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Liu C, Sun L, Niu N, Hou P, Chen G, Wang H, Zhang Z, Jiang X, Xu Q, Zhao Y, Wang Y, Shi Y, Liu M, Yang Y, Qian W, Wang J, Liu C. Molecular classification of hormone receptor-positive /HER2-positive breast cancer reveals potential neoadjuvant therapeutic strategies. Signal Transduct Target Ther 2025; 10:97. [PMID: 40133264 PMCID: PMC11937365 DOI: 10.1038/s41392-025-02181-3] [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: 06/23/2024] [Revised: 02/11/2025] [Accepted: 02/17/2025] [Indexed: 03/27/2025] Open
Abstract
Significant heterogeneity exists in hormone receptor (HR)-positive/HER2-positive (HR+/HER2+) breast cancer, contributing to suboptimal pathological complete response rates with conventional neoadjuvant treatment regimens. Overcoming this challenge requires precise molecular classification, which is pivotal for the development of targeted therapies. We conducted molecular typing on a cohort of 211 patients with HR+/HER2+ breast cancer and performed a comprehensive analysis of the efficacy of various neoadjuvant treatment regimens. Our findings revealed four distinct molecular subtypes, each exhibiting unique characteristics and therapeutic implications. The HER2-enriched subtype, marked by activation of the HER2 signaling and hypoxia-inducible factor 1 (HIF-1) pathway, may benefit from intensified anti-HER2-targeted therapy. Estrogen receptor (ER)-activated subtype demonstrated potential sensitivity to combined therapeutic strategies targeting both ER and HER2 pathways. Characterized by high immune cell infiltration, the immunomodulatory subtype showed sensitivity to HER2-targeted antibody-drug conjugates (ADCs) and promise for immune checkpoint therapy. The highly heterogeneous subtype requires a multifaceted therapeutic approach. Organoid susceptibility assays suggested phosphoinositide 3-kinase inhibitors may be a potential treatment option. These findings underscore the importance of molecular subtyping in HR+/HER2+ breast cancer, offering a framework for developing precise and personalized treatment strategies. By addressing the heterogeneity of the disease, these approaches have the potential to optimize therapeutic outcomes and improve patient care.
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Affiliation(s)
- Chao Liu
- Cancer Stem Cell and Translation Medicine Lab, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lisha Sun
- Cancer Stem Cell and Translation Medicine Lab, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Nan Niu
- Cancer Stem Cell and Translation Medicine Lab, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Pengjie Hou
- Cancer Stem Cell and Translation Medicine Lab, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Guanglei Chen
- Cancer Stem Cell and Translation Medicine Lab, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hao Wang
- Cancer Stem Cell and Translation Medicine Lab, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhan Zhang
- Cancer Stem Cell and Translation Medicine Lab, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaofan Jiang
- Cancer Stem Cell and Translation Medicine Lab, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qianshi Xu
- Cancer Stem Cell and Translation Medicine Lab, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yafei Zhao
- Cancer Stem Cell and Translation Medicine Lab, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yimin Wang
- Cancer Stem Cell and Translation Medicine Lab, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yuan Shi
- Department of Breast Surgery, Anyang Tumor Hospital, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang, China
| | - Mingxin Liu
- Cancer Stem Cell and Translation Medicine Lab, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yongliang Yang
- Shanghai General Medical Center, School of Clinical Medicine, Shanghai University of Medicine & Health Science, Shanghai, China
| | - Wei Qian
- College of Medicine and Biological Information Engineering, Northeastern University, Shenyang, China
| | - Jiandong Wang
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
| | - Caigang Liu
- Cancer Stem Cell and Translation Medicine Lab, Shengjing Hospital of China Medical University, Shenyang, China.
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China.
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Liu S, Yu M, Mou E, Wang M, Liu S, Xia L, Li H, Tang H, Feng Y, Yu X, Mi K, Wang H. The optimal neoadjuvant treatment strategy for HR+/HER2 + breast cancer: a network meta-analysis. Sci Rep 2025; 15:713. [PMID: 39753653 PMCID: PMC11699132 DOI: 10.1038/s41598-024-84039-2] [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: 07/19/2024] [Accepted: 12/19/2024] [Indexed: 01/06/2025] Open
Abstract
The efficacy of neoadjuvant therapy varies significantly with hormone receptor (HR) status for patients with human epidermal growth factor receptor 2 (HER2) positive breast cancer (BC). Despite extensive research on HER2 + BC, the optimal neoadjuvant strategy for HR+/HER2 + BC remains inconclusive. This study aimed to identify the optimal neoadjuvant regimen for HR+/HER2 + BC treatment. We conducted a systematic search for trials comparing neoadjuvant regimens for HR+/HER2 + BC and a network meta-analysis. Odds ratios for pathological complete response (pCR) and hazard ratios for event-free survival (EFS) were calculated. Treatment regimens were ranked using the surface under the cumulative ranking curve. 20 trials with 2809 patients were included. In pCR analysis, three neoadjuvant regimens sequentially ranked at the top, namely those comprising T-DM1, pertuzumab with trastuzumab, and tyrosine kinase inhibitor with trastuzumab, demonstrating significantly higher pCR rates than monotherapies. In EFS analysis, pertuzumab with trastuzumab ranked the first while T-DM1 containing regimen ranked the last. Anthracycline-free regimens showed a marginally higher pCR rate than anthracycline-containing regimens, while carboplatin-containing regimens demonstrated a numerically higher pCR rate than carboplatin-free regimens. Significant heterogeneity was observed in endocrine therapy analysis, which may be caused by different strategies for incorporating endocrine therapy. In conclusion, trastuzumab plus pertuzumab stands out as the optimal neoadjuvant HER2-targeting regimen for HR+/HER2 + BC Furthermore, anthracycline-free carboplatin-containing chemotherapy emerges as a promising combination treatment. Further investigation is required to clarify the role of endocrine therapy in HR+/HER2 + BC to guide its clinical application.
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Affiliation(s)
- Shiwei Liu
- Department of Breast, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Miao Yu
- Department of Breast, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Exian Mou
- Department of Breast, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Meihua Wang
- Department of Breast, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shuanghua Liu
- Department of Breast, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Li Xia
- Department of Breast, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Hui Li
- Department of Breast, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Hao Tang
- Shanghai Roche Pharmaceuticals Ltd, Shanghai, China
| | - Yajing Feng
- Shanghai Roche Pharmaceuticals Ltd, Shanghai, China
| | - Xin Yu
- Shanghai Roche Pharmaceuticals Ltd, Shanghai, China
| | - Kun Mi
- Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China.
| | - Hao Wang
- Department of Breast, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China.
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Chen XC, Jiao DC, Qiao JH, Wang CZ, Sun XF, Lu ZD, Li LF, Zhang CJ, Yan M, Wei Y, Chen B, Feng YQ, Deng M, Ma MD, Plichta JK, He YW, Liu ZZ. De-escalated neoadjuvant weekly nab-paclitaxel with trastuzumab and pertuzumab versus docetaxel, carboplatin, trastuzumab, and pertuzumab in patients with HER2-positive early breast cancer (HELEN-006): a multicentre, randomised, phase 3 trial. Lancet Oncol 2025; 26:27-36. [PMID: 39612919 DOI: 10.1016/s1470-2045(24)00581-3] [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: 07/11/2024] [Revised: 10/02/2024] [Accepted: 10/09/2024] [Indexed: 12/01/2024]
Abstract
BACKGROUND A previous phase 2 trial showed promising outcomes for patients with HER2-positive early-stage breast cancer using neoadjuvant de-escalation chemotherapy with paclitaxel, trastuzumab, and pertuzumab. We aimed to evaluate the efficacy of weekly nab-paclitaxel compared with the standard regimen of docetaxel plus carboplatin, both with trastuzumab and pertuzumab, as neoadjuvant therapies for patients with HER2-positive breast cancer. METHODS HELEN-006 was a multicentre, randomised, phase 3 trial done at six hospitals in China. We enrolled patients aged 18-70 years with untreated, histologically confirmed stage II-III invasive HER2-positive breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. Using an interactive response system, patients were randomly assigned (1:1) under a permuted block randomisation scheme (block size of four), stratified by tumour stage, nodal status, and hormone receptor status. Patients received either intravenous nab-paclitaxel (125 mg/m2 on days 1, 8, and 15) for six 3-week cycles, or intravenous docetaxel (75 mg/m2 on day 1) plus intravenous carboplatin (area under the concentration-time curve 6 mg/mL per min on day 1) for six 3-week cycles. Both groups also received concurrent intravenous trastuzumab, with an initial loading dose of 8 mg/kg and a maintenance dose of 6 mg/kg on day 1, as well as intravenous pertuzumab with a loading dose of 840 mg and a maintenance dose of 420 mg on day 1. This report is the final analysis of the primary endpoint, pathological complete response (ypT0/is ypN0), analysed in all patients who started treatment (modified intention to treat). The trial is registered with ClinicalTrials.gov, NCT04547907, and follow-up of the adjuvant phase is ongoing. FINDINGS Between Sept 20, 2020, and March 1, 2023, 789 patients were screened for eligibility, 689 of whom were randomly assigned (343 to the nab-paclitaxel group and 346 to the docetaxel plus carboplatin group). All 689 patients were Asian women. 669 patients received at least one dose of the study treatment and were included in the full analysis set (332 in the nab-paclitaxel group and 337 in the docetaxel plus carboplatin group). Median age of the patients was 50 years (IQR 43-55). Median follow-up time was 26 months (IQR 19-32). 220 (66·3% [95% CI 61·2-71·4]) patients in the nab-paclitaxel group had a pathological complete response, compared with 194 (57·6% [52·3-62·9]) in the docetaxel plus carboplatin group (combined odds ratio 1·54 [95% CI 1·10-2·14]; stratified p=0·011). 100 (30%) patients in the nab-paclitaxel group and 128 (38%) in the docetaxel plus carboplatin group had grade 3-4 adverse events. The most common grade 3-4 adverse events were nausea (22 [7%] in the nab-paclitaxel group vs 76 [23%] in the docetaxel plus carboplatin group), diarrhoea (25 [8%] vs 55 [16%]), and neuropathy (43 [13%] vs eight [2%]). Serious drug-related adverse events were reported in three (1%) patients in the nab-paclitaxel group and five (2%) in the docetaxel plus carboplatin group. No treatment-related deaths were reported in either group. INTERPRETATION These findings might suggest a potential advantage of nab-paclitaxel combined with trastuzumab and pertuzumab compared with the standard regimen in neoadjuvant therapy for patients with HER2-positive early breast cancer, suggesting that this new combination might establish a new standard for neoadjuvant treatment in this patient population. FUNDING National Natural Science Foundation of China, and Science and Technology Research Projects of Henan Province, China. TRANSLATION For the Chinese translation of the abstract see Supplementary Materials section.
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Affiliation(s)
- Xiu-Chun Chen
- Department of Breast Disease, Henan Breast Cancer Centre, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - De-Chuang Jiao
- Department of Breast Disease, Henan Breast Cancer Centre, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Jiang-Hua Qiao
- Department of Breast Disease, Henan Breast Cancer Centre, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Cheng-Zheng Wang
- Department of Breast Disease, Henan Breast Cancer Centre, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Xian-Fu Sun
- Department of Breast Disease, Henan Breast Cancer Centre, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Zhen-Duo Lu
- Department of Breast Disease, Henan Breast Cancer Centre, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Lian-Fang Li
- Department of Breast Disease, Henan Breast Cancer Centre, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Chong-Jian Zhang
- Department of Breast Disease, Henan Breast Cancer Centre, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Min Yan
- Department of Breast Disease, Henan Breast Cancer Centre, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Ya Wei
- Department of Breast Surgery, Anyang Tumor Hospital, Anyang, China
| | - Bo Chen
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Yue-Qing Feng
- Department of Breast Surgery, Xinxiang Central Hospital, Xinxiang, China
| | - Miao Deng
- Department of Breast Surgery, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China
| | - Ming-De Ma
- Department of Thyroid and Breast Surgery, Huaihe Hospital of Henan University, Kaifeng, China
| | - Jennifer K Plichta
- Department of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - You-Wen He
- Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC, USA
| | - Zhen-Zhen Liu
- Department of Breast Disease, Henan Breast Cancer Centre, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China.
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Waks AG, Martínez-Sáez O, Tarantino P, Braso-Maristany F, Pascual T, Cortés J, Tolaney SM, Prat A. Dual HER2 inhibition: mechanisms of synergy, patient selection, and resistance. Nat Rev Clin Oncol 2024; 21:818-832. [PMID: 39271787 DOI: 10.1038/s41571-024-00939-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/15/2024] [Indexed: 09/15/2024]
Abstract
HER2-targeted therapies for patients with HER2+ breast cancer are rapidly evolving, offering a range of more complex and personalized treatment options. Currently, an array of anti-HER2 monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates are administered, sometimes alongside chemotherapy or endocrine therapy, both in curative and palliative contexts. However, the heterogeneous nature of HER2+ breast cancer demands a deeper understanding of disease biology and its role in responsiveness to novel HER2-targeted agents, as well as non-HER2-targeted therapies, in order to optimize patient outcomes. In this Review, we revisit the mechanisms of action of HER2-targeted agents, examine the evidence supporting the use of dual HER2 blockade in patients with HER2-amplified tumours, and explore the role of biomarkers in guiding future treatment strategies. We also discuss potential implications for the future treatment of patients with HER2+ breast cancer.
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Affiliation(s)
- Adrienne G Waks
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Olga Martínez-Sáez
- Cancer Institute, Hospital Clinic of Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Department of Medicine, University of Barcelona, Barcelona, Spain
| | - Paolo Tarantino
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, USA
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Fara Braso-Maristany
- Cancer Institute, Hospital Clinic of Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Tomás Pascual
- Cancer Institute, Hospital Clinic of Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Department of Medicine, University of Barcelona, Barcelona, Spain
- SOLTI Cancer Research Group, Barcelona, Spain
| | - Javier Cortés
- International Breast Cancer Center (IBCC), Pangaea Oncology, Quironsalud Group, Barcelona, Spain
- IOB Madrid, Hospital Beata Maria Ana, Madrid, Spain
- Universidad Europea de Madrid, Faculty of Biomedical and Health Sciences, Department of Medicine, Madrid, Spain
| | - Sara M Tolaney
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Aleix Prat
- Cancer Institute, Hospital Clinic of Barcelona, Barcelona, Spain.
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
- Department of Medicine, University of Barcelona, Barcelona, Spain.
- Breast Cancer Unit, IOB-QuirónSalud, Barcelona, Spain.
- Reveal Genomics, Barcelona, Spain.
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Ran R, Zhao S, Zhou Y, Hang X, Wang H, Fan Y, Zhang Y, Qiao Y, Yang J, Dong D. Clinicopathological characteristics, treatment patterns and outcomes in patients with HER2-positive breast cancer based on hormone receptor status: a retrospective study. BMC Cancer 2024; 24:1216. [PMID: 39350043 PMCID: PMC11443648 DOI: 10.1186/s12885-024-12974-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 09/23/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Different hormone receptor (HR) expression patterns have significant biological and therapeutic implications in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, the distinction between HR-positive /HER2-positive (HR+/HER2+) and HR-negative/HER2-positive (HR-/HER2+) subtypes remains unclear. METHODS This retrospective study analyzed 828 patients with HER2-positive breast cancer at the First Affiliated Hospital of Xi'an Jiaotong University from 2012 to 2022. Baseline characteristics were compared by chi-square test. Survival outcomes were estimated by Kaplan-Meier method. RESULTS In total, 56.3% (n = 466) had HR-positive and 43.7% (n = 362) had HR-negative disease. Comparatively, HR+/HER2 + breast cancers presented favorable clinicopathological features. At a median follow-up of 49 months, 199 disease-free survival (DFS) events and 99 deaths were observed. HR+/HER2 + patients had significantly better survival outcomes than HR-/HER2 + patients. HR-positive status was an independent protective factor for overall survival (OS) [P = 0.032; hazard ratio, 0.61; 95% confidence interval (CI), 0.39-0.96] and DFS (P = 0.001; hazard ratio, 0.61; 95% CI, 0.46-0.81). HR+/HER2 + patients were significantly less sensitive to neoadjuvant therapy than HR-/HER2 + patients. In the first-line treatment for HR+/HER2 + advanced breast cancer, receiving endocrine therapy significantly improved advanced-OS (P < 0.001; hazard ratio, 0.33; 95% CI, 0.18-0.59) and progression-free survival (PFS) (P < 0.001; hazard ratio, 0.38; 95% CI, 0.25-0.58) compared with not receiving endocrine therapy. Moreover, maintenance endocrine therapy after HER2-targeted therapy and chemotherapy is associated with significant advanced-OS and PFS benefits compared with no maintenance endocrine therapy (advanced-OS: P < 0.001; hazard ratio, 0.05; 95% CI, 0.03-0.12; PFS: P < 0.001; hazard ratio, 0.35; 95% CI, 0.21-0.57). CONCLUSIONS This study reveals the high heterogeneity of HER2-positive breast cancer related to HR status in clinicopathological features, metastasis patterns, and outcomes. Large randomized controlled trials are warranted to optimize treatment strategies for the HER2-positive breast cancer population.
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Affiliation(s)
- Ran Ran
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shidi Zhao
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yan Zhou
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xinyue Hang
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Hui Wang
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yuan Fan
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yusi Zhang
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yifan Qiao
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jin Yang
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Danfeng Dong
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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Cipolla C, Gebbia V, D’Agati E, Greco M, Mesi C, Scandurra G, Valerio MR. Comprehensive Axillary Management of Clinically Node-Positive (cN+) Breast Cancer Patients: A Narrative Review on Neoadjuvant Chemotherapy. Cancers (Basel) 2024; 16:3354. [PMID: 39409973 PMCID: PMC11482584 DOI: 10.3390/cancers16193354] [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: 08/27/2024] [Revised: 09/23/2024] [Accepted: 09/27/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND In breast cancer (BC) patients, axillary management has undergone major improvements over the last few years, and efforts to identify the optimal strategy for the management of axillary surgery are still ongoing. METHODS In current clinical practice, women with clinically node-positive (cN+) BC usually receive neoadjuvant chemotherapy (NACT) with the aim of reducing the extent of primary disease and, thus, allowing for axillary-conservative surgery. Remarkably, after NACT, up to one out of three patients achieves an axillary pathologic complete response, which, in turn, is associated with a more favorable prognosis than residual axillary disease. However, NACT is not without drawbacks, as NACT-associated inflammation can damage lymphatic vessels. Furthermore, varying degrees of response may occur in the axillary lymph nodes, increasing the false negative rate for sentinel biopsy. RESULTS At present, there is no consensus on the optimal approach in patients with cN+ BC undergoing NACT, although multidisciplinary management seems to be recommended. CONCLUSIONS This narrative review provides a comprehensive overview of axillary management in cN+ BC patients undergoing NACT. It uses a multidisciplinary approach that encompasses the oncological management perspectives, as well as surgical and chemotherapeutic viewpoints.
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Affiliation(s)
- Calogero Cipolla
- Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), University of Palermo, 90100 Palermo, Italy; (C.C.); (E.D.); (M.G.); (C.M.); (M.R.V.)
- Breast Unit, AOUP Policlinico Paolo Giaccone, 90100 Palermo, Italy
| | - Vittorio Gebbia
- Department of Medicine and Surgery, Kore University of Enna, 94100 Enna, Italy;
- Medical Oncology Unit, Cdc Torina, 90100 Palermo, Italy
| | - Eleonora D’Agati
- Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), University of Palermo, 90100 Palermo, Italy; (C.C.); (E.D.); (M.G.); (C.M.); (M.R.V.)
- Medical Oncology Unit, AOUP Policlinico Paolo Giaccone, 90100 Palermo, Italy
| | - Martina Greco
- Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), University of Palermo, 90100 Palermo, Italy; (C.C.); (E.D.); (M.G.); (C.M.); (M.R.V.)
- Medical Oncology Unit, AOUP Policlinico Paolo Giaccone, 90100 Palermo, Italy
| | - Chiara Mesi
- Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), University of Palermo, 90100 Palermo, Italy; (C.C.); (E.D.); (M.G.); (C.M.); (M.R.V.)
- Medical Oncology Unit, AOUP Policlinico Paolo Giaccone, 90100 Palermo, Italy
| | - Giuseppa Scandurra
- Department of Medicine and Surgery, Kore University of Enna, 94100 Enna, Italy;
- Medical Oncology Unit, Ospedale Cannizzaro, 95126 Catania, Italy
| | - Maria Rosaria Valerio
- Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), University of Palermo, 90100 Palermo, Italy; (C.C.); (E.D.); (M.G.); (C.M.); (M.R.V.)
- Medical Oncology Unit, AOUP Policlinico Paolo Giaccone, 90100 Palermo, Italy
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7
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Dieci MV, Guarneri V. Gaining ground in personalized breast cancer therapy: lesson learned from PHERGain. Nat Rev Clin Oncol 2024; 21:643-644. [PMID: 38778084 DOI: 10.1038/s41571-024-00907-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Affiliation(s)
- Maria Vittoria Dieci
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | - Valentina Guarneri
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
- Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy.
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Huo S, Xue J, Wang S, Shan H, Chen G, Niu N, Wang Y, Qiu F, Zhao Y, Xing F, Zheng X, Tu W, Li K, Zhao H, Tang M, Xu Q, Liu C, Zhao Y, Jiang X, Pang Z, Zhang K, Zhang D, Chen Z, Liu C. A pilot trial of neoadjuvant pyrotinib plus trastuzumab, dalpiciclib, and letrozole for triple-positive breast cancer. MedComm (Beijing) 2024; 5:e505. [PMID: 38469548 PMCID: PMC10925486 DOI: 10.1002/mco2.505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 01/11/2024] [Accepted: 01/16/2024] [Indexed: 03/13/2024] Open
Abstract
Triple-positive breast cancer (TPBC) poorly responds to current standard neoadjuvant therapy (trastuzumab plus pertuzumab and chemotherapy). Our previous MUKDEN 01 study showed a promising total pathological complete response (tpCR) rate of 30.4% with neoadjuvant pyrotinib (pan-human epidermal growth factor receptor tyrosine kinase inhibitor) plus dalpiciclib (cyclin-dependent kinase 4/6 inhibitor) and letrozole, but the efficacy remains suboptimal. This pilot study (NCT05228951) explored adding trastuzumab to this triplet neoadjuvant regimen in patients with stage II-III TPBC. The primary endpoint was tpCR (ypT0/is, ypN0) rate. Between February 2022 and June 2022, 12 patients were enrolled, and seven (58%; 95% confidence interval [CI], 27.7%-84.8%) patients achieved tpCR. The rate of residual cancer burden (RCB) 0-I was 75% (95% CI, 46.8%-91.1%). The objective response rate (ORR) was 92% (95% CI, 64.6%-98.5%). Mean Ki-67 level was significantly reduced from 45.0% (95% CI, 19.5%-70.5%) at baseline to 17.2% (95% CI, 0.7%-33.7%) after neoadjuvant therapy (p = 0.03). The most common grade 3 adverse events were diarrhea (four [33%]) and decreased neutrophil count (three [25%]). No grade 4 adverse events or treatment-related deaths occurred. This four-drug neoadjuvant regimen shows promising pathological response with an acceptable safety profile in patients with TPBC. A randomized controlled trial (NCT05638594) of this regimen is being conducted.
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López-Velazco JI, Manzano S, Otaño M, Elorriaga K, Bultó N, Herrero J, Lahuerta A, Segur V, Álvarez-López I, Caffarel MM, Urruticoechea A. A prospective study on tumour response assessment methods after neoadjuvant endocrine therapy in early oestrogen receptor-positive breast cancer. Breast Cancer Res 2024; 26:3. [PMID: 38173005 PMCID: PMC10765775 DOI: 10.1186/s13058-023-01756-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 12/18/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Neoadjuvant endocrine therapy (NET) in oestrogen receptor-positive (ER+) /HER2-negative (HER2-) breast cancer allows real-time evaluation of drug efficacy as well as investigation of the biological and molecular changes that occur after estrogenic deprivation. Clinical and pathological evaluation after NET may be used to obtain prognostic and predictive information of tumour response to decide adjuvant treatment. In this setting, clinical scales developed to evaluate response after neoadjuvant chemotherapy are not useful and there are not validated biomarkers to assess response to NET beyond Ki67 levels and preoperative endocrine prognostic index score (mPEPI). METHODS In this prospective study, we extensively analysed radiological (by ultrasound scan (USS) and magnetic resonance imaging (MRI)) and pathological tumour response of 104 postmenopausal patients with ER+ /HER2- resectable breast cancer, treated with NET for a mean of 7 months prior to surgery. We defined a new score, tumour cellularity size (TCS), calculated as the product of the residual tumour cellularity in the surgical specimen and the tumour pathological size. RESULTS Our results show that radiological evaluation of response to NET by both USS and MRI underestimates pathological tumour size (path-TS). Tumour size [mean (range); mm] was: path-TS 20 (0-80); radiological-TS by USS 9 (0-31); by MRI: 12 (0-60). Nevertheless, they support the use of MRI over USS to clinically assess radiological tumour response (rad-TR) due to the statistically significant association of rad-TR by MRI, but not USS, with Ki67 decrease (p = 0.002 and p = 0.3, respectively) and mPEPI score (p = 0.002 and p = 0.6, respectively). In addition, we propose that TCS could become a new tool to standardize response assessment to NET given its simplicity, reproducibility and its good correlation with existing biomarkers (such as ΔKi67, p = 0.001) and potential added value. CONCLUSION Our findings shed light on the dynamics of tumour response to NET, challenge the paradigm of the ability of NET to decrease surgical volume and point to the utility of the TCS to quantify the scattered tumour response usually produced by endocrine therapy. In the future, these results should be validated in independent cohorts with associated survival data.
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Affiliation(s)
- Joanna I López-Velazco
- Biogipuzkoa (Previously Known As Biodonostia) Health Research Institute, Paseo Dr Begiristain S/N, 20014, San Sebastian, Spain
| | - Sara Manzano
- Biogipuzkoa (Previously Known As Biodonostia) Health Research Institute, Paseo Dr Begiristain S/N, 20014, San Sebastian, Spain
| | - María Otaño
- Gipuzkoa Cancer Unit, OSI Donostialdea - Onkologikoa Foundation, Paseo Dr Begiristain 121, 20014, San Sebastian, Spain
| | - Kepa Elorriaga
- Gipuzkoa Cancer Unit, OSI Donostialdea - Onkologikoa Foundation, Paseo Dr Begiristain 121, 20014, San Sebastian, Spain
| | - Núria Bultó
- Gipuzkoa Cancer Unit, OSI Donostialdea - Onkologikoa Foundation, Paseo Dr Begiristain 121, 20014, San Sebastian, Spain
| | - Julio Herrero
- Gipuzkoa Cancer Unit, OSI Donostialdea - Onkologikoa Foundation, Paseo Dr Begiristain 121, 20014, San Sebastian, Spain
| | - Ainhara Lahuerta
- Biogipuzkoa (Previously Known As Biodonostia) Health Research Institute, Paseo Dr Begiristain S/N, 20014, San Sebastian, Spain
- Gipuzkoa Cancer Unit, OSI Donostialdea - Onkologikoa Foundation, Paseo Dr Begiristain 121, 20014, San Sebastian, Spain
| | - Virginia Segur
- Gipuzkoa Cancer Unit, OSI Donostialdea - Onkologikoa Foundation, Paseo Dr Begiristain 121, 20014, San Sebastian, Spain
| | - Isabel Álvarez-López
- Biogipuzkoa (Previously Known As Biodonostia) Health Research Institute, Paseo Dr Begiristain S/N, 20014, San Sebastian, Spain
- Gipuzkoa Cancer Unit, OSI Donostialdea - Onkologikoa Foundation, Paseo Dr Begiristain 121, 20014, San Sebastian, Spain
| | - Maria M Caffarel
- Biogipuzkoa (Previously Known As Biodonostia) Health Research Institute, Paseo Dr Begiristain S/N, 20014, San Sebastian, Spain.
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
| | - Ander Urruticoechea
- Biogipuzkoa (Previously Known As Biodonostia) Health Research Institute, Paseo Dr Begiristain S/N, 20014, San Sebastian, Spain.
- Gipuzkoa Cancer Unit, OSI Donostialdea - Onkologikoa Foundation, Paseo Dr Begiristain 121, 20014, San Sebastian, Spain.
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10
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Yang J, Cheng Y, Nie Y, Tian B, Huang J, Gong R, Li Z, Zhu J, Gong Y. TRPC5 expression promotes the proliferation and invasion of papillary thyroid carcinoma through the HIF-1α/Twist pathway. Transl Oncol 2024; 39:101809. [PMID: 37918167 PMCID: PMC10638037 DOI: 10.1016/j.tranon.2023.101809] [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: 07/14/2023] [Revised: 09/30/2023] [Accepted: 10/15/2023] [Indexed: 11/04/2023] Open
Abstract
OBJECTIVE This study aimed to investigate the effect of TRPC5 on PTC (papillary thyroid carcinoma) proliferation and invasion. METHODS Immunofluorescence and western blot were used to evaluate the expression of TRPC5 in paraffin sections and clinical tissues. Overexpression and silencing of TRPC5 to generate the cells for in vitro experiments. Wound-healing assay, transwell invasion assay, MTT assay, and in vivo tumorigenicity assay were used to determine cell proliferation and cell migration in vitro and in vivo. Real-time PCR was used to test the expression of TRPC5. Western blot was used to test the expression of downstream factors: E-cadherin, Vimentin, MMP-9, MMP-2, TRPC5, ZEB, Snail, and Twist. RESULTS The level of TRPC5 protein expression was higher in PTC than in adjacent normal thyroid tissue. TPC-1 cells overexpressing TRPC5 were more proliferative, had longer migration distances, and increased the number of invading cells. TPC-1 cells silenced with TRPC5 had a weaker proliferation capacity, shorter migration distances, and a reduced number of invading cells. Overexpression and silencing of TRPC5 modulated E-cadherin, Vimentin, MMP-9, MMP-2, TRPC5, and Twist, but did not affect ZEB and Snail. The results of tumor formation experiments in nude mice showed that inhibition of TRPC5 expression suppressed the volume and weight of transplanted tumors. CONCLUSION TRPC5 induced papillary thyroid cancer metastasis and progression via up-regulated HIF-1α signaling in vivo and in vitro. High TRPC5 expression is a biomarker for lymph node metastasis at its early stages.
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Affiliation(s)
- Jing Yang
- Department of Thyroid Surgery, West China Hospital, Sichuan University, China; Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yue Cheng
- Department of Otorhinolaryngology-Head and Neck Surgery, Sichuan Electric Power Hospital, China
| | - Yan Nie
- West China School of Medicine, Sichuan University, China
| | - Bole Tian
- Department of pancreatic Surgery, West China Hospital, Sichuan University, China
| | - Jing Huang
- Department of Thyroid Surgery, West China Hospital, Sichuan University, China; Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Rixiang Gong
- Department of Thyroid Surgery, West China Hospital, Sichuan University, China; Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Zhihui Li
- Department of Thyroid Surgery, West China Hospital, Sichuan University, China; Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jingqiang Zhu
- Department of Thyroid Surgery, West China Hospital, Sichuan University, China; Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yanping Gong
- Department of Thyroid Surgery, West China Hospital, Sichuan University, China; Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
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11
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Graeser M, Gluz O. HER2+ Early Breast Cancer: From Escalation via Targeted and Post-Neoadjuvant Treatment to De-Escalation. Breast Care (Basel) 2023; 18:455-463. [PMID: 38125917 PMCID: PMC10730100 DOI: 10.1159/000534670] [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: 09/01/2023] [Accepted: 10/17/2023] [Indexed: 12/23/2023] Open
Abstract
Background Human epidermal growth factor receptor 2 positive (HER2+, also referred to as ERBB2+) breast cancer is a subtype, historically associated with a particularly poor prognosis. Research into biological and molecular pathomechanisms of breast cancer has resulted in the development and adoption of several therapies targeting HER2. In parallel, various escalation/de-escalation strategies have been examined to further optimize patient outcomes and care. Summary In this review, we highlighted the landmark trials in the evolution of treatment and management of HER2+ early breast cancer (eBC). Key Messages Continuous research over the last two decades has gradually prolonged survival in patients with early HER2+ eBC. Incorporation of post-neoadjuvant setting into clinical practice improved long-term outcomes in high-risk patients with residual disease after neoadjuvant therapy. In parallel, use of modern anti-HER2 agents may potentially allow omission of chemotherapy without compromising the survival in a significant number of selected patients. Current research focused on exploring the molecular heterogeneity of HER2+ breast cancer resulted in identification of new prognostic and predictive biomarkers which could pave the way toward the development of truly personalized therapy.
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Affiliation(s)
- Monika Graeser
- West German Study Group, Moenchengladbach, Germany
- Breast Center Niederrhein, Ev. Hospital Bethesda, Moenchengladbach, Germany
- Department of Gynecology, University Medical Center Hamburg, Hamburg, Germany
| | - Oleg Gluz
- West German Study Group, Moenchengladbach, Germany
- Breast Center Niederrhein, Ev. Hospital Bethesda, Moenchengladbach, Germany
- University Clinics Cologne, Cologne, Germany
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12
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Huober J, Weder P, Ribi K, Thürlimann B, Thery JC, Li Q, Vanlemmens L, Guiu S, Brain E, Grenier J, Dalenc F, Levy C, Savoye AM, Müller A, Membrez-Antonioli V, Gérard MA, Lemonnier J, Hawle H, Dietrich D, Boven E, Bonnefoi H. Pertuzumab Plus Trastuzumab With or Without Chemotherapy Followed by Emtansine in ERBB2-Positive Metastatic Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol 2023; 9:1381-1389. [PMID: 37561451 PMCID: PMC10416088 DOI: 10.1001/jamaoncol.2023.2909] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 05/09/2023] [Indexed: 08/11/2023]
Abstract
Importance In ERBB2 (formerly HER2)-positive metastatic breast cancer (MBC), combining trastuzumab and pertuzumab with taxane-based chemotherapy is the first line of standard care. Given that trastuzumab plus pertuzumab was proven effective in ERBB2-positive MBC, even without chemotherapy, whether the optimal first-line strategy could be trastuzumab plus pertuzumab alone instead of with chemotherapy is unresolved. Objective To assess overall survival (OS) at 2 years and progression-free survival (PFS) for patients randomly assigned to receive first-line pertuzumab plus trastuzumab alone or with chemotherapy followed by trastuzumab and emtansine at progression; PFS of second-line trastuzumab and emtansine treatment following trastuzumab plus pertuzumab; and OS and PFS in the ERBB2-enriched and ERBB2-nonenriched subtypes. Design, Setting, and Participants This was a secondary analysis of a multicenter, open-label, phase 2 randomized clinical trial conducted at 27 sites in France, 20 sites in Switzerland, 9 sites in the Netherlands, and 1 site in Germany. Overall, 210 patients with centrally confirmed ERBB2-positive MBC were randomized between May 3, 2013, and January 4, 2016, with termination of the trial May 26, 2020. Data were analyzed from December 18, 2020, to May 10, 2022. Interventions Patients randomly received pertuzumab (840 mg intravenously [IV], then 420 mg IV every 3 weeks) plus trastuzumab (8 mg/kg IV, then 6 mg/kg IV every 3 weeks) without chemotherapy (group A) or pertuzumab plus trastuzumab (same doses) with either paclitaxel (90 mg/m2 for days 1, 8, and 15, then every 4 weeks for ≥4 months) or vinorelbine tartrate (25 mg/m2 for first administration followed by 30 mg/m2 on days 1 and 8 and every 3 weeks for ≥4 months) followed by pertuzumab plus trastuzumab maintenance after chemotherapy discontinuation (group B). Main Outcomes and Measures Overall survival at 24 months by treatment group, PFS for first-line treatment, PFS for second-line treatment, and patient-reported quality of life (QOL). Results A total of 210 patients were included in the analysis, with a median age of 58 (range, 26-85) years. For group A, 24-month OS was 79.0% (90% CI, 71.4%-85.4%); for group B, 78.1% (90% CI, 70.4%-84.5%). Median PFS with first-line treatment was 8.4 (95% CI, 7.9-12.0) months in group A and 23.3 (95% CI, 18.9-33.1) months in group B. Unlike expectations, OS and PFS did not markedly differ between populations with ERBB2-enriched and ERBB2-nonenriched cancer. Adverse events were less common without chemotherapy, with small QOL improvements from baseline in group A and stable QOL in group B. Conclusions and Relevance The findings of this secondary analysis of a randomized clinical trial suggest that the chemotherapy-free anti-ERBB2 strategy is feasible without being detrimental in terms of OS. The 50-gene prediction analysis of microarray signature could not help to identify the most appropriate patient population for this approach. Trial Registration ClinicalTrials.gov Identifier: NCT01835236.
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Affiliation(s)
- Jens Huober
- Breast Center St Gallen, Cantonal Hospital St Gallen, St Gallen, Switzerland
- Swiss Group for Clinical Cancer Research Coordinating Center, Bern, Switzerland
| | - Patrik Weder
- Breast Center St Gallen, Cantonal Hospital St Gallen, St Gallen, Switzerland
- Swiss Group for Clinical Cancer Research Coordinating Center, Bern, Switzerland
| | - Karin Ribi
- Quality of Life Office, International Breast Cancer Study Group, Bern, Switzerland
| | - Beat Thürlimann
- Breast Center St Gallen, Cantonal Hospital St Gallen, St Gallen, Switzerland
| | | | - Qiyu Li
- Swiss Group for Clinical Cancer Research Coordinating Center, Bern, Switzerland
| | | | - Séverine Guiu
- Department of Medical Oncology, Regional Cancer Institute, Montpellier, France
| | - Etienne Brain
- Department of Medical Oncology, Institute Curie, Paris & Saint-Cloud, France
| | - Julien Grenier
- Department of Medical Oncology, Institute Sainte Catherine, Avignon, France
| | - Florence Dalenc
- Department of Medical Oncology, Institute Claudius Regaud–Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
| | - Christelle Levy
- Department of Medical Oncology, Center Francois Baclesse, Caen, France
| | - Aude-Marie Savoye
- Department of Medical Oncology, Institute Jean Godinot, Reims, France
| | - Andreas Müller
- Breast Center, Cantonal Hospital of Winterthur, Winterthur, Switzerland
| | | | - Marie-Aline Gérard
- Swiss Group for Clinical Cancer Research Coordinating Center, Bern, Switzerland
| | | | - Hanne Hawle
- Swiss Group for Clinical Cancer Research Coordinating Center, Bern, Switzerland
| | - Daniel Dietrich
- Swiss Group for Clinical Cancer Research Coordinating Center, Bern, Switzerland
| | - Epie Boven
- Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam/Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Hervé Bonnefoi
- Department of Medical Oncology, Institut Bergonié Unicancer, Universitaire Bordeaux, Institut National de la Santé et de la Recherche Médicale U1218, Bordeaux, France
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13
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Gluz O, Nitz UA, Christgen M, Kuemmel S, Holtschmidt J, Schumacher J, Hartkopf A, Potenberg J, Lüedtke-Heckenkamp K, Just M, Schem C, von Schumann R, Kolberg-Liedtke C, Eulenburg CZ, Schinköthe T, Graeser M, Wuerstlein R, Kates RE, Kreipe HH, Harbeck N. Efficacy of Endocrine Therapy Plus Trastuzumab and Pertuzumab vs De-escalated Chemotherapy in Patients with Hormone Receptor-Positive/ERBB2-Positive Early Breast Cancer: The Neoadjuvant WSG-TP-II Randomized Clinical Trial. JAMA Oncol 2023; 9:946-954. [PMID: 37166817 PMCID: PMC10176180 DOI: 10.1001/jamaoncol.2023.0646] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 01/27/2023] [Indexed: 05/12/2023]
Abstract
Importance Combination of chemotherapy with (dual) ERBB2 blockade is considered standard in hormone receptor (HR)-positive/ERBB2-positive early breast cancer (EBC). Despite some promising data on endocrine therapy (ET) combination with dual ERBB2 blockade in HR-positive/ERBB2-positive BC, to our knowledge, no prospective comparison of neoadjuvant chemotherapy vs ET plus ERBB2 blockade in particular with focus on molecular markers has yet been performed. Objective To determine whether neoadjuvant de-escalated chemotherapy is superior to endocrine therapy, both in combination with pertuzumab and trastuzumab, in a highly heterogeneous HR-positive/ERBB2-positive EBC. Design, Setting, and Participants This prospective, multicenter, neoadjuvant randomized clinical trial allocated 207 patients with centrally confirmed estrogen receptor-positive and/or progesterone receptor-positive (>1%) HR-positive/ERBB2-positive EBC to 12 weeks of standard ET (n = 100) vs paclitaxel (n = 107) plus trastuzumab and pertuzumab. A total of 186 patients were required to detect a statistically significant difference in pathological complete response (pCR) (assumptions: 19% absolute difference in pCR; power, ≥80%; 1-sided Fisher exact test, 2.5% significance level). Interventions Standard ET (aromatase inhibitor or tamoxifen) or paclitaxel, 80 mg/m2, weekly plus trastuzumab and pertuzumab every 21 days. Main Outcomes and Measures The primary end point was pCR (ypT0/is, ypN0). Secondary end points included safety, translational research, and health-related quality of life. Omission of further chemotherapy was allowed in patients with pCR. PAM50 analysis was performed on baseline tumor biopsies. Results Of the 207 patients included (median [range] age, 53 [25-83] years), 121 (58%) had cT2 to cT4 tumors, and 58 (28%) had clinically node-positive EBC. The pCR rate in the ET plus trastuzumab and pertuzumab arm was 23.7% (95% CI, 15.7%-33.4%) vs 56.4% (95% CI, 46.2%-66.3%) in the paclitaxel plus trastuzumab and pertuzumab arm (odds ratio, 0.24; 95% CI, 0.12-0.46; P < .001). Both immunohistochemical ERBB2 score of 3 or higher and ERBB2-enriched subtype were independent predictors for pCR in both arms. Paclitaxel was superior to ET only in the first through third quartiles but not in the highest ERBB2 quartile by messenger RNA. In contrast with the paclitaxel plus trastuzumab and pertuzumab arm, no decrease in health-related quality of life after 12 weeks was observed in the ET plus trastuzumab and pertuzumab arm. Conclusions and Relevance The WSG-TP-II randomized clinical trial is, to our knowledge, the first prospective trial comparing 2 neoadjuvant de-escalation treatments in HR-positive/ERBB2-positive EBC and demonstrated an excellent pCR rate after 12 weeks of paclitaxel plus trastuzumab and pertuzumab that was clearly superior to the pCR rate after ET plus trastuzumab and pertuzumab. Trial Registration ClinicalTrials.gov Identifier: NCT03272477.
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Affiliation(s)
- Oleg Gluz
- West German Study Group, Mönchengladbach, Germany
- Breast Center Niederrhein, Ev. Hospital Bethesda, Mönchengladbach, Germany
- University Clinics Cologne, Cologne, Germany
| | - Ulrike A. Nitz
- West German Study Group, Mönchengladbach, Germany
- Breast Center Niederrhein, Ev. Hospital Bethesda, Mönchengladbach, Germany
| | | | - Sherko Kuemmel
- West German Study Group, Mönchengladbach, Germany
- Breast Unit, Kliniken Essen-Mitte, Essen, Germany
- Department of Gynecology with Breast Center, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Johannes Holtschmidt
- Breast Unit, Kliniken Essen-Mitte, Essen, Germany
- Breast Center, St Elisabeth-Krankenhaus Köln-Hohenlind, Cologne, Germany
| | | | - Andreas Hartkopf
- Department of Gynecology and Obstetrics, Tüebingen University Hospital, Tüebingen, Germany
| | | | | | | | | | | | - Cornelia Kolberg-Liedtke
- Department of Gynecology with Breast Center, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Women’s Clinic, University Clinics Essen, Essen, Germany
| | - Christine Zu Eulenburg
- West German Study Group, Mönchengladbach, Germany
- Department of Medical Biometry and Epidemiology, University Medical Center Hamburg, Hamburg, Germany
| | - Timo Schinköthe
- Breast Center, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Munich, Ludwig Maximilians University Hospital, Munich, Germany
- CANKADO Service GmbH, Kirchheim bei München, Germany
| | - Monika Graeser
- West German Study Group, Mönchengladbach, Germany
- Breast Center Niederrhein, Ev. Hospital Bethesda, Mönchengladbach, Germany
- Department of Gynecology, University Medical Center Hamburg, Hamburg, Germany
| | - Rachel Wuerstlein
- West German Study Group, Mönchengladbach, Germany
- Breast Center, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Munich, Ludwig Maximilians University Hospital, Munich, Germany
| | | | | | - Nadia Harbeck
- West German Study Group, Mönchengladbach, Germany
- Breast Center, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Munich, Ludwig Maximilians University Hospital, Munich, Germany
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Martínez-Sáez O, Waks AG. Individualizing Curative-Intent Therapy in HER2-Positive Early-Stage Breast Cancer. Curr Treat Options Oncol 2023; 24:479-495. [PMID: 36995527 DOI: 10.1007/s11864-023-01070-7] [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] [Accepted: 02/13/2023] [Indexed: 03/31/2023]
Abstract
OPINION STATEMENT Human epidermal growth factor receptor 2-positive (HER2+) breast cancers have been historically considered an aggressive entity with high rates of recurrence and poor survival. However, during the last 20 years, there has been a dramatic change in prognosis due to the incorporation of different anti-HER2 therapies into the neo/adjuvant chemotherapy backbone. Neoadjuvant dual blockade with trastuzumab and pertuzumab has become the standard of care for women with stage II and III HER2+ breast cancer. Trastuzumab emtansine (T-DM1) has been shown to improve outcomes if pathological complete response (pCR) is not achieved, and adjuvant extended therapy with neratinib has increased disease-free survival (DFS) and may have an impact in central nervous system (CNS) recurrences. However, these agents are both toxic for individual patients and costly for the overall healthcare system, and there are still patients that experience recurrence despite therapy improvements. At the same time, it has been shown that some patients with early-stage HER2+ breast cancer can be effectively treated with less intensive systemic therapy, using only taxane and trastuzumab, or that the chemotherapy backbone can be omitted completely. The current challenge is to properly identify which patients can receive a de-intensified regimen and which need new intensification strategies. Tumor size, nodal status, and pCR achievement after neoadjuvant treatment are well-known risk factors that can aid in making clinical decisions, but they do not accurately predict all patient outcomes. Various biomarkers have been proposed to better characterize the clinical and biological heterogeneity of HER2+ breast cancer. Immune infiltration, intrinsic subtype, intratumoral heterogeneity, and dynamic changes during treatment have been described as important prognostic and/or predictive features. The integration of all these factors will be key in the proper identification of the true risk, and individualized treatment strategy, for each patient.
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Affiliation(s)
- Olga Martínez-Sáez
- Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, USA
| | - Adrienne G Waks
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
- Division of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Yawkey 1250, Boston, MA, 02215, USA.
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Harbeck N, Nitz UA, Christgen M, Kümmel S, Braun M, Schumacher C, Potenberg J, Tio J, Aktas B, Forstbauer H, Grischke EM, Scheffen I, Malter W, von Schumann R, Just M, Zu Eulenburg C, Biehl C, Kolberg-Liedtke C, Deurloo R, de Haas S, Jóźwiak K, Hauptmann M, Kates R, Graeser M, Wuerstlein R, Kreipe HH, Gluz O. De-Escalated Neoadjuvant Trastuzumab-Emtansine With or Without Endocrine Therapy Versus Trastuzumab With Endocrine Therapy in HR+/HER2+ Early Breast Cancer: 5-Year Survival in the WSG-ADAPT-TP Trial. J Clin Oncol 2023:JCO2201816. [PMID: 36809046 DOI: 10.1200/jco.22.01816] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/23/2023] Open
Abstract
PURPOSE Neoadjuvant chemotherapy is standard of care in human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC), irrespective of the hormone receptor status. Trastuzumab-emtansine (T-DM1), antibody-drug conjugate, is highly effective in HER2+ EBC; however, no survival data are available for de-escalated antibody-drug conjugate-based neoadjuvant therapy without conventional chemotherapy. PATIENTS AND METHODS In the WSG-ADAPT-TP (ClinicalTrials.gov identifier: NCT01779206) phase II trial, 375 centrally reviewed patients with hormone receptor-positive (HR+)/HER2+ EBC (clinical stage I-III) were randomly assigned to 12 weeks of T-DM1 with or without endocrine therapy (ET) or trastuzumab + ET once every 3 weeks (ratio 1:1:1). Adjuvant chemotherapy (ACT) omission was allowed in patients with pathologic complete response (pCR). In this study, we report the secondary survival end points and biomarker analysis. Patients who received at least one dose of study treatment were analyzed. Survival was analyzed using the Kaplan-Meier method, two-sided log-rank statistics, and Cox regression models stratified for nodal and menopausal status. P values < .05 were considered statistically significant. RESULTS T-DM1, T-DM1 + ET, and trastuzumab + ET induced similar 5-year invasive disease-free survival (iDFS; 88.9%, 85.3%, 84.6%; Plog-rank = .608) and overall survival rates (97.2%, 96.4%, 96.3%; Plog-rank = .534). Patients with pCR versus non-pCR had improved 5-year iDFS rates (92.7% v 82.7%; hazard ratio, 0.40; 95% CI, 0.18 to 0.85). Among the 117 patients with pCR, 41 did not receive ACT; 5-year iDFS rates were similar in those with (93.0%; 95% CI, 84.0 to 97.0) and without ACT (92.1%; 95% CI, 77.5 to 97.4; Plog-rank = .848). Translational research revealed that tumors with PIK3CA wild type, high immune marker expression, and luminal-A tumors (by PAM50) had an excellent prognosis with de-escalated anti-HER2 therapy. CONCLUSION The WSG-ADAPT-TP trial demonstrated that pCR after 12 weeks of chemotherapy-free de-escalated neoadjuvant therapy was associated with excellent survival in HR+/HER2+ EBC without further ACT. Despite higher pCR rates for T-DM1 ± ET versus trastuzumab + ET, all trial arms had similar outcomes because of mandatory standard chemotherapy after non-pCR. WSG-ADAPT-TP demonstrated that such de-escalation trials in HER2+ EBC are feasible and safe for patients. Patient selection on the basis of biomarkers or molecular subtypes may increase the efficacy of systemic chemotherapy-free HER2-targeted approaches.
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Affiliation(s)
- Nadia Harbeck
- West German Study Group, Moenchengladbach, Germany.,Department of Gynecology and Obstetrics and CCCMunich, Breast Center, LMU University Hospital, Munich, Germany
| | - Ulrike A Nitz
- West German Study Group, Moenchengladbach, Germany.,Breast Center Niederrhein, Ev. Hospital Bethesda, Moenchengladbach, Germany
| | | | - Sherko Kümmel
- West German Study Group, Moenchengladbach, Germany.,Breast Unit, Kliniken Essen-Mitte, Essen, Germany.,Department of Gynecology with Breast Center, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Michael Braun
- Breast Center, Rotkreuz Clinics Munich, Munich, Germany
| | | | | | - Joke Tio
- Department of Gynecology, University Hospital Münster, Münster, Germany
| | - Bahriye Aktas
- Women's Clinic, University Clinics Essen, Essen, Germany.,University Clinics Leipzig, Women's Clinic, Leipzig, Germany
| | | | | | - Iris Scheffen
- West German Study Group, Moenchengladbach, Germany.,Breast Center Niederrhein, Ev. Hospital Bethesda, Moenchengladbach, Germany
| | - Wolfram Malter
- Department of Obstetrics and Gynecology, Breast Center, University Hospital, Cologne, Germany
| | | | | | - Christine Zu Eulenburg
- West German Study Group, Moenchengladbach, Germany.,Department of Medical Biometry and Epidemiology, University Medical Center Hamburg, Hamburg, Germany
| | - Claudia Biehl
- Westphalian Brest Center Dortmund, Dortmund, Germany
| | - Cornelia Kolberg-Liedtke
- Department of Gynecology with Breast Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.,Women's Clinic, University Clinics Essen, Essen, Germany
| | | | | | - Katarzyna Jóźwiak
- Institute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, Neuruppin, Germany
| | - Michael Hauptmann
- Institute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, Neuruppin, Germany
| | - Ronald Kates
- West German Study Group, Moenchengladbach, Germany
| | - Monika Graeser
- West German Study Group, Moenchengladbach, Germany.,Breast Center Niederrhein, Ev. Hospital Bethesda, Moenchengladbach, Germany.,Department of Gynecology, University Medical Center Hamburg, Hamburg, Germany
| | - Rachel Wuerstlein
- West German Study Group, Moenchengladbach, Germany.,Department of Gynecology and Obstetrics and CCCMunich, Breast Center, LMU University Hospital, Munich, Germany
| | - Hans H Kreipe
- Institute of Pathology, Medical School Hannover, Hannover, Germany
| | - Oleg Gluz
- West German Study Group, Moenchengladbach, Germany.,Breast Center Niederrhein, Ev. Hospital Bethesda, Moenchengladbach, Germany.,University Clinics Cologne, Cologne, Germany
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Conte B, Montemurro F, Levaggi A, Blondeaux E, Molinelli C, Cardinali B, Poggio F, Buzzatti G, Bighin C, Lambertini M, Del Mastro L. Anthracycline, taxane, and trastuzumab-based neoadjuvant chemotherapy in HER2-positive early breast cancer: phase II trial. TUMORI JOURNAL 2023; 109:71-78. [PMID: 34989265 DOI: 10.1177/03008916211067568] [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: 02/03/2023]
Abstract
OBJECTIVE Neoadjuvant chemotherapy has become the preferred treatment in HER2-positive early breast cancer. Several trials investigated the neoadjuvant efficacy of dual HER2 blockade with anthracycline-free chemotherapy, whereas few data are available on single-agent trastuzumab and anthracycline-based regimens, which represent the standard of care in the adjuvant setting. This phase II, single-arm trial assessed anthracycline-based chemotherapy and trastuzumab as neoadjuvant treatment for high-risk HER2-positive breast cancer. METHODS Forty-three patients with stage II-III HER2-positive breast cancer were treated with 4 courses of neoadjuvant 5-fluorouracil 600 mg/m2, epirubicin 90 mg/m2, cyclophosphamide 600 mg/m2 (FEC ×4) every 21 days, followed by 12 courses of weekly paclitaxel 80 mg/m2 and trastuzumab 2 mg/Kg IV (loading dose 4 mg/kg). RESULTS Pathologic complete response (pCR) was observed in 22 (51%) of 43 patients. After a median follow-up of 6 years, the 5-year disease-free survival and overall survival were 85.8% (95% confidence interval 75.9%-97%) and 89.6% (80.4%-99.8%), respectively. A temporary decrease in left ventricular ejection fraction was observed in two patients. No cardiac death or congestive heart failure occurred. One patient died due to febrile neutropenia. CONCLUSIONS FEC ×4 followed by paclitaxel and trastuzumab was associated with high pCR rates and favorable long-term outcomes. However, this regimen was associated with relevant hematologic toxicity.
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Affiliation(s)
- Benedetta Conte
- Department of Medical Oncology, Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Filippo Montemurro
- Multidisciplinary Outpatient Oncology Clinic, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Alessia Levaggi
- Department of Medical Oncology, Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Eva Blondeaux
- Department of Medical Oncology, Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Chiara Molinelli
- Department of Medical Oncology, Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Barbara Cardinali
- Department of Medical Oncology, Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Francesca Poggio
- Department of Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genova, U.O. Oncologia Medica 2, Genova, Italy
| | - Giulia Buzzatti
- Department of Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genova, U.O. Oncologia Medica 2, Genova, Italy
| | - Claudia Bighin
- Department of Medical Oncology, Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Matteo Lambertini
- Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genoa, Genoa, Italy.,Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Lucia Del Mastro
- Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genoa, Genoa, Italy.,Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
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17
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Lin ZM, Wang TT, Zhu JY, Xu YY, Chen F, Huang PT. A nomogram based on combining clinical features and contrast enhanced ultrasound is not able to identify Her-2 over-expressing cancer from other breast cancers. Front Oncol 2023; 13:1035645. [PMID: 36776315 PMCID: PMC9909531 DOI: 10.3389/fonc.2023.1035645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 01/02/2023] [Indexed: 01/27/2023] Open
Abstract
Objective The aim of this study was to evaluate whether a predictive model based on a contrast enhanced ultrasound (CEUS)-based nomogram and clinical features (Clin) could differentiate Her-2-overexpressing breast cancers from other breast cancers. Methods A total of 152 pathology-proven breast cancers including 55 Her-2-overexpressing cancers and 97 other cancers from two units that underwent preoperative CEUS examination, were included and divided into training (n = 102) and validation cohorts (n = 50). Multivariate regression analysis was utilized to identify independent indicators for developing predictive nomogram models. The area under the receiver operating characteristic (AUC) curve was also calculated to establish the diagnostic performance of different predictive models. The corresponding sensitivities and specificities of different models at the cutoff nomogram value were compared. Results In the training cohort, 7 clinical features (menstruation, larger tumor size, higher CA153 level, BMI, diastolic pressure, heart rate and outer upper quarter (OUQ)) + enlargement in CEUS with P < 0.2 according to the univariate analysis were submitted to the multivariate analysis. By incorporating clinical information and enlargement on the CEUS pattern, independently significant indicators for Her-2-overexpression were used for further predictive modeling as follows: Model I, nomogram model based on clinical features (Clin); Model II, nomogram model combining enlargement (Clin + Enlargement); Model III, nomogram model based on typical clinical features combining enlargement (MC + BMI + diastolic pressure (DP) + outer upper quarter (OUQ) + Enlargement). Model II achieved an AUC value of 0.776 at nomogram cutoff score value of 190, which was higher than that of the other models in the training cohort without significant differences (all P>0.05). In the test cohort, the diagnostic efficiency of predictive model was poor (all AUC<0.6). In addition, the sensitivity and specificity were not significantly different between Models I and II (all P>0.05), in either the training or the test cohort. In addition, Clin exhibited an AUC similar to that of model III (P=0.12). Moreover, model III exhibited a higher sensitivity (70.0%) than the other models with similar AUC and specificity, only in the test cohort. Conclusion The main finding of the study was that the predictive model based on a CEUS-based nomogram and clinical features could not differentiate Her-2-overexpressing breast cancers from other breast cancers.
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Affiliation(s)
- Zi-mei Lin
- Department of Ultrasound in Medicine, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Ting-ting Wang
- Department of Ultrasound in Medicine, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Jun-Yan Zhu
- Department of Ultrasound, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yong-yuan Xu
- Department of Ultrasound in Medicine, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Fen Chen
- Department of Ultrasound, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Pin-tong Huang
- Department of Ultrasound in Medicine, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China,*Correspondence: Pin-tong Huang,
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18
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Ran R, Ma Y, Wang H, Yang J, Yang J. Treatment strategies for hormone receptor-positive, human epidermal growth factor receptor 2-positive (HR+/HER2+) metastatic breast cancer: A review. Front Oncol 2022; 12:975463. [PMID: 36620573 PMCID: PMC9822772 DOI: 10.3389/fonc.2022.975463] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 11/11/2022] [Indexed: 12/25/2022] Open
Abstract
Hormone receptor-positive HER2-positive (HR+/HER2+) metastatic breast cancer (MBC) is a unique subtype of breast cancer. Most current guidelines recommend that combination regimens based on anti-HER2 therapy should be used as first-line treatment for HER2+ MBC, irrespective of HR status. Endocrine therapy can be applied as maintenance therapy for patients who are intolerant to chemotherapy or post-chemotherapy. Increasing evidence suggests that complex molecular crosstalk between HR and HER2 pathways may affect the sensitivity to both HER2-targeted and endocrine therapy in patients with HR+/HER2+ breast cancer. Recent research and clinical trials have revealed that a combination of endocrine therapy and anti-HER2 approaches without chemotherapy provides along-term disease control for some patients, but the challenge lies in how to accurately identify the subsets of patients who can benefit from such a de-chemotherapy treatment strategy. In this review, we aim to summarize the results of preclinical and clinical studies in HR+/HER2+ MBC and discuss the possibility of sparing chemotherapy in this subgroup of patients.
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Affiliation(s)
| | | | | | - Jin Yang
- *Correspondence: Jin Yang, ; Jiao Yang,
| | - Jiao Yang
- *Correspondence: Jin Yang, ; Jiao Yang,
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19
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Guarneri V, Brasó-Maristany F, Dieci MV, Griguolo G, Paré L, Marín-Aguilera M, Miglietta F, Bottosso M, Giorgi CA, Blasco P, Castillo O, Galván P, Vivancos A, Villagrasa P, Parker JS, Perou CM, Conte P, Prat A. HER2DX genomic test in HER2-positive/hormone receptor-positive breast cancer treated with neoadjuvant trastuzumab and pertuzumab: A correlative analysis from the PerELISA trial. EBioMedicine 2022; 85:104320. [PMCID: PMC9626543 DOI: 10.1016/j.ebiom.2022.104320] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/06/2022] [Accepted: 10/06/2022] [Indexed: 11/11/2022] Open
Abstract
Background HER2DX is a prognostic and predictive assay in early-stage HER2-positive breast cancer based on clinical features and the expression of 4 gene signatures (immune, proliferation, luminal differentiation and HER2 amplicon), including ERBB2 mRNA levels. Here, we evaluated the ability of HER2DX to predict efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HER2-positive/hormone receptor-positive breast cancer. Methods HER2DX was evaluated on pre-treatment tumour samples from the PerELISA phase II study focused on postmenopausal patients with operable HER2-positive/hormone receptor-positive breast cancer. Patients received 2-weeks of letrozole, and then underwent a re-biopsy for Ki67 evaluation. Patients with endocrine therapy sensitive disease (ESD) (i.e., >20.0% Ki67 relative reduction at week 2) continued letrozole and 5 cycles of trastuzumab and pertuzumab. Primary aim was to test the ability of HER2DX risk-score, HER2DX pCR score and HER2DX ERBB2 mRNA score (as continuous variables and group categories) to predict pathological complete response (pCR) in patients with ESD. Logistic regression and receiver–operator curve (ROC) analysis assessed associations of HER2DX scores with pCR and ESD. Findings HER2DX was evaluated in 55 patients (86.0%) enrolled in PerELISA and 40 patients (73.0%) had ESD. The pCR rate in patients with ESD was 22.5% (9/40). In this group, HER2DX pCR score and HER2DX ERBB2 mRNA score were significantly associated with pCR (p = 0.008 and p = 0.003, univariate logistic regression model; area under ROC [AUC] = 0.803 and 0.896). The pCR rate in low, medium, and high HER2DX pCR score groups was 7.7% (2/26), 46.2% (6/13) and 100.0% (1/1), respectively. The pCR rate in low, medium, and high HER2DX ERBB2 score groups was 0.0% (0/12), 7.7% (1/13) and 53.3% (8/15), respectively. HER2DX pCR score was also significantly associated with Ki-67 response following 2-weeks of letrozole (p = 0.002, univariate logistic regression model; AUC = 0.775). The rate of ESD in low, medium, and high HER2DX pCR score groups was 89.7% (26/29), 65.0% (13/20) and 16.7% (1/6), respectively. Interpretation HER2DX predicts response following neoadjuvant letrozole in combination with dual HER2 blockade with trastuzumab and pertuzumab in early-stage HER2-positive/hormone receptor-positive breast cancer. Funding This study received funding from Reveal Genomics.
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Affiliation(s)
- Valentina Guarneri
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Istituto Oncologico Veneto, IRCCS, Padova, Italy
| | - Fara Brasó-Maristany
- Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Maria Vittoria Dieci
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Istituto Oncologico Veneto, IRCCS, Padova, Italy
| | - Gaia Griguolo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Istituto Oncologico Veneto, IRCCS, Padova, Italy
| | | | | | - Federica Miglietta
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Istituto Oncologico Veneto, IRCCS, Padova, Italy
| | - Michele Bottosso
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Istituto Oncologico Veneto, IRCCS, Padova, Italy
| | - Carlo Alberto Giorgi
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Istituto Oncologico Veneto, IRCCS, Padova, Italy
| | - Paula Blasco
- Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Oleguer Castillo
- Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Patricia Galván
- Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Ana Vivancos
- Cancer Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | | | - Joel S. Parker
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA
| | - Charles M. Perou
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA
- Department of Genetics, University of North Carolina, Chapel Hill, USA
| | - PierFranco Conte
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Istituto Oncologico Veneto, IRCCS, Padova, Italy
| | - Aleix Prat
- Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Reveal Genomics, Barcelona, Spain
- Department of Medical Oncology, Hospital Clinic of Barcelona, Spain
- Department of Medicine, University of Barcelona, Barcelona, Spain
- Institute of Oncology (IOB)-Hospital Quirónsalud, Barcelona, Spain
- Corresponding author. Translational Genomic and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and Department of Medical Oncology, Hospital Clinic, Carrer de Villarroel, 170, 08036, Barcelona, Spain.
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20
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The role of HER2 alterations in clinicopathological and molecular characteristics of breast cancer and HER2-targeted therapies: a comprehensive review. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:210. [PMID: 36175719 DOI: 10.1007/s12032-022-01817-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 08/03/2022] [Indexed: 12/24/2022]
Abstract
Breast cancer (BC) is the most common malignancy in women and one of the leading causes of cancer mortality, despite significant treatment advancements over the last decades. Human epidermal growth factor receptor-2 (HER2) is a member of the ERBB family of receptor tyrosine kinases which have long been known to mediate cancer cell growth and invasion through constitutive activation of oncogenic downstream signaling, such as PI3K/Akt/mTOR and MAPK. Overexpression/amplification of HER2 in various tumors, especially BC, offers the possible therapeutic potential for target therapies. HER2-targeted therapies, either with a combination of chemotherapy or through multi-anti-HER2 therapies without chemotherapy, have significantly improved the prognosis of HER2-positive tumors. In recent years, novel anti-HER2 agents and combination therapies have garnered much attention, especially for heavily treated advanced or metastatic BCs. HER2-positive BC is biologically a heterogeneous group depending on HER2 activation mechanisms, hormone receptor status, genome variations, tumor heterogeneity, and treatment resistance, which affect the treatment benefit and patients' outcomes. This review will discuss HER2 alternations (gene amplification or receptor overexpression) in BC, their correlation with clinicopathological characteristics and molecular characteristics, and HER2-based therapies in tumors with HER2 overexpression/amplification.
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21
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Bergamino MA, López-Knowles E, Morani G, Tovey H, Kilburn L, Schuster EF, Alataki A, Hills M, Xiao H, Holcombe C, Skene A, Robertson JF, Smith IE, Bliss JM, Dowsett M, Cheang MCU. HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer. EBioMedicine 2022; 83:104205. [PMID: 35985932 PMCID: PMC9482930 DOI: 10.1016/j.ebiom.2022.104205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 07/22/2022] [Accepted: 07/22/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks' presurgical AI treatment in ER+/HER2+ BCs. METHODS All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14-5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse. FUNDING Cancer Research UK (CRUK/07/015).
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Affiliation(s)
- Milana A Bergamino
- Clinical Trials and Statistics Unit (ICR-CTSU)- Division of Clinical Studies, The Institute of Cancer Research, London, UK
| | - Elena López-Knowles
- Royal Marsden Hospital, London, UK; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Gabriele Morani
- Clinical Trials and Statistics Unit (ICR-CTSU)- Division of Clinical Studies, The Institute of Cancer Research, London, UK
| | - Holly Tovey
- Clinical Trials and Statistics Unit (ICR-CTSU)- Division of Clinical Studies, The Institute of Cancer Research, London, UK
| | - Lucy Kilburn
- Clinical Trials and Statistics Unit (ICR-CTSU)- Division of Clinical Studies, The Institute of Cancer Research, London, UK
| | - Eugene F Schuster
- Royal Marsden Hospital, London, UK; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Anastasia Alataki
- Royal Marsden Hospital, London, UK; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | | | - Hui Xiao
- Clinical Trials and Statistics Unit (ICR-CTSU)- Division of Clinical Studies, The Institute of Cancer Research, London, UK; Royal Marsden Hospital, London, UK
| | - Chris Holcombe
- Liverpool University Hospitals Foundation Trust, Liverpool, UK
| | | | - John F Robertson
- Faculty of Medicine & Health Sciences, Queen's Medical Centre, Nottingham, UK
| | | | - Judith M Bliss
- Clinical Trials and Statistics Unit (ICR-CTSU)- Division of Clinical Studies, The Institute of Cancer Research, London, UK
| | | | - Maggie C U Cheang
- Clinical Trials and Statistics Unit (ICR-CTSU)- Division of Clinical Studies, The Institute of Cancer Research, London, UK.
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22
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Zhang Z, Gu W, Hu M, Zhang G, Yu F, Xu J, Deng J, Xu L, Mei J, Wang C, Qiu F. Based on clinical Ki-67 expression and serum infiltrating lymphocytes related nomogram for predicting the diagnosis of glioma-grading. Front Oncol 2022; 12:696037. [PMID: 36147928 PMCID: PMC9488114 DOI: 10.3389/fonc.2022.696037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 07/12/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundCompelling evidence indicates that elevated peripheral serum lymphocytes are associated with a favorable prognosis in various cancers. However, the association between serum lymphocytes and glioma is contradictory. In this study, a nomogram was established to predict the diagnosis of glioma-grading through Ki-67 expression and serum lymphocytes.MethodsWe performed a retrospective analysis of 239 patients diagnosed with LGG and 178 patients with HGG. Immunohistochemistry was used to determine the Ki-67 expression. Following multivariate logistic regression analysis, a nomogram was established and used to identify the most related factors associated with HGG. The consistency index (C-index), decision curve analysis (DCA), and a calibration curve were used to validate the model.ResultsThe number of LGG patients with more IDH1/2 mutations and 1p19q co-deletion was greater than that of HGG patients. The multivariate logistic analysis identified Ki-67 expression, serum lymphocyte count, and serum albumin (ALU) as independent risk factors associated with HGG, and these factors were included in a nomogram in the training cohort. In the validation cohort, the nomogram demonstrated good calibration and high consistency (C-index = 0.794). The Spearman correlation analysis revealed a significant association between HGG and serum lymphocyte count (r = −0.238, P <0.001), ALU (r = −0.232, P <0.001), and Ki-67 expression (r = 0.457, P <0.001). Furthermore, the Ki-67 expression was negatively correlated with the serum lymphocyte count (r = −0.244, P <0.05). LGG patients had lower Ki-67 expression and higher serum lymphocytes compared with HGG patients, and a combination of these two variables was significantly higher in HGG patients.ConclusionThe constructed nomogram is capable of predicting the diagnosis of glioma-grade. A decrease in the level of serum lymphocyte count and increased Ki-67 expression in HGG patients indicate that their immunological function is diminished and the tumor is more aggressive.
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Affiliation(s)
- Zhi Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Weiguo Gu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Nanchang Key Laboratory of Tumor Gene Diagnosis and Innovative Treatment Research, Nanchang, China
| | - Mingbin Hu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Guohua Zhang
- Nanchang Key Laboratory of Tumor Gene Diagnosis and Innovative Treatment Research, Nanchang, China
| | - Feng Yu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Oncology, Gaoxin Branch of the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jinbiao Xu
- Department of Oncology, Gaoxin Branch of the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jianxiong Deng
- Department of Oncology, Gaoxin Branch of the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Linlin Xu
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Molecular Pathology Center, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jinhong Mei
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Molecular Pathology Center, The First Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Feng Qiu, ; Jinhong Mei, ; Chunliang Wang,
| | - Chunliang Wang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Feng Qiu, ; Jinhong Mei, ; Chunliang Wang,
| | - Feng Qiu
- Nanchang Key Laboratory of Tumor Gene Diagnosis and Innovative Treatment Research, Nanchang, China
- Department of Oncology, Gaoxin Branch of the First Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Feng Qiu, ; Jinhong Mei, ; Chunliang Wang,
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Chen P, Mao X, Ma N, Wang C, Yao G, Ye G, Zhou D. Dynamic changes in intrinsic subtype, immunity status, and risk score before and after neoadjuvant chemo- and HER2-targeted therapy without pCR in HER2-positive breast cancers: A cross-sectional analysis. Medicine (Baltimore) 2022; 101:e29877. [PMID: 35945759 PMCID: PMC9351872 DOI: 10.1097/md.0000000000029877] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Very few studies have been done in HER2 positive patients without complete pathological response (pCR) after combined neoadjuvant chemo- and HER2-target therapy to investigate changes in intrinsic subtype, risk of recurrence (ROR) score, and immunity status before and after treatment. Patients with nonmetastatic HER2-positive breast cancer failed to achieve pCR after neoadjuvant chemotherapy plus trastuzumab were included in current study. We examined the distribution of PAM50 subtypes, ROR score and immunity score in 25 paired baseline and surgical samples. The Miller-Payne grading system was used to evaluate the efficacy of the neoadjuvant therapy. It was observed that the distribution of intrinsic subtype, ROR category and immunity subgroup varied according to hormone receptor (HR) status. HER2-enriched and basal-like subtypes, median-high ROR categories and immunity-weak subgroup were dominant in baseline tumors. Compared to baseline samples, conversion of intrinsic subtype, ROR categories and immunity subgroups were found in 15 (60.0%), 13(52.0%), and 11(44.0%) surgical samples, respectively. The PAM50 subtype, ROR category, and immunity subgroup were concordant between baseline and surgical samples where nonluminal subtypes, median-high ROR categories and i-weak subgroup were still common. In conclusion, the HER2-positive breast cancer is highly heterogeneous with a distribution of 72-gene expression varying according to HR co-expression. The dynamics of the 72-gene expression pre- and posttreatment may become novel biomarker for guiding adjuvant therapy and hence warrant further investigation.
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Affiliation(s)
- Peixian Chen
- Department of Breast Surgery, The First People’s Hospital of Foshan, Guangdong, China
| | - Xiaofan Mao
- Clinical Research Institute, The First People’s Hospital of Foshan, Guangdong, China
| | - Na Ma
- Department of Pathology, The First People’s Hospital of Foshan, Guangdong, China
| | - Chuan Wang
- The First People’s Hospital of Foshan, Guangdong, China
| | - Guangyu Yao
- Breast Center, Department of General Surgery, Nanfang Hospital, Southern Medical University, Province, hina
| | - Guolin Ye
- Department of Breast Surgery, The First People’s Hospital of Foshan, Guangdong, China
| | - Dan Zhou
- Department of Breast Surgery, The First People’s Hospital of Foshan, Guangdong, China
- * Correspondence: Dan Zhou, MD, Department of Breast Surgery, The First People’s Hospital of Foshan, #81, North Lingnan Avenue, Chancheng, Foshan, Guangdong, China (e-mail: )
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Neoadjuvant Trastuzumab and Pertuzumab for Early HER2-Positive Breast Cancer: A Real World Experience. Breast J 2022; 2022:7146172. [PMID: 35833190 PMCID: PMC9262537 DOI: 10.1155/2022/7146172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 02/22/2022] [Accepted: 05/26/2022] [Indexed: 11/18/2022]
Abstract
Background Randomized studies of neoadjuvant (NA) trastuzumab and pertuzumab combined with chemotherapy for HER2-positive breast cancers (BC) have reported pathological complete response (pCR) rates of 39 to 61%. This study aimed to determine the real-world efficacy and toxicity of NA trastuzumab and pertuzumab combined with chemotherapy in a UK tertiary referral cancer centre. Methods HER2-positive early BC patients given neoadjuvant chemotherapy with trastuzumab and pertuzumab between October 2016 and February 2018 at our tertiary referral cancer centre were identified via pharmacy records. Clinico-pathological information, treatment regimens, treatment-emergent toxicities, operative details, and pathological responses and outcomes were recorded. Results 78 female patients were identified; 2 had bilateral diseases and 48 of 78 (62%) were node positive at presentation. 55 of 80 (71%) tumours were ER-positive. PCR occurred in 37 of 78 (46.3%; 95% CI: 35.3–57.2%) patients. 14 of 23 (60.8%) patients with ER-negative tumours achieved pCR; 23 of 55 (41.8%) were ER-positive and 6 of 19 (31.6%) were ER-positive and PgR-positive. No cardiac toxicity was documented. Diarrhoea occurred in 53 of 72 (74%) patients. Grade 3–4 toxicity occurred in ≥2% patients. These were diarrhoea, fatigue, and infection. The Median follow up period was 45.2 months (95% CI 43.8–46.3) with 71 of 78 (91.0%) remaining disease-free and 72 of 78 (92.3%) alive. Estimated OS at 2 years 86% (95% CI: 75–99%). Conclusion This data confirms the efficacy of neoadjuvant chemotherapy combined with dual HER2 directed therapy. While no cardiac toxicity was observed, diarrhoea occurred frequently. The low pCR rate observed in ER and PgR-positive BCs warrants further investigation and consideration of strategies to increase the pCR rate.
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25
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Bundred N, Porta N, Brunt AM, Cramer A, Hanby A, Shaaban AM, Rakha EA, Armstrong A, Cutress RI, Dodwell D, Emson MA, Evans A, Hartup SM, Horgan K, Miller SE, McIntosh SA, Morden JP, Naik J, Narayanan S, Ooi J, Skene AI, Cameron DA, Bliss JM. Combined Perioperative Lapatinib and Trastuzumab in Early HER2-Positive Breast Cancer Identifies Early Responders: Randomized UK EPHOS-B Trial Long-Term Results. Clin Cancer Res 2022; 28:1323-1334. [PMID: 35165099 PMCID: PMC9610457 DOI: 10.1158/1078-0432.ccr-21-3177] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/11/2021] [Accepted: 01/20/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE EPHOS-B aimed to determine whether perioperative anti-HER2 therapy inhibited proliferation and/or increased apoptosis in HER2-positive breast cancer. PATIENTS AND METHODS This randomized phase II, two-part, multicenter trial included newly diagnosed women with HER2-positive invasive breast cancer due to undergo surgery. Patients were randomized to: part 1 (1:2:2), no treatment (control), trastuzumab or lapatinib; part 2 (1:1:2) control, trastuzumab, or lapatinib and trastuzumab combination. Treatment was given for 11 days presurgery. Coprimary endpoints were change in Ki67 and apoptosis between baseline and surgery tumor samples (biologic response: ≥30% change). Central pathology review scored residual cancer burden (RCB). Relapse-free survival (RFS) explored long-term effects. RESULTS Between November 2010 and September 2015, 257 patients were randomized (part 1: control 22, trastuzumab 57, lapatinib 51; part 2: control 29, trastuzumab 32, combination 66). Ki67 response was evaluable for 223 patients: in part 1 Ki67 response occurred in 29/44 (66%) lapatinib versus 18/49 (37%) trastuzumab (P = 0.007) and 1/22 (5%) control (P < 0.0001); in part 2 in 36/49 (74%) combination versus 14/31 (45%) trastuzumab (P = 0.02) and 2/28 (7%) control (P < 0.0001). No significant increase in apoptosis after 11 days was seen in treatment groups. Six patients achieved complete pathologic response (pCR, RCB0) and 13 RCB1, all but two in the combination group. After 6 years median follow-up, 28 (11%) had recurrence and 19 (7%) died. No recurrences or deaths were observed among patients who achieved a pCR. Ki67% falls ≥50% associated with fewer recurrences (P = 0.002). CONCLUSIONS Early response after short duration anti-HER2 dual therapy identifies cancers dependent on the HER2 pathway providing a strategy for exploring risk-adapted individualized treatment de-escalation.
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Affiliation(s)
- Nigel Bundred
- Manchester University NHS Foundation Trust and University of Manchester, Manchester, United Kingdom
| | - Nuria Porta
- The Institute of Cancer Research, Clinical Trials and Statistics Unit, London, United Kingdom
| | | | - Angela Cramer
- The Christie Pathology Partnership, Manchester, United Kingdom
| | - Andrew Hanby
- Leeds Institute of Medical Research at St. James's, Leeds, United Kingdom
| | - Abeer M. Shaaban
- Queen Elizabeth Hospital Birmingham and University of Birmingham, Birmingham, United Kingdom
| | - Emad A. Rakha
- University of Nottingham, Nottingham, United Kingdom
| | - Anne Armstrong
- The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Ramsey I. Cutress
- University of Southampton and University Hospital Southampton, Southampton, United Kingdom
| | - David Dodwell
- Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Marie A. Emson
- The Institute of Cancer Research, Clinical Trials and Statistics Unit, London, United Kingdom
| | | | - Sue M. Hartup
- St James's University Hospital, Leeds, United Kingdom
| | - Kieran Horgan
- St James's University Hospital, Leeds, United Kingdom
| | - Sarah E. Miller
- The Institute of Cancer Research, Clinical Trials and Statistics Unit, London, United Kingdom
| | | | - James P. Morden
- The Institute of Cancer Research, Clinical Trials and Statistics Unit, London, United Kingdom
| | - Jay Naik
- Mid Yorkshire NHS Hospitals Trust, United Kingdom
| | | | - Jane Ooi
- Royal Bolton Hospital, Manchester, United Kingdom
| | | | - David A. Cameron
- University of Edinburgh Cancer Research Centre, Institute of Genetics and Cancer, Western General Hospital, Edinburgh, United Kingdom
| | - Judith M. Bliss
- The Institute of Cancer Research, Clinical Trials and Statistics Unit, London, United Kingdom
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26
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Nitz U, Gluz O, Graeser M, Christgen M, Kuemmel S, Grischke EM, Braun M, Augustin D, Potenberg J, Krauss K, Schumacher C, Forstbauer H, Reimer T, Stefek A, Fischer HH, Pelz E, zu Eulenburg C, Kates R, Wuerstlein R, Kreipe HH, Harbeck N, von Schumann R, Kuhn W, Polata S, Bielecki W, Meyer R, Just M, Kraudelt S, Siggelkow W, Wortelmann H, Kleine-Tebbe A, Leitzen L, Kirchhof H, Krabisch P, Hackmann J, Depenbusch R, Gnauert K, Staib P, Lehnert A, Hoffmann O, Briest S, Lindner C, Heyl V, Bauer L, Uleer C, Mohrmann S, Viehstaedt N, Malter W, Link T, Buendgen N, Tio J. De-escalated neoadjuvant pertuzumab plus trastuzumab therapy with or without weekly paclitaxel in HER2-positive, hormone receptor-negative, early breast cancer (WSG-ADAPT-HER2+/HR–): survival outcomes from a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol 2022; 23:625-635. [DOI: 10.1016/s1470-2045(22)00159-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 02/28/2022] [Accepted: 03/07/2022] [Indexed: 12/18/2022]
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Bueno Muiño C, Martín M, del Monte-Millán M, García-Saénz JÁ, López-Tarruella S. HER2+ Breast Cancer Escalation and De-Escalation Trial Design: Potential Role of Intrinsic Subtyping. Cancers (Basel) 2022; 14:512. [PMID: 35158778 PMCID: PMC8833556 DOI: 10.3390/cancers14030512] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/09/2022] [Accepted: 01/16/2022] [Indexed: 12/29/2022] Open
Abstract
Long-term outcomes in breast cancer patients differ based on the molecular subtype, with HER2-E being the most aggressive one. Advances in clinical practice have dramatically shifted HER2+ breast cancer prognosis. Risk adapted strategies to individualize therapies are necessary. De-escalation approaches have been encouraged based on the risks of clinical-pathological factors. Molecular gene subtyping could further accurately define HER2 addicted tumours that are sensitive to anti-HER2 therapies, thus sparing unnecessary treatments. The transition from immunochemistry to molecular profiling in HER2+ breast cancer is discussed.
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Affiliation(s)
- Coralia Bueno Muiño
- Medical Oncology Department, Hospital Infanta Cristina (Parla), Fundación de Investigación Biomédica del H.U. Puerta de Hierro, Majadahonda, 28009 Madrid, Spain;
| | - Miguel Martín
- Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigacion Sanitaria Gregorio Marañon (IiSGM), CIBERONC, Geicam, Universidad Complutense, 28007 Madrid, Spain;
| | - María del Monte-Millán
- Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigacion Sanitaria Gregorio Marañon (IiSGM) CIBERONC, 28007 Madrid, Spain;
| | - José Ángel García-Saénz
- Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), CIBERONC, 28040 Madrid, Spain;
| | - Sara López-Tarruella
- Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigacion Sanitaria Gregorio Marañon (IiSGM), CIBERONC, Geicam, Universidad Complutense, 28007 Madrid, Spain;
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28
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Gianni L, Colleoni M, Bisagni G, Mansutti M, Zamagni C, Del Mastro L, Zambelli S, Bianchini G, Frassoldati A, Maffeis I, Valagussa P, Viale G. Effects of neoadjuvant trastuzumab, pertuzumab and palbociclib on Ki67 in HER2 and ER-positive breast cancer. NPJ Breast Cancer 2022; 8:1. [PMID: 35013314 PMCID: PMC8748500 DOI: 10.1038/s41523-021-00377-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 12/06/2021] [Indexed: 12/05/2022] Open
Abstract
The crosstalk between estrogen and HER2 receptors and cell-cycle regulation sustains resistance to endocrine therapy of HER2- and hormone receptor-positive breast cancer. We earlier reported that women with HER2 and ER-positive breast cancer receiving neoadjuvant dual HER2-block and palbociclib in the NA-PHER2 trial had Ki67 decrease and 27% pathological complete responses (pCR). We extended NA-PHER2 to Cohort B using dual HER2-block and palbociclib without fulvestrant and report here Ki67 drops at week-2 (mean change −25.7), at surgery (after 16 weeks, mean change −9.5), high objective response (88.5%) and pCR (19.2%). In Cohort C [Ki67 > 20% and HER2low (IHC 1+/2+ without gene amplification)], women also received fulvestrant, had dramatic Ki67 drop at week 2 (−29.5) persisting at surgery (−19.3), and objective responses in 78.3%. In view of the favorable tolerability and of the efficacy-predictive value of Ki67 drop at week-2, the chemotherapy-free approach of NA-PHER2 deserves further investigation in HER2 and ER-positive breast cancer. The trial is registered with ClinicalTrials.gov, number NCT02530424.
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Affiliation(s)
| | - Marco Colleoni
- IEO, European Institute of Oncology, IRCCS, Milano, Italy
| | | | - Mauro Mansutti
- Department of Oncology, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
| | - Claudio Zamagni
- Addarii Medical Oncology IRCCS Azienda Ospedaliero-universitaria di Bologna, Bologna, Italy
| | - Lucia Del Mastro
- IRCCS Ospedale Policlinico San Martino, UO Breast Unit, Genova, Italy.,Università di Genova, Dipartimento di Medicina Interna e Specialità Mediche (Di.M.I.), Genova, Italy
| | - Stefania Zambelli
- Department of Medical Oncology, San Raffaele Scientific Institute, Milano, Italy
| | - Giampaolo Bianchini
- Department of Medical Oncology, San Raffaele Scientific Institute, Milano, Italy
| | - Antonio Frassoldati
- Department of Oncology, Azienda Ospedaliero Universitaria di Ferrara - Arcispedale Sant'Anna, Ferrara, Italy
| | | | | | - Giuseppe Viale
- IRCCS European Institute of Oncology, Milano, University of Milan, School of Medicine, Milano, Italy
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Osuna-Gómez R, Arqueros C, Galano C, Mulet M, Zamora C, Barnadas A, Vidal S. Effector Mechanisms of CD8+ HLA-DR+ T Cells in Breast Cancer Patients Who Respond to Neoadjuvant Chemotherapy. Cancers (Basel) 2021; 13:cancers13246167. [PMID: 34944786 PMCID: PMC8699550 DOI: 10.3390/cancers13246167] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/01/2021] [Accepted: 12/04/2021] [Indexed: 01/09/2023] Open
Abstract
Simple Summary This study contributes to the characterization of CD8+ HLA-DR+ T cell mediated-mechanisms involved in the anti-tumor response in breast cancer patients who respond to neoadyuvant chemotherapy (NACT). Cultures with plasma from responder (R), but not from non-responder (NR), patients increased the intracellular production of cytotoxic molecules and pro-inflammatory cytokines in CD8+HLA-DR+ T cells. However, the addition of neutralizing anti-IFN-γ or anti-IL-12 antibodies to cultures with plasma from R patients decreased this effector function on CD8+HLA-DR+ T cells. These results suggest the presence of soluble factors in the plasma of R patients inducing the effector function of CD8+HLA-DR+ T cells. Abstract Cytotoxic T lymphocyte (CTLs) activation is an independent predictor of response to neoadjuvant chemotherapy (NACT) in breast cancer (BC) patients. Here, we go deeper into the function of CD8+ HLA-DR+ T cells from NACT treated HER2 negative BC patients. Flow cytometry analysis revealed that CD8+ HLA-DR+ T cell percentage was increased in NACT responder (R) compared to non-responder (NR) patients. R patients with ER-/PR- hormone receptors had the highest CD8+ HLA-DR+ T cell frequencies, while no differences were found when patients were classified according to cancer stage or menopause status. Interestingly, the cytotoxicity and production of anti-tumor cytokines were enhanced when CD8+ HLA-DR+ T cells from healthy donors were cultured with plasma from R, but not from NR patients. The induced anti-tumor profile of CD8+ HLA-DR+ T cells was associated with plasmatic IL-12 and IFN-γ levels, increased cytokines in R patients. IL-12 or IFN-γ neutralization decreased cytotoxic activity and TNF-α production by cultured CD8+ HLA-DR+ T cells in R plasma presence. All these data suggest that an effective response to NACT in BC patients is associated with increased IL-12 or IFN-γ levels involved in the induction of cytotoxic and pro-inflammatory mechanisms in CD8+ HLA-DR+ T cells.
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Affiliation(s)
- Rubén Osuna-Gómez
- Inflammatory Diseases, Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (R.O.-G.); (C.G.); (M.M.); (C.Z.)
| | - Cristina Arqueros
- Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; (C.A.); (A.B.)
- Centro de Investigación Biomedica en Red Cancer (CIBERONC), 28029 Madrid, Spain
| | - Carla Galano
- Inflammatory Diseases, Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (R.O.-G.); (C.G.); (M.M.); (C.Z.)
| | - Maria Mulet
- Inflammatory Diseases, Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (R.O.-G.); (C.G.); (M.M.); (C.Z.)
| | - Carlos Zamora
- Inflammatory Diseases, Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (R.O.-G.); (C.G.); (M.M.); (C.Z.)
| | - Agustí Barnadas
- Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; (C.A.); (A.B.)
- Centro de Investigación Biomedica en Red Cancer (CIBERONC), 28029 Madrid, Spain
- School of Medicine, Universitat Autònoma Barcelona, 08193 Bellaterra, Spain
| | - Silvia Vidal
- Inflammatory Diseases, Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (R.O.-G.); (C.G.); (M.M.); (C.Z.)
- Correspondence:
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30
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Gu W, Hu M, Xu L, Ren Y, Mei J, Wang W, Wang C. The Ki-67 Proliferation Index-Related Nomogram to Predict the Response of First-Line Tyrosine Kinase Inhibitors or Chemotherapy in Non-small Cell Lung Cancer Patients With Epidermal Growth Factor Receptor-Mutant Status. Front Med (Lausanne) 2021; 8:728575. [PMID: 34805200 PMCID: PMC8602562 DOI: 10.3389/fmed.2021.728575] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 09/28/2021] [Indexed: 12/24/2022] Open
Abstract
Background: The correlation between Ki-67 and epidermal growth factor receptor (EGFR)- or Kristen rat sarcoma viral oncogene homolog (KRAS)-mutant status in advanced or postoperative-recurrent non-small cell lung cancer (NSCLC) has fewer studies reported, and the prognostic role of Ki-67 with first-line EGFR-tyrosine kinase inhibitors (TKIs) or chemotherapy remains controversial. Methods: A total of 295 patients were tested for EGFR-mutant status in advanced or postoperative-recurrent NSCLC and received first-line EGFR-TKIs or chemotherapy for treatment. Ki-67 expression was retrospectively analyzed by immunohistochemistry. The Kaplan-Meier method was used to calculate survival rates. The multivariate Cox proportional hazards model was used to generate a nomogram. The established nomogram was validated using the calibration plots. Results: The expression levels of Ki-67 were divided into low (<60%, n = 186) and high (≥60%, n = 109) groups, based on the receiver operating characteristic curve. The expression levels of Ki-67 were found to be higher in patients with KRAS mutations when compared to KRAS wildtype, and EGFR wildtype was higher than EGFR mutations. The median overall survival (OS) of the low Ki-67 expression group was significantly longer than that of the high Ki-67 group, no matter in all NSCLC, EGFR mutations, EGFR wildtype, KRAS-mutant status, EGFR-TKIs, or chemotherapy of patients (P < 0.05). Subgroup analysis showed that the KRAS wildtype or EGFR mutations combine with low Ki-67 expression group had the longest median OS than KRAS mutations or EGFR wildtype combine with Ki-67 high expression group (P < 0.05). In the training cohort, the multivariate Cox analysis identified age, serum lactate dehydrogenase (LDH), serum Cyfra211, EGFR mutations, and Ki-67 as independent prognostic factors, and a nomogram was developed based on these covariates. The calibration curve for predicting the 12-, 24-, and 30-month OS showed an optimal agreement between the predicted and actual observed outcomes. Conclusions: The Ki-67 expression-based nomogram can well predict the efficacy of first-line therapy in NSCLC patients with EGFR- or KRAS-mutant status, high expression levels of Ki-67 correlated with a poor prognosis.
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Affiliation(s)
- Weiguo Gu
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, China.,Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Mingbin Hu
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, China.,Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Linlin Xu
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, China.,Institute of Molecular Pathology, Nanchang University, Nanchang, China
| | - Yuanhui Ren
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jinhong Mei
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, China.,Institute of Molecular Pathology, Nanchang University, Nanchang, China
| | - Weijia Wang
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chunliang Wang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
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Zhao F, Huo X, Wang M, Liu Z, Zhao Y, Ren D, Xie Q, Liu Z, Li Z, Du F, Shen G, Zhao J. Comparing Biomarkers for Predicting Pathological Responses to Neoadjuvant Therapy in HER2-Positive Breast Cancer: A Systematic Review and Meta-Analysis. Front Oncol 2021; 11:731148. [PMID: 34778044 PMCID: PMC8581664 DOI: 10.3389/fonc.2021.731148] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 10/08/2021] [Indexed: 01/09/2023] Open
Abstract
INTRODUCTION The predictive strength and accuracy of some biomarkers for the pathological complete response (pCR) to neoadjuvant therapy for HER2-positive breast cancer remain unclear. This study aimed to compare the accuracy of the HER2-enriched subtype and the presence of PIK3CA mutations, namely, TILs, HRs, and Ki-67, in predicting the pCR to HER2-positive breast cancer therapy. METHODS We screened studies that included pCR predicted by one of the following biomarkers: the HER2-enriched subtype and the presence of PIK3CA mutations, TILs, HRs, or Ki-67. We then calculated the pooled sensitivity, specificity, positive and negative predictive values (PPVs and NPVs, respectively), and positive and negative likelihood ratios (LRs). Summary receiver operating characteristic (SROC) curves and areas under the curve (AUCs) were used to estimate the diagnostic accuracy. RESULTS The pooled estimates of sensitivity and specificity for the HER2-enriched subtype and the presence of PIK3CA mutations, namely, TILs, HRs, and Ki-67, were 0.66 and 0.62, 0.85 and 0.27, 0.49 and 0.61, 0.54 and 0.64, and 0.68 and 0.51, respectively. The AUC of the HER2-enriched subtype was significantly higher (0.71) than those for the presence of TILs (0.59, p = 0.003), HRs (0.65, p = 0.003), and Ki-67 (0.62, p = 0.005). The AUC of the HER2-enriched subtype had a tendency to be higher than that of the presence of PIK3CA mutations (0.58, p = 0.220). Moreover, it had relatively high PPV (0.58) and LR+ (1.77), similar NPV (0.73), and low LR- (0.54) compared with the other four biomarkers. CONCLUSIONS The HER2-enriched subtype has a moderate breast cancer diagnostic accuracy, which is better than those of the presence of PIK3CA mutations, TILs, HRs, and Ki-67.
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Affiliation(s)
- Fuxing Zhao
- Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Xingfa Huo
- Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Miaozhou Wang
- Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Zhen Liu
- Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Yi Zhao
- Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Dengfeng Ren
- Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Qiqi Xie
- Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Zhilin Liu
- Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Zitao Li
- Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Feng Du
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), The VIPII Gastrointestinal Cancer Division of Medical Department, Peking University Cancer Hospital and Institute, Beijing, China
| | - Guoshuang Shen
- Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Jiuda Zhao
- Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining, China
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Liotta LA, Pappalardo PA, Carpino A, Haymond A, Howard M, Espina V, Wulfkuhle J, Petricoin E. Laser Capture Proteomics: spatial tissue molecular profiling from the bench to personalized medicine. Expert Rev Proteomics 2021; 18:845-861. [PMID: 34607525 PMCID: PMC10720974 DOI: 10.1080/14789450.2021.1984886] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 09/21/2021] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Laser Capture Microdissection (LCM) uses a laser to isolate, or capture, specific cells of interest in a complex heterogeneous tissue section, under direct microscopic visualization. Recently, there has been a surge of publications using LCM for tissue spatial molecular profiling relevant to a wide range of research topics. AREAS COVERED We summarize the many advances in tissue Laser Capture Proteomics (LCP) using mass spectrometry for discovery, and protein arrays for signal pathway network mapping. This review emphasizes: a) transition of LCM phosphoproteomics from the lab to the clinic for individualized cancer therapy, and b) the emerging frontier of LCM single cell molecular analysis combining proteomics with genomic, and transcriptomic analysis. The search strategy was based on the combination of MeSH terms with expert refinement. EXPERT OPINION LCM is complemented by a rich set of instruments, methodology protocols, and analytical A.I. (artificial intelligence) software for basic and translational research. Resolution is advancing to the tissue single cell level. A vision for the future evolution of LCM is presented. Emerging LCM technology is combining digital and AI guided remote imaging with automation, and telepathology, to a achieve multi-omic profiling that was not previously possible.
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Affiliation(s)
- Lance A. Liotta
- Center For Applied Proteomics and Molecular Medicine (CAPMM) School of Systems Biology, College of Sciences, George Mason University, Manassas, VA 20110, USA
| | - Philip A. Pappalardo
- Center For Applied Proteomics and Molecular Medicine (CAPMM) School of Systems Biology, College of Sciences, George Mason University, Manassas, VA 20110, USA
| | - Alan Carpino
- Fluidigm Corporation, South San Francisco, CA, USA
| | - Amanda Haymond
- Center For Applied Proteomics and Molecular Medicine (CAPMM) School of Systems Biology, College of Sciences, George Mason University, Manassas, VA 20110, USA
| | - Marissa Howard
- Center For Applied Proteomics and Molecular Medicine (CAPMM) School of Systems Biology, College of Sciences, George Mason University, Manassas, VA 20110, USA
| | - Virginia Espina
- Center For Applied Proteomics and Molecular Medicine (CAPMM) School of Systems Biology, College of Sciences, George Mason University, Manassas, VA 20110, USA
| | - Julie Wulfkuhle
- Center For Applied Proteomics and Molecular Medicine (CAPMM) School of Systems Biology, College of Sciences, George Mason University, Manassas, VA 20110, USA
| | - Emanuel Petricoin
- Center For Applied Proteomics and Molecular Medicine (CAPMM) School of Systems Biology, College of Sciences, George Mason University, Manassas, VA 20110, USA
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Schettini F, Prat A. Dissecting the biological heterogeneity of HER2-positive breast cancer. Breast 2021; 59:339-350. [PMID: 34392185 PMCID: PMC8374722 DOI: 10.1016/j.breast.2021.07.019] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 07/19/2021] [Accepted: 07/29/2021] [Indexed: 12/24/2022] Open
Abstract
HER2-positive (HER2+) breast cancer (BC) is a heterogenous and multifaceted disease, with interesting therapeutic implications. First, all intrinsic molecular subtypes can be identified in HER2+ tumors, with the HER2-enriched being the most frequent. Such subtypes do not differ much from their counterparts in HER2-negative disease, apart for the high expression of genes in/near the HER2 amplicon on chromosome 17. Intrinsic subtyping, along with the quantification of ERBB2 mRNA levels, is associated with higher rates of pathologic complete response across neoadjuvant trials of dual HER2 blockade and might help select patients for de-escalation and escalation treatment strategies. Secondly, HER2+ tumors have a broad range of DNA alterations. ERBB2 mutations and alterations in the PI3K/Akt/mTOR pathway are among the most frequent and might predict benefit from potent pan-HER, PI3K and mTOR inhibitors. Moreover, HER2+ tumors are usually infiltrated by lymphocytes. These tumor infiltrating-lymphocytes (TILs) predict response to neoadjuvant anti-HER2-based treatment and exert a prognostic role. PD-L1, detected in ∼42 % of HER2+ BC, might also be useful to define patients responding to novel anti-PD1/PD-L1 immunotherapies. New multiparametric clinicopathologic and genomic tools accounting for this complexity, such as HER2DX, are under development to define more tailored treatment approaches. Finally, HER2-targeted antibody-drug conjugates (ADC) such as trastuzumab deruxtecan might be active in tumors with low expression of HER2. Overall, there is a need to molecularly characterize and develop novel targeted therapies for HER2+ disease.
Almost 50 % of HER2+ breast cancer (BC) are molecularly HER2-Enriched (HER2-E). Most relevant mutations are found in ERBB2 (∼4 %) and PI3K/AKT/mTOR pathway (>30 %). Tumor infiltrating lymphocytes are frequent, predictive and prognostic in HER2+ BC. HER2 heterogeneity and HER2 low status are gaining therapeutic relevance. New treatments need to consider HER2+ molecular and microenvironmental complexity.
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Affiliation(s)
- Francesco Schettini
- Translational Genomics and Targeted Therapies in Solid Tumors Group, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; SOLTI Breast Cancer Research Group, Barcelona, Spain
| | - Aleix Prat
- Translational Genomics and Targeted Therapies in Solid Tumors Group, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; SOLTI Breast Cancer Research Group, Barcelona, Spain; Department of Medical Oncology, Hospital Clinic de Barcelona, Barcelona, Spain; Department of Medicine, University of Barcelona, Barcelona, Spain; Institute of Oncology (IOB)-Quirón, Barcelona, Spain.
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Pernas S, Tolaney SM. Management of Early-Stage Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer. JCO Oncol Pract 2021; 17:320-330. [PMID: 34111378 DOI: 10.1200/op.21.00020] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The addition of trastuzumab to chemotherapy dramatically improved the prognosis of early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, 15%-31% of patients still develop disease recurrence, on the basis of long-term follow-up of adjuvant pivotal trials. A better understanding of tumor biology has led to the development of optimized anti-HER2 drugs and add-on strategies to further improve survival outcomes. In the neoadjuvant setting, dual HER2 blockade with trastuzumab and pertuzumab plus chemotherapy has increased the rate of pathologic complete response, a surrogate marker of improved long-term outcome; yet, in the adjuvant setting, it has led to small benefits in invasive disease-free survival. Extended adjuvant therapy with the irreversible pan-HER2 inhibitor neratinib is an option for selected patients with HER2-positive and estrogen receptor-positive disease who have received neoadjuvant or adjuvant chemotherapy plus trastuzumab. Additionally, the use of the antibody-drug conjugate trastuzumab-emtansine has led to a significant improvement in invasive disease-free survival for patients with residual disease following neoadjuvant therapy and has taught us the importance of using preoperative therapy to adapt adjuvant treatment. Nevertheless, recurrences in the brain remain an important caveat, and not all patients benefit to the same extent from anti-HER2 therapies. Biologic heterogeneity within HER2-positive disease may modulate treatment response and prognosis. De-escalating treatment strategies to avoid unnecessary treatments and toxicities, without compromising outcomes, have become a crucial focus of research. To stratify patient risks and optimize treatment selection, other biomarkers including intrinsic subtype, level of HER2, and tumor-infiltrating lymphocytes should be further evaluated. We discuss the latest evidence on the current approach of early-stage, HER2-positive breast cancer and present future perspectives on its management.
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Affiliation(s)
- Sonia Pernas
- Department of Medical Oncology, Catalan Institute of Oncology-ICO, L'Hospitalet de Llobregat, Barcelona, Spain.,Breast Cancer Group, Institut d'Investigacio Biomedica de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Sara M Tolaney
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
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Pascual T, Fernandez-Martinez A, Tanioka M, Dieci MV, Pernas S, Gavila J, Guarneri V, Cortes J, Villagrasa P, Chic N, Vidal M, Adamo B, Muñoz M, Griguolo G, Llombart A, Conte P, Oliveira M, Conte B, Paré L, Galvan P, Carey LA, Perou CM, Prat A. Independent Validation of the PAM50-Based Chemo-Endocrine Score (CES) in Hormone Receptor-Positive HER2-Positive Breast Cancer Treated with Neoadjuvant Anti-HER2-Based Therapy. Clin Cancer Res 2021; 27:3116-3125. [PMID: 33632929 PMCID: PMC8172481 DOI: 10.1158/1078-0432.ccr-20-4102] [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] [Received: 10/23/2020] [Revised: 01/08/2021] [Accepted: 02/22/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE We do not yet have validated biomarkers to predict response and outcome within hormone receptor-positive/HER2-positive (HR+/HER2+) breast cancer. The PAM50-based chemo-endocrine score (CES) predicts chemo-endocrine sensitivity in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer. Here, we evaluate the relationship of CES with response and survival in HR+/HER2+ breast cancer. EXPERIMENTAL DESIGN Intrinsic subtype and clinicopathologic data were obtained from seven studies in which patients were treated with HER2-targeted therapy either with endocrine therapy (ET) or with chemotherapy (CTX). CES was evaluated as a continuous variable and categorically from low to high scores [CES-C (chemo-sensitive), CES-U (uncertain), and CES-E (endocrine-sensitive)]. We first analyzed each dataset individually, and then all combined. Multivariable analyses were used to test CES association with pathologic complete response (pCR) and disease-free survival (DFS). RESULTS A total of 457 patients were included (112 with ET and 345 with CTX). In the combined cohort, CES-C, CES-U, and CES-E were identified in 60%, 23%, and 17% of the patients, respectively. High CES (i.e., CES-E) was associated with a lower probability of achieving pCR independently of clinical characteristics, therapy, intrinsic subtype, and study (adjusted OR = 0.42; P = 0.016). A total of 295 patients were analyzed for DFS with a median follow-up of 66 months. High CES was also associated with better DFS (adjusted HR, 0.174; P = 0.003) independently of pCR, clinical characteristics and intrinsic subtype. In patients with residual disease, the adjusted DFS HR of CES was 0.160 (P = 0.012). CONCLUSIONS In HER2+/HR+ breast cancer, CES is useful for predicting chemo-endocrine sensitivity and provides additional prognostication beyond intrinsic subtype and clinicopathologic characteristics.
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Affiliation(s)
- Tomás Pascual
- Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Department of Medical Oncology, Hospital Clínic de Barcelona, Spain
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- SOLTI Breast Cancer Research Group, Barcelona, Spain
| | - Aranzazu Fernandez-Martinez
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Maki Tanioka
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - M Vittoria Dieci
- Department of Surgery, Oncology, and Gastroenterology, University of Padova, Padova, Italy
- Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy
| | - Sonia Pernas
- Institut Catala d' Oncologia (ICO)-Hospitalet, Barcelona, Spain
| | - Joaquin Gavila
- Fundación Instituto Valenciano de Oncología, Valencia, Spain
| | - Valentina Guarneri
- Department of Surgery, Oncology, and Gastroenterology, University of Padova, Padova, Italy
- Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy
| | - Javier Cortes
- Oncology department, IOB Institute of Oncology, Barcelona & Madrid, Spain
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | | | - Núria Chic
- Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Department of Medical Oncology, Hospital Clínic de Barcelona, Spain
| | - Maria Vidal
- Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Department of Medical Oncology, Hospital Clínic de Barcelona, Spain
- SOLTI Breast Cancer Research Group, Barcelona, Spain
| | - Barbara Adamo
- Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Department of Medical Oncology, Hospital Clínic de Barcelona, Spain
| | - Montserrat Muñoz
- Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Department of Medical Oncology, Hospital Clínic de Barcelona, Spain
- SOLTI Breast Cancer Research Group, Barcelona, Spain
| | - Gaia Griguolo
- Department of Surgery, Oncology, and Gastroenterology, University of Padova, Padova, Italy
- Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy
| | | | - Pierfranco Conte
- Department of Surgery, Oncology, and Gastroenterology, University of Padova, Padova, Italy
- Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy
| | - Mafalda Oliveira
- Hospital Arnau de Vilanova, Valencia, Spain
- Hospital Universitari Vall d' Hebron, Barcelona, Spain
| | - Benedetta Conte
- Department of Medical Oncology, Ospedale Policlinico San Martino, University of Genova, Genova, Italy
| | - Laia Paré
- SOLTI Breast Cancer Research Group, Barcelona, Spain
| | - Patricia Galvan
- Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Lisa A Carey
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Charles M Perou
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Aleix Prat
- Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
- Department of Medical Oncology, Hospital Clínic de Barcelona, Spain
- SOLTI Breast Cancer Research Group, Barcelona, Spain
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The Present and Future of Neoadjuvant Endocrine Therapy for Breast Cancer Treatment. Cancers (Basel) 2021; 13:cancers13112538. [PMID: 34064183 PMCID: PMC8196711 DOI: 10.3390/cancers13112538] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/16/2021] [Accepted: 05/19/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary The treatment of breast cancer has evolved considerably over the last two decades, leading toward individualized disease management. Hormone-sensitive breast cancers constitute the vast majority of cases and endocrine therapy is the mainstay of their treatment. On the other hand, neoadjuvant or pre-surgical treatments provide a number of advantages for tumor management. In this review we will discuss the existing evidence on neoadjuvant endocrine therapy, as well as its possible future indications. Abstract Endocrine therapy (ET) has established itself as an efficacious treatment for estrogen receptor-positive (ER+) breast cancers, with a reduction in recurrence rates and increased survival rates. The pre-surgical approach with chemotherapy (NCT) has become a common form of management for large, locally advanced, or high-risk tumors. However, a good response to NCT is not usually expected in ER+ tumors. Good results with primary ET, mainly in elderly women, have encouraged studies in other stages of life, and nowadays neoadjuvant endocrine treatment (NET) has become a useful approach to many ER+ breast cancers. The aim of this review is to provide an update on the current state of art regarding the present and the future role of NET.
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Jackisch C, Cortazar P, Geyer CE, Gianni L, Gligorov J, Machackova Z, Perez EA, Schneeweiss A, Tolaney SM, Untch M, Wardley A, Piccart M. Risk-based decision-making in the treatment of HER2-positive early breast cancer: Recommendations based on the current state of knowledge. Cancer Treat Rev 2021; 99:102229. [PMID: 34139476 DOI: 10.1016/j.ctrv.2021.102229] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 05/14/2021] [Accepted: 05/17/2021] [Indexed: 01/05/2023]
Abstract
Treatment of HER2-positive early breast cancer (EBC) continues to evolve with neoadjuvant (pre-operative) and adjuvant (post-operative) HER2-targeted therapies as standard of care. There are two important decision points. The first involves deciding between neoadjuvant therapy or proceeding directly to surgery. Neoadjuvant chemotherapy (NACT) plus pertuzumab-trastuzumab is appropriate for patients with high-risk HER2-positive EBC (tumour diameter ≥2 cm, and/or node-positive disease). Patients with node-negative disease and tumour diameter <2 cm are candidates for upfront surgery followed by paclitaxel for 12 weeks plus 18 cycles of trastuzumab, with the option to add pertuzumab (if pN+). The second decision point involves the pathohistological result at surgery after neoadjuvant therapy. Total pathological complete response (tpCR: ypT0/is, ypN0) is associated with improved survival endpoints. Patients with tumours ≥2 cm and/or node-positive disease at diagnosis who have a tpCR after dual blockade should continue pertuzumab-trastuzumab in the adjuvant setting to complete 1 year (18cycles) of treatment. For patients with invasive residual disease, 14cycles of post-neoadjuvant trastuzumab emtansine (T-DM1) therapy significantly increases invasive-DFS compared with trastuzumab. Extended adjuvant therapy with neratinib is an option in selected patients (HER2-positive and oestrogen receptor [ER]-positive) who have completed adjuvant trastuzumab-based therapy. Less aggressive chemotherapy regimens are recommended in populations with a lower risk of recurrence (patients with small tumours without axillary involvement; patients unlikely to tolerate anthracycline-taxane or taxane-carboplatin regimens). Ultimately, treatment recommendations should be consistent with local and international guidelines. Further studies will guide optimisation of treatment for patients with HER2-positive EBC according to the risk of disease recurrence.
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Affiliation(s)
| | | | - Charles E Geyer
- NSABP Foundation and Houston Methodist Cancer Center, Houston, TX, USA
| | | | - Joseph Gligorov
- Institut Universitaire de Cancérologie, APHP-Sorbonne Université, Hôpital Tenon, Paris, France
| | | | - Edith A Perez
- Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
| | - Andreas Schneeweiss
- National Center for Tumor Diseases, Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany
| | - Sara M Tolaney
- Dana-Farber Cancer Institute, and Department of Hematology-Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Michael Untch
- AGO-B and HELIOS Klinikum Berlin Buch, Berlin, Germany
| | - Andrew Wardley
- Outreach Research & Innovation Group and Manchester Breast Centre, Division of Cancer Sciences and University of Manchester, Manchester, UK; AstraZeneca PLC, UK
| | - Martine Piccart
- Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
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Wu L, Zhao Y, Lin P, Qin H, Liu Y, Wan D, Li X, He Y, Yang H. Preoperative ultrasound radiomics analysis for expression of multiple molecular biomarkers in mass type of breast ductal carcinoma in situ. BMC Med Imaging 2021; 21:84. [PMID: 34001017 PMCID: PMC8130392 DOI: 10.1186/s12880-021-00610-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 04/21/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The molecular biomarkers of breast ductal carcinoma in situ (DCIS) have important guiding significance for individualized precision treatment. This study was intended to explore the significance of radiomics based on ultrasound images to predict the expression of molecular biomarkers of mass type of DCIS. METHODS 116 patients with mass type of DCIS were included in this retrospective study. The radiomics features were extracted based on ultrasound images. According to the ratio of 7:3, the data sets of molecular biomarkers were split into training set and test set. The radiomics models were developed to predict the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), Ki67, p16, and p53 by using combination of multiple feature selection and classifiers. The predictive performance of the models were evaluated using the area under the curve (AUC) of the receiver operating curve. RESULTS The investigators extracted 5234 radiomics features from ultrasound images. 12, 23, 41, 51, 31 and 23 features were important for constructing the models. The radiomics scores were significantly (P < 0.05) in each molecular marker expression of mass type of DCIS. The radiomics models showed predictive performance with AUC greater than 0.7 in the training set and test set: ER (0.94 and 0.84), PR (0.90 and 0.78), HER2 (0.94 and 0.74), Ki67 (0.95 and 0.86), p16 (0.96 and 0.78), and p53 (0.95 and 0.74), respectively. CONCLUSION Ultrasonic-based radiomics analysis provided a noninvasive preoperative method for predicting the expression of molecular markers of mass type of DCIS with good accuracy.
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Affiliation(s)
- Linyong Wu
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Yujia Zhao
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Peng Lin
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Hui Qin
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Yichen Liu
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Da Wan
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Xin Li
- GE Healthcare, Shanghai, People's Republic of China
| | - Yun He
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China.
| | - Hong Yang
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China.
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Graeser M, Schrading S, Gluz O, Strobel K, Würstlein R, Kümmel S, Schumacher C, Grischke E, Forstbauer H, Braun M, Christgen M, Adams J, Nitzsche H, Just M, Fischer HH, Aktas B, Potenberg J, von Schumann R, Kolberg‐Liedtke C, Harbeck N, Kuhl CK, Nitz U. Early response by MR imaging and ultrasound as predictor of pathologic complete response to 12-week neoadjuvant therapy for different early breast cancer subtypes: Combined analysis from the WSG ADAPT subtrials. Int J Cancer 2021; 148:2614-2627. [PMID: 33533487 PMCID: PMC8048810 DOI: 10.1002/ijc.33495] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 12/18/2020] [Accepted: 12/21/2020] [Indexed: 12/31/2022]
Abstract
We evaluated the role of early response after 3 weeks of neoadjuvant treatment (NAT) assessed by ultrasound (US), magnetic resonance imaging (MRI) and Ki-67 dynamics for prediction of pathologic complete response (pCR) in different early breast cancer subtypes. Patients with HR+/HER2+, HR-/HER2- and HR-/HER2+ tumors enrolled into three neoadjuvant WSG ADAPT subtrials underwent US, MRI and Ki-67 assessment at diagnosis and after 3 weeks of NAT. Early response was defined as complete or partial response (US, MRI) and ≥30% proliferation decrease or <500 invasive tumor cells (Ki-67). Predictive values and area under the receiver operating characteristic (AUC) curves for prediction of pCR (ypT0/is ypN0) after 12-week NAT were calculated. Two hundred twenty-six had MRI and 401 US; 107 underwent both MRI and US. All three methods yielded a similar AUC in HR+/HER2+ (0.66-0.67) and HR-/HER2- tumors (0.53-0.63), while MRI and Ki-67 performed better than US in HR-/HER2+ tumors (0.83 and 0.79 vs 0.56). Adding MRI+/-Ki-67 increased AUC of US in HR-/HER2+ tumors to 0.64 to 0.75. MRI and Ki-67 demonstrated highest sensitivity in HR-/HER2- (0.8-1) and HR-/HER2+ tumors (1, both). Negative predictive value was similar for all methods in HR+/HER2+ (0.71-0.74) and HR-/HER2- tumors (0.85-1), while it was higher for MRI and Ki-67 compared to US in HR-/HER2+ subtype (1 vs 0.5). Early response assessed by US, MRI and Ki-67 is a strong predictor for pCR after 12-week NAT. Strength of pCR prediction varies according to tumor subtype. Adding MRI+/-Ki-67 to US did not improve pCR prediction in majority of our patients.
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Affiliation(s)
- Monika Graeser
- West German Study GroupMoenchengladbachGermany
- Ev. Hospital Bethesda, Breast Center NiederrheinMoenchengladbachGermany
- Department of GynecologyUniversity Medical Center HamburgHamburgGermany
| | - Simone Schrading
- Department of Diagnostic and Interventional RadiologyHospital of the University of Aachen, RWTHAachenGermany
| | - Oleg Gluz
- West German Study GroupMoenchengladbachGermany
- Ev. Hospital Bethesda, Breast Center NiederrheinMoenchengladbachGermany
- University Hospital CologneCologneGermany
| | - Kevin Strobel
- Department of Diagnostic and Interventional RadiologyHospital of the University of Aachen, RWTHAachenGermany
| | - Rachel Würstlein
- West German Study GroupMoenchengladbachGermany
- Breast Center, Department of Gynecology and Obstetrics and CCCLMULMU University HospitalMunichGermany
| | - Sherko Kümmel
- West German Study GroupMoenchengladbachGermany
- Breast UnitKliniken Essen‐MitteEssenGermany
- University Hospital Charité, Humboldt University BerlinBerlinGermany
| | | | | | | | - Michael Braun
- Department of GynecologyBreast Center, Red Cross Hospital MunichMunichGermany
| | | | | | - Henrik Nitzsche
- Ev. Hospital Bethesda, Breast Center NiederrheinMoenchengladbachGermany
| | | | | | - Bahriye Aktas
- Department of Gynecology and ObstetricsUniversity Clinics EssenEssenGermany
- Department of GynecologyUniversity Hospital LeipzigLeipzigGermany
| | | | | | - Cornelia Kolberg‐Liedtke
- University Hospital Charité, Humboldt University BerlinBerlinGermany
- Department of Gynecology and ObstetricsUniversity Clinics EssenEssenGermany
| | - Nadia Harbeck
- West German Study GroupMoenchengladbachGermany
- Breast Center, Department of Gynecology and Obstetrics and CCCLMULMU University HospitalMunichGermany
| | - Christiane K. Kuhl
- Department of Diagnostic and Interventional RadiologyHospital of the University of Aachen, RWTHAachenGermany
| | - Ulrike Nitz
- West German Study GroupMoenchengladbachGermany
- Ev. Hospital Bethesda, Breast Center NiederrheinMoenchengladbachGermany
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Miglietta F, Dieci MV, Griguolo G, Guarneri V. Neoadjuvant approach as a platform for treatment personalization: focus on HER2-positive and triple-negative breast cancer. Cancer Treat Rev 2021; 98:102222. [PMID: 34023642 DOI: 10.1016/j.ctrv.2021.102222] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/06/2021] [Accepted: 05/09/2021] [Indexed: 10/21/2022]
Abstract
The neoadjuvant setting provides unquestionable clinical benefits for high-risk breast cancer (BC) patients, mainly in terms of expansion of locoregional treatment options and prognostic stratification. Additionally, it is also emerging as a strategical tool in the research field. In the present review, by focusing on HER2-positive and triple-negative subtypes, we examined the role of the neoadjuvant setting as a research platform to facilitate and rationalize the placement of escalation strategies, promote the adoption of biomarker-driven approaches for the investigation of de-escalated treatments, and foster the conduction of comprehensive translational analyses, thus ultimately aiming at pursuing treatment personalization. The solid prognostic role of pathologic complete response after neoadjuvant therapy, and its use as a surrogate endpoint to accelerate the drug approval process were discussed. In this context, available data on escalated treatment strategies capable of enhancing pathologic complete response (pCR) rate or improving prognosis of patients with residual disease (RD) after neoadjuvant treatment, were comprehensively reviewed. We also summarized evidence regarding the possibility of obtaining pCR with de-escalated strategies, with particular emphasis on the role of biomarker-driven approaches for patient selection. Pitfalls of the dichotomy of pCR/RD were also deepened, and data on alternative/complementary biomarkers with a possible clinical relevance in this regard were reviewed.
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Affiliation(s)
- Federica Miglietta
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Medical Oncology 2, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy
| | - Maria Vittoria Dieci
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Medical Oncology 2, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
| | - Gaia Griguolo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Medical Oncology 2, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy
| | - Valentina Guarneri
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Medical Oncology 2, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy
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41
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Lv H, Yan M, Jiang Z. Recent advances in the treatment of hormone receptor-positive/human epidermal growth factor 2-positive advanced breast cancer. Ther Adv Med Oncol 2021; 13:17588359211013326. [PMID: 33995599 PMCID: PMC8111512 DOI: 10.1177/17588359211013326] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 04/09/2021] [Indexed: 12/17/2022] Open
Abstract
Hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-positive (HR+/HER2+) advanced breast cancer is a special subtype of cancer with unique features. Major guidelines recommend that combination therapy containing anti-HER2 therapy (e.g., trastuzumab and pertuzumab) should be applied as the first-line treatment for HER2+ advanced breast cancer, regardless of HR status. Endocrine therapy could be relegated to patients who cannot tolerate chemotherapy or as a post-chemotherapy empirical maintenance strategy. Previous studies have shown that the HR pathway interacts with the HER2 pathway, and the HR and HER2 pathways of endocrine therapy combined with targeted therapy can effectively avoid tumor resistance. Therefore, the combination of endocrine and targeted therapies is the preferred treatment plan for HR+/HER2+ patients to replace chemotherapy. In this review, we will discuss research progress regarding endocrine therapy combined with anti-HER2 therapy in patients with advanced breast cancer, to provide more evidence for clinical practice and broader perspectives for related research. In the future, we hope there will be more studies on HR+/HER2+ advanced breast cancer to elucidate the optimal and appropriate treatment for these patients.
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Affiliation(s)
- Huimin Lv
- Department of Breast Disease, Henan Breast Cancer Center, The affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Min Yan
- Department of Breast Disease, Henan Breast Cancer Center. The affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Zefei Jiang
- The Fifth Medical Centre of Chinese PLA General Hospital, Beijing, 10070, China
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42
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Pérez-García JM, Gebhart G, Ruiz Borrego M, Stradella A, Bermejo B, Schmid P, Marmé F, Escrivá-de-Romani S, Calvo L, Ribelles N, Martinez N, Albacar C, Prat A, Dalenc F, Kerrou K, Colleoni M, Afonso N, Di Cosimo S, Sampayo-Cordero M, Malfettone A, Cortés J, Llombart-Cussac A. Chemotherapy de-escalation using an 18F-FDG-PET-based pathological response-adapted strategy in patients with HER2-positive early breast cancer (PHERGain): a multicentre, randomised, open-label, non-comparative, phase 2 trial. Lancet Oncol 2021; 22:858-871. [DOI: 10.1016/s1470-2045(21)00122-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 02/11/2021] [Accepted: 02/18/2021] [Indexed: 10/21/2022]
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Griguolo G, Serna G, Pascual T, Fasani R, Guardia X, Chic N, Paré L, Pernas S, Muñoz M, Oliveira M, Vidal M, Llombart-Cussac A, Cortés J, Galván P, Bermejo B, Martínez N, López R, Morales S, Garau I, Manso L, Alarcón J, Martínez E, Villagrasa P, Prat A, Nuciforo P. Immune microenvironment characterisation and dynamics during anti-HER2-based neoadjuvant treatment in HER2-positive breast cancer. NPJ Precis Oncol 2021; 5:23. [PMID: 33742063 PMCID: PMC7979716 DOI: 10.1038/s41698-021-00163-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 02/18/2021] [Indexed: 12/12/2022] Open
Abstract
Despite their recognised role in HER2-positive (HER2+) breast cancer (BC), the composition, localisation and functional orientation of immune cells within tumour microenvironment, as well as its dynamics during anti-HER2 treatment, is largely unknown. We here investigate changes in tumour-immune contexture, as assessed by stromal tumour-infiltrating lymphocytes (sTILs) and by multiplexed spatial cellular phenotyping, during treatment with lapatinib-trastuzumab in HER2+ BC patients (PAMELA trial). Moreover, we evaluate the relationship of tumour-immune contexture with hormone receptor status, intrinsic subtype and immune-related gene expression. sTIL levels increase after 2 weeks of HER2 blockade in HR-negative disease and HER2-enriched subtype. This is linked to a concomitant increase in cell density of all four immune subpopulations (CD3+, CD4+, CD8+, Foxp3+). Moreover, immune contexture analysis showed that immune cells spatially interacting with tumour cells have the strongest association with response to anti-HER2 treatment. Subsequently, sTILs consistently decrease at the surgery in patients achieving pathologic complete response, whereas most residual tumours at surgery remain inflamed, possibly reflecting a progressive loss of function of T cells. Understanding the features of the resulting tumour immunosuppressive microenvironment has crucial implications for the design of new strategies to de-escalate or escalate systemic therapy in early-stage HER2+ BC.
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Affiliation(s)
- G Griguolo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Division of Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy
- Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - G Serna
- Molecular oncology group, Vall d´Hebron Institute of Oncology, Barcelona, Spain
| | - T Pascual
- Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Department of Medical Oncology, Hospital Clínic de Barcelona, Barcelona, Spain
- SOLTI Breast Cancer Research Group, Barcelona, Spain
| | - R Fasani
- Molecular oncology group, Vall d´Hebron Institute of Oncology, Barcelona, Spain
| | - X Guardia
- Molecular oncology group, Vall d´Hebron Institute of Oncology, Barcelona, Spain
| | - N Chic
- Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Department of Medical Oncology, Hospital Clínic de Barcelona, Barcelona, Spain
| | - L Paré
- SOLTI Breast Cancer Research Group, Barcelona, Spain
| | - S Pernas
- Institut Catala d'Oncologia-H.U.Bellvitge-IDIBELL, Hospitalet, Barcelona, Spain
| | - M Muñoz
- Department of Medical Oncology, Hospital Clínic de Barcelona, Barcelona, Spain
| | - M Oliveira
- Medical Oncology Department, Vall d'Hebrón University Hospital, Barcelona, Spain
- Breast Cancer and Melanoma Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - M Vidal
- Department of Medical Oncology, Hospital Clínic de Barcelona, Barcelona, Spain
| | - A Llombart-Cussac
- Hospital Universitario Arnau de Vilanova de Valencia, Valencia, Spain
| | - J Cortés
- IOB Institute of Oncology, Quironsalud Group, Madrid & Barcelona, Spain
| | - P Galván
- Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - B Bermejo
- Hospital Clínico Universitario de Valencia/INCLIVA/CIBERONC, Valencia, Spain
| | - N Martínez
- Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - R López
- Hospital Clínico Universitario de Santiago, IDIS, CIBERONC, Santiago de Compostela, Spain
| | - S Morales
- Hospital Universitario Arnau de Vilanova de Lleida, Lleida, Spain
| | - I Garau
- Hospital Son Llàtzer, Palma de Mallorca, Spain
| | - L Manso
- Hospital Universitario 12 de Octubre, Madrid, Spain
| | - J Alarcón
- Hospital Universitario Son Espases, Palma de Mallorca, Spain
| | - E Martínez
- Consorcio Hospitalario Provincial de Castellón, Castellón de la Plana, Spain
| | - P Villagrasa
- SOLTI Breast Cancer Research Group, Barcelona, Spain
| | - A Prat
- Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
- Department of Medical Oncology, Hospital Clínic de Barcelona, Barcelona, Spain.
- SOLTI Breast Cancer Research Group, Barcelona, Spain.
| | - P Nuciforo
- Molecular oncology group, Vall d´Hebron Institute of Oncology, Barcelona, Spain.
- SOLTI Breast Cancer Research Group, Barcelona, Spain.
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Mano MS. Pathologic response at the epicenter of the treatment decision-making process in Human Epidermal Receptor-Type 2 overexpressing (Her2+) Early Breast Cancer (EBC): Challenges and opportunities for financially-constrained healthcare systems. Breast 2020; 54:331-334. [PMID: 33279792 PMCID: PMC7724193 DOI: 10.1016/j.breast.2020.11.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 11/10/2020] [Accepted: 11/20/2020] [Indexed: 12/24/2022] Open
Abstract
After more than two decades of intensive research, tremendous progress has been achieved in the management of Human Epidermal Receptor-2 overexpressing (Her2+) Early Breast Cancer (EBC). In the latest years, major clinical trials have explored the neoadjuvant scenario, in addition to the prognostic role of pathologic complete response (pCR) and the possibility of a 'tumor biology-driven' patient selection provided by the assessment pathologic response. However, the introduction of new agents has been a major burden for financially-constrained healthcare systems-which includes those from most emerging markets (currently representing 85% of the world population) but also, to some extent, public systems from welfare states. This manuscript addresses evidence-based opportunities to promote a more rational utilization of the available resources in Her2+ EBC, in addition to areas of interest for future research in cost-efficiency.
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Affiliation(s)
- Max S Mano
- Grupo Oncoclínicas, Av. Brg. Faria Lima, 4300, 04538-132, Vila Olímpia, São Paulo, SP, Brazil; Latin American Cooperative Oncology Group (LACOG), 99A, Av. Ipiranga, 6681-806, Partenon, Porto Alegre, RS, 90619-900, Brazil.
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45
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Thanopoulou E, Khader L, Caira M, Wardley A, Ettl J, Miglietta F, Neven P, Guarneri V. Therapeutic Strategies for the Management of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Positive (HR+/HER2+) Breast Cancer: A Review of the Current Literature. Cancers (Basel) 2020; 12:E3317. [PMID: 33182657 PMCID: PMC7696181 DOI: 10.3390/cancers12113317] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 10/22/2020] [Accepted: 11/05/2020] [Indexed: 02/07/2023] Open
Abstract
Enormous advances have been made in the understanding and treatment of human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) in the last 30 years that have resulted in survival gains for affected patients. A growing body of evidence suggests that hormone receptor-positive (HR+)/HER2+ BC and HR-negative (HR-)/HER2+ BC are biologically different, with complex molecular bidirectional crosstalk between the estrogen receptor and HER2 pathway potentially affecting sensitivity to both HER2-targeted and endocrine therapy in patients with HR+/HER2+ BC. Subgroup analyses from trials enrolling patients with HER2+ BC and the results of clinical trials specifically designed to evaluate therapy in patients with HR+/HER2+ BC are helping to guide treatment decisions. In this context, encouraging results with strategies aimed at delaying or reversing drug resistance, including extended adjuvant therapy and the addition of drugs targeting alternative pathways, such as cyclin-dependent kinase (CDK) 4 and 6 inhibitors, have recently emerged. We have reached the point where tailoring the treatment according to risk and biology has become the paradigm in early BC. However, further clinical trials are needed that integrate translational research principles and identify and consider specific patient subgroups and biomarkers.
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Affiliation(s)
- Eirini Thanopoulou
- Eli Lilly and Company Limited, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK;
| | - Leila Khader
- Eli Lilly Italia S.p.A., 50019 Comune di Sesto Fiorentino, Florence, Italy; (L.K.); (M.C.)
| | - Morena Caira
- Eli Lilly Italia S.p.A., 50019 Comune di Sesto Fiorentino, Florence, Italy; (L.K.); (M.C.)
| | - Andrew Wardley
- The NIHR Manchester Clinical Research Facility at The Christie NHS Foundation Trust, School of Medical Sciences, Faculty of Biology Medicine & Health, University of Manchester, Manchester M204BX, UK;
| | - Johannes Ettl
- Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany;
| | - Federica Miglietta
- Medical Oncology 2, Istituto Oncologico Veneto IOV IRCCS, 35128 Padua, Italy;
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padua, Italy
| | - Patrick Neven
- Multidisciplinary Breast Center and Department of Gynecology and Obstetrics, UZ Leuven, 3000 Leuven, Belgium;
- Department of Oncology, KU Leuven, 3000 Leuven, Belgium
| | - Valentina Guarneri
- Medical Oncology 2, Istituto Oncologico Veneto IOV IRCCS, 35128 Padua, Italy;
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padua, Italy
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Muñoz M, Prat A. Implementing preoperative endocrine therapy in breast cancer. Lancet Oncol 2020; 21:1390-1392. [PMID: 33152280 DOI: 10.1016/s1470-2045(20)30478-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 08/06/2020] [Accepted: 08/06/2020] [Indexed: 10/23/2022]
Affiliation(s)
- Montserrat Muñoz
- Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona 08036, Spain; SOLTI Breast Cancer Research Group, Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain; Department of Medicine, University of Barcelona, Barcelona, Spain
| | - Aleix Prat
- Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona 08036, Spain; SOLTI Breast Cancer Research Group, Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain; Department of Medicine, University of Barcelona, Barcelona, Spain.
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47
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Mano M. Trastuzumab emtansine: a game changer in HER2-positive early breast cancer. Future Oncol 2020; 16:2595-2609. [PMID: 32734779 DOI: 10.2217/fon-2020-0219] [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: 11/21/2022] Open
Abstract
Trastuzumab emtansine (T-DM1), given postoperatively for 14 cycles to patients with human epidermal growth factor receptor 2-positive (HER2-positive) early breast cancer (EBC) who failed to achieve a pathological complete response after standard chemotherapy and HER2 blockade, represents probably the greatest progress in the management of this aggressive form of breast cancer since the adjuvant trastuzumab pivotal trials. This article addresses the rationale behind the conception of the KATHERINE trial, T-DM1's structure and pharmacokinetics data, clinical efficacy data of the KATHERINE trial and of other EBC trials with T-DM1, safety aspects, implications of the KATHERINE trial results to clinical practice and future perspectives in the management of HER2-positive EBC.
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Affiliation(s)
- Max Mano
- Hospital Sírio-Libanês, Oncology Center, Rua Dona Adma Jafet, 91 - Bela Vista, São Paulo - SP, 01308-050, Brazil
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48
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Dieci MV, Guarneri V. Should triple-positive breast cancer be recognized as a distinct subtype? Expert Rev Anticancer Ther 2020; 20:1011-1014. [PMID: 33021124 DOI: 10.1080/14737140.2020.1829484] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Maria Vittoria Dieci
- Department of Surgery, Oncology and Gastroenterology, University of Padova , Padova, Italy.,Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS , Padova, Italy
| | - Valentina Guarneri
- Department of Surgery, Oncology and Gastroenterology, University of Padova , Padova, Italy.,Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS , Padova, Italy
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49
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Dieci MV, Miglietta F, Griguolo G, Guarneri V. Biomarkers for HER2-positive metastatic breast cancer: Beyond hormone receptors. Cancer Treat Rev 2020; 88:102064. [PMID: 32622272 DOI: 10.1016/j.ctrv.2020.102064] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/16/2020] [Accepted: 06/18/2020] [Indexed: 12/17/2022]
Abstract
The overexpression of human epidermal growth factor receptor-2 (HER2) results in a biologically and clinically aggressive breast cancer (BC) subtype. Since the introduction of anti-HER2 targeted agents, survival rates of patients with HER2-positive metastatic BC have dramatically improved. Currently, although the treatment decision process in metastatic BC is primarily based on HER2 and hormone-receptor (HR) status, a rapidly growing body of data suggests that several other sources of biological heterogeneity may characterize HER2-positive metastatic BC. Moreover, pivotal clinical trials of new anti-HER2 antibody-drug conjugates showed encouraging results in HER2-low metastatic BC, thus leading to the possibility, in the near future, to expand the pool of patients suitable for HER2-targeted treatments. The present review summarizes and puts in perspective available evidence on biomarkers that hold the greatest promise to become potentially useful tools for optimizing HER2-positive metastatic BC patients' prognostic stratification and treatment in the next future. These biomarkers include HER2 levels and heterogeneity, HER3, intrinsic molecular subtypes by PAM50 analysis, DNA mutations, and immune-related factors. Molecular discordance between primary and metastatic tumors is also discussed.
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Affiliation(s)
- Maria Vittoria Dieci
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Medical Oncology 2, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
| | - Federica Miglietta
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Gaia Griguolo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Medical Oncology 2, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy
| | - Valentina Guarneri
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Medical Oncology 2, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy
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50
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Brandão M, Caparica R, Malorni L, Prat A, Carey LA, Piccart M. What Is the Real Impact of Estrogen Receptor Status on the Prognosis and Treatment of HER2-Positive Early Breast Cancer? Clin Cancer Res 2020; 26:2783-2788. [PMID: 32046997 PMCID: PMC8324078 DOI: 10.1158/1078-0432.ccr-19-2612] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 11/12/2019] [Accepted: 02/06/2020] [Indexed: 12/24/2022]
Abstract
HER2+ early breast cancer is a heterogeneous disease, comprising all the intrinsic breast cancer subtypes. The only biomarker available nowadays for anti-HER2 treatment selection is HER2 status itself, but estrogen receptor (ER) status is emerging as a robust predictive marker within HER2+ disease. In this Perspective, we discuss the biological and clinical differences between patients with HER2+/ER-positive (ER+) disease versus those with HER2+/ER-negative (ER-neg) tumors, namely, short-term and long-term (>5 years after diagnosis) prognosis, response to neoadjuvant treatment and benefit from adjuvant anti-HER2-targeted therapies. We also address other possible biomarkers to be used for patient selection in future clinical trials, such as gene signatures, PAM50 subtypes, tumor-infiltrating lymphocytes, PIK3CA mutations, and changes in Ki67 score during treatment and discuss their limitations. Finally, we suggest new clinical trial designs that can have an impact on clinical practice, aiming to test treatment deescalation separately for patients with HER2+/ER+ and HER2+/ER-neg tumors. We also propose an integrated classification of HER2+ disease, comprising DNA, RNA, protein expression, and microenvironment characteristics, in order to identify those tumors that are truly "HER2-addicted" and may benefit the most from anti-HER2 treatment.
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Affiliation(s)
- Mariana Brandão
- Institut Jules Bordet and Université Libre de Bruxelles (U.L.B.), Boulevard de Waterloo 121, 1000, Brussels, Belgium
| | - Rafael Caparica
- Institut Jules Bordet and Université Libre de Bruxelles (U.L.B.), Boulevard de Waterloo 121, 1000, Brussels, Belgium
| | - Luca Malorni
- "Sandro Pitigliani" Oncology Department and Translational Research Unit, Hospital of Prato, Via Suor Niccolina, Prato, Italy
| | - Aleix Prat
- Translational Genomics and Targeted Therapeutics in Solid Tumors, IDIBAPS, Barcelona, Spain
- Medical Oncology Department, Hospital Clínic of Barcelona, University of Barcelona, Barcelona, Spain
| | - Lisa A Carey
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Martine Piccart
- Institut Jules Bordet and Université Libre de Bruxelles (U.L.B.), Boulevard de Waterloo 121, 1000, Brussels, Belgium.
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