast cancer receiving NAC, and the index can assist physicians in formulating personalized treatment strategies.
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