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Nakamura S, Kojima Y, Takeuchi S. Causative Genes of Homologous Recombination Deficiency (HRD)-Related Breast Cancer and Specific Strategies at Present. Curr Oncol 2025; 32:90. [PMID: 39996890 PMCID: PMC11854191 DOI: 10.3390/curroncol32020090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/29/2025] [Accepted: 01/30/2025] [Indexed: 02/26/2025] Open
Abstract
Recently, homologous recombination deficiency (HRD) has become a new target for hereditary cancers. Molecular-based approaches for hereditary cancers in the clinical setting have been reviewed. In particular, the efficacy of the PARP inhibitor has been considered by several clinical trials for various kinds of hereditary cancers. This indicates that the PARP inhibitor can be effective for any kind of BRCA mutated cancers, regardless of the organ-specific cancer. Homologous recombination deficiency (HRD) has become a new target for hereditary cancers, indicating the necessity to confirm the status of HRD-related genes. ARID1A, ATM, ATRX, PALB2, BARD1, RAD51C and CHEK2 are known as HRD-related genes for which simultaneous examination as part of panel testing is more suitable. Both surgical and medical oncologists should learn the basis of genetics including HRD. An understanding of the basic mechanism of homologous repair recombination (HRR) in BRCA-related breast cancer is mandatory for all surgical or medical oncologists because PARP inhibitors may be effective for these cancers and a specific strategy of screening for non-cancers exists. The clinical behavior of each gene should be clarified based on a large-scale database in the future, or, in other words, on real-world data. Firstly, HRD-related genes should be examined when the hereditary nature of a cancer is placed in doubt after an examination of the relevant family history. Alternatively, HRD score examination is a solution by which to identify HRD-related genes at the first step. If lifetime risk is estimated at over 20%, an annual breast MRI is necessary for high-risk screening. However, there are limited data to show its benefit compared with BRCA. Therefore, a large-scale database, including clinical information and a long-term follow-up should be established, after which a periodical assessment is mandatory. The clinical behavior of each gene should be clarified based on a large-scale database, or, in other words, real-world data.
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Affiliation(s)
- Seigo Nakamura
- Institute for Clinical Genetics and Genomics, Showa University, Tokyo 142-8555, Japan; (Y.K.); (S.T.)
- Division of Breast Surgical Oncology, Department of Surgery, Showa University, Tokyo 142-8666, Japan
| | - Yasuyuki Kojima
- Institute for Clinical Genetics and Genomics, Showa University, Tokyo 142-8555, Japan; (Y.K.); (S.T.)
- Division of Breast Surgical Oncology, Department of Surgery, Showa University, Tokyo 142-8666, Japan
| | - Sayoko Takeuchi
- Institute for Clinical Genetics and Genomics, Showa University, Tokyo 142-8555, Japan; (Y.K.); (S.T.)
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Wang Z, Lu Y, Han M, Li A, Ruan M, Tong Y, Yang C, Zhang X, Zhu C, Wang C, Shen K, Dong L, Chen X. Association between homologous recombination deficiency status and carboplatin treatment response in early triple-negative breast cancer. Breast Cancer Res Treat 2024; 208:429-440. [PMID: 39048852 PMCID: PMC11457550 DOI: 10.1007/s10549-024-07436-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 07/10/2024] [Indexed: 07/27/2024]
Abstract
BACKGROUND The aim of this study was to assess homologous recombination deficiency (HRD) status and its correlation with carboplatin treatment response in early triple-negative breast cancer (TNBC) patients. METHODS Tumor tissues from 225 consecutive TNBC patients were evaluated with an HRD panel and homologous recombination-related (HRR) gene expression data. HRD positivity was defined as a high HRD score and/or BRCA1/2 pathogenic or likely pathogenic mutation. Clinicopathological factors, neoadjuvant treatment response, and prognosis were analyzed with respect to HRD status in these TNBC patients. RESULTS HRD positivity was found in 53.3% of patients and was significantly related to high Ki67 levels (P = 0.001). In patients who received neoadjuvant chemotherapy, HRD positivity (P = 0.005) or a high HRD score (P = 0.003) was significantly associated with a greater pathological complete response (pCR) rate, especially in those treated with carboplatin-containing neoadjuvant regimens (HRD positivity vs. negativity: 50.00% vs. 17.65%, P = 0.040). HRD positivity was associated with favorable distant metastasis-free survival (hazard ratio HR 0.49, 95% confidence interval CI 0.26-0.90, P = 0.022) and overall survival (HR 0.45, 95% CI 0.20-0.99, P = 0.049), irrespective of carboplatin treatment. CONCLUSION TNBC patients with high HRDs had high Ki67 levels and BRCA mutations. HRD-positive TNBC patients treated with carboplatin had a higher pCR rate. Patients with HRD positivity had a better prognosis, irrespective of carboplatin treatment, warranting further evaluation.
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Affiliation(s)
- Zheng Wang
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Yujie Lu
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Mengyuan Han
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Anqi Li
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Miao Ruan
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Yiwei Tong
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Cuiyan Yang
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Xiaotian Zhang
- Department of Translational Oncology, Amoy Diagnostics Co., Ltd., Xiamen, 361026, China
| | - Changbin Zhu
- Department of Translational Oncology, Amoy Diagnostics Co., Ltd., Xiamen, 361026, China
| | - Chaofu Wang
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
| | - Kunwei Shen
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
| | - Lei Dong
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
| | - Xiaosong Chen
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
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Sun HK, Jiang WL, Zhang SL, Xu PC, Wei LM, Liu JB. Predictive value of tumor-infiltrating lymphocytes for neoadjuvant therapy response in triple-negative breast cancer: A systematic review and meta-analysis. World J Clin Oncol 2024; 15:920-935. [PMID: 39071463 PMCID: PMC11271722 DOI: 10.5306/wjco.v15.i7.920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 05/21/2024] [Accepted: 06/06/2024] [Indexed: 07/16/2024] Open
Abstract
BACKGROUND The association between tumor-infiltrating lymphocyte (TIL) levels and the response to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC) remains unclear. AIM To investigate the predictive potential of TIL levels for the response to NAT in TNBC patients. METHODS A systematic search of the National Center for Biotechnology Information PubMed database was performed to collect relevant published literature prior to August 31, 2023. The correlation between TIL levels and the NAT pathologic complete response (pCR) in TNBC patients was assessed using a systematic review and meta-analysis. Subgroup analysis, sensitivity analysis, and publication bias analysis were also conducted. RESULTS A total of 32 studies were included in this meta-analysis. The overall meta-analysis results indicated that the pCR rate after NAT treatment in TNBC patients in the high TIL subgroup was significantly greater than that in patients in the low TIL subgroup (48.0% vs 27.7%) (risk ratio 2.01; 95% confidence interval 1.77-2.29; P < 0.001, I 2 = 56%). Subgroup analysis revealed that the between-study heterogeneity originated from differences in study design, TIL level cutoffs, and study populations. Publication bias could have existed in the included studies. The meta-analysis based on different NAT protocols revealed that all TNBC patients with high levels of TILs had a greater rate of pCR after NAT treatment in all protocols (all P ≤ 0.01), and there was no significant between-protocol difference in the statistics among the different NAT protocols (P = 0.29). Additionally, sensitivity analysis demonstrated that the overall results of the meta-analysis remained consistent when the included studies were individually excluded. CONCLUSION TILs can serve as a predictor of the response to NAT treatment in TNBC patients. TNBC patients with high levels of TILs exhibit a greater NAT pCR rate than those with low levels of TILs, and this predictive capability is consistent across different NAT regimens.
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Affiliation(s)
- Hai-Kuan Sun
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Wen-Long Jiang
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Shi-Lei Zhang
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Peng-Cheng Xu
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Li-Min Wei
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Jiang-Bo Liu
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
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Park J, Kim JC, Lee YJ, Kim S, Kim SW, Shin EC, Lee JY, Park SH. Unique immune characteristics and differential anti-PD-1-mediated reinvigoration potential of CD8 + TILs based on BRCA1/2 mutation status in epithelial ovarian cancers. J Immunother Cancer 2024; 12:e009058. [PMID: 38964784 PMCID: PMC11227838 DOI: 10.1136/jitc-2024-009058] [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] [Accepted: 06/21/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND We aimed to investigate the distinct immunological characteristics of the tumor immune microenvironment in epithelial ovarian cancer (EOC) according to BRCA1/2 mutations status and differential PD-1 expression levels. METHODS Tumor-infiltrating lymphocytes (TILs) were collected from patients with newly diagnosed advanced-stage EOC (YUHS cohort, n=117). This YUHS cohort was compared with The Cancer Genome Atlas (TCGA) data for ovarian serous cystadenocarcinoma (n=482), in terms of survival outcomes and immune-related gene profiles according to BRCA1/2 status. We used multicolor flow cytometry to characterize the immune phenotypes and heterogeneity of TILs with or without BRCA1/2 mutations. In vitro functional assays were conducted to evaluate the reinvigorating ability of CD8+ TILs on anti-PD-1 treatment. RESULTS We found that EOC patients with BRCA1/2 mutations (BRCA1/2mt) exhibited better survival outcomes and significantly higher tumor mutation burden (TMB), compared with BRCA1/2 non-mutated (BRCA1/2wt) patients. Furthermore, CD8+ TILs within BRCA1/2mt tumors displayed characteristics indicating more severe T-cell exhaustion than their BRCA1/2wt counterparts. Notably, the capacity for anti-PD-1-mediated reinvigoration of CD8+ TILs was significantly greater in BRCA1/2wt tumors compared with BRCA1/2mt tumors. Additionally, within the BRCA1/2wt group, the frequency of PD-1highCD8+ TILs was positively correlated with the reinvigoration capacity of CD8+ TILs after anti-PD-1 treatment. CONCLUSION Our results highlight unique immune features of CD8+ TILs in EOC and a differential response to anti-PD-1 treatment, contingent on BRCA1/2 mutation status. These findings suggest that immune checkpoint blockade may be a promising frontline therapeutic option for selected BRCA1/2wt EOC patients.
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Affiliation(s)
- Junsik Park
- Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
- Department of Obstetrics and Gynecology, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea (the Republic of)
| | - Jung Chul Kim
- Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
- Department of Obstetrics and Gynecology, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea (the Republic of)
| | - Yong Jae Lee
- Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Sunghoon Kim
- Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Sang Wun Kim
- Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Eui-Cheol Shin
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (the Republic of)
| | - Jung Yun Lee
- Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Su-Hyung Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (the Republic of)
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Lee M, Yoo TK, Chae BJ, Lee A, Cha YJ, Lee J, Ahn SG, Kang J. Luminal androgen receptor subtype and tumor-infiltrating lymphocytes groups based on triple-negative breast cancer molecular subclassification. Sci Rep 2024; 14:11278. [PMID: 38760384 PMCID: PMC11101432 DOI: 10.1038/s41598-024-61640-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 05/08/2024] [Indexed: 05/19/2024] Open
Abstract
In our previous study, we developed a triple-negative breast cancer (TNBC) subtype classification that correlated with the TNBC molecular subclassification. In this study, we aimed to evaluate the predictor variables of this subtype classification on the whole slide and to validate the model's performance by using an external test set. We explored the characteristics of this subtype classification and investigated genomic alterations, including genomic scar signature scores. First, TNBC was classified into the luminal androgen receptor (LAR) and non-luminal androgen receptor (non-LAR) subtypes based on the AR Allred score (≥ 6 and < 6, respectively). Then, the non-LAR subtype was further classified into the lymphocyte-predominant (LP), lymphocyte-intermediate (LI), and lymphocyte-depleted (LD) groups based on stromal tumor-infiltrating lymphocytes (TILs) (< 20%, > 20% but < 60%, and ≥ 60%, respectively). This classification showed fair agreement with the molecular classification in the test set. The LAR subtype was characterized by a high rate of PIK3CA mutation, CD274 (encodes PD-L1) and PDCD1LG2 (encodes PD-L2) deletion, and a low homologous recombination deficiency (HRD) score. The non-LAR LD TIL group was characterized by a high frequency of NOTCH2 and MYC amplification and a high HRD score.
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Affiliation(s)
- Miseon Lee
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Tae-Kyung Yoo
- Division of Breast Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Byung Joo Chae
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ahwon Lee
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Cancer Research Institute, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yoon Jin Cha
- Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Breast Cancer Precision Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jieun Lee
- Cancer Research Institute, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung Gwe Ahn
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
- Institute for Breast Cancer Precision Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - Jun Kang
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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Wang Y, Dackus GMHE, Rosenberg EH, Cornelissen S, de Boo LW, Broeks A, Brugman W, Chan TWS, van Diest PJ, Hauptmann M, Ter Hoeve ND, Isaeva OI, de Jong VMT, Jóźwiak K, Kluin RJC, Kok M, Koop E, Nederlof PM, Opdam M, Schouten PC, Siesling S, van Steenis C, Voogd AC, Vreuls W, Salgado RF, Linn SC, Schmidt MK. Long-term outcomes of young, node-negative, chemotherapy-naïve, triple-negative breast cancer patients according to BRCA1 status. BMC Med 2024; 22:9. [PMID: 38191387 PMCID: PMC10775514 DOI: 10.1186/s12916-023-03233-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 12/15/2023] [Indexed: 01/10/2024] Open
Abstract
BACKGROUND Due to the abundant usage of chemotherapy in young triple-negative breast cancer (TNBC) patients, the unbiased prognostic value of BRCA1-related biomarkers in this population remains unclear. In addition, whether BRCA1-related biomarkers modify the well-established prognostic value of stromal tumor-infiltrating lymphocytes (sTILs) is unknown. This study aimed to compare the outcomes of young, node-negative, chemotherapy-naïve TNBC patients according to BRCA1 status, taking sTILs into account. METHODS We included 485 Dutch women diagnosed with node-negative TNBC under age 40 between 1989 and 2000. During this period, these women were considered low-risk and did not receive chemotherapy. BRCA1 status, including pathogenic germline BRCA1 mutation (gBRCA1m), somatic BRCA1 mutation (sBRCA1m), and tumor BRCA1 promoter methylation (BRCA1-PM), was assessed using DNA from formalin-fixed paraffin-embedded tissue. sTILs were assessed according to the international guideline. Patients' outcomes were compared using Cox regression and competing risk models. RESULTS Among the 399 patients with BRCA1 status, 26.3% had a gBRCA1m, 5.3% had a sBRCA1m, 36.6% had tumor BRCA1-PM, and 31.8% had BRCA1-non-altered tumors. Compared to BRCA1-non-alteration, gBRCA1m was associated with worse overall survival (OS) from the fourth year after diagnosis (adjusted HR, 2.11; 95% CI, 1.18-3.75), and this association attenuated after adjustment for second primary tumors. Every 10% sTIL increment was associated with 16% higher OS (adjusted HR, 0.84; 95% CI, 0.78-0.90) in gBRCA1m, sBRCA1m, or BRCA1-non-altered patients and 31% higher OS in tumor BRCA1-PM patients. Among the 66 patients with tumor BRCA1-PM and ≥ 50% sTILs, we observed excellent 15-year OS (97.0%; 95% CI, 92.9-100%). Conversely, among the 61 patients with gBRCA1m and < 50% sTILs, we observed poor 15-year OS (50.8%; 95% CI, 39.7-65.0%). Furthermore, gBRCA1m was associated with higher (adjusted subdistribution HR, 4.04; 95% CI, 2.29-7.13) and tumor BRCA1-PM with lower (adjusted subdistribution HR, 0.42; 95% CI, 0.19-0.95) incidence of second primary tumors, compared to BRCA1-non-alteration. CONCLUSIONS Although both gBRCA1m and tumor BRCA1-PM alter BRCA1 gene transcription, they are associated with different outcomes in young, node-negative, chemotherapy-naïve TNBC patients. By combining sTILs and BRCA1 status for risk classification, we were able to identify potential subgroups in this population to intensify and optimize adjuvant treatment.
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Affiliation(s)
- Yuwei Wang
- Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Gwen M H E Dackus
- Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Efraim H Rosenberg
- Division of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Sten Cornelissen
- Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
- Core Facility Molecular Pathology and Biobanking, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Leonora W de Boo
- Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Annegien Broeks
- Core Facility Molecular Pathology and Biobanking, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wim Brugman
- Genomics Core Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Terry W S Chan
- Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Paul J van Diest
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Michael Hauptmann
- Institute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, Neuruppin, Germany
| | - Natalie D Ter Hoeve
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Olga I Isaeva
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Vincent M T de Jong
- Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Katarzyna Jóźwiak
- Institute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, Neuruppin, Germany
| | - Roelof J C Kluin
- Genomics Core Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Marleen Kok
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Esther Koop
- Department of Pathology, Gelre Ziekenhuizen, Apeldoorn, The Netherlands
| | - Petra M Nederlof
- Division of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Mark Opdam
- Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Philip C Schouten
- Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Sabine Siesling
- Department of Research and Development, Netherlands Comprehensive Cancer Organization, Utrecht, The Netherlands
- Department of Health Technology and Services Research, Technical Medical Centre, University of Twente, Enschede, The Netherlands
| | | | - Adri C Voogd
- Department of Epidemiology, Maastricht University, Maastricht, The Netherlands
| | - Willem Vreuls
- Department of Pathology, Canisius Wilhelmina Ziekenhuis, Nijmegen, The Netherlands
| | - Roberto F Salgado
- Department of Pathology, GZA-ZNA Hospitals, Antwerp, Belgium
- Division of Research, Peter MacCallum Cancer Center, Melbourne, Australia
| | - Sabine C Linn
- Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Marjanka K Schmidt
- Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
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Heimes AS, Riedel N, Almstedt K, Krajnak S, Schwab R, Stewen K, Lebrecht A, Battista MJ, Brenner W, Hasenburg A, Schmidt M. Prognostic Impact of CD38- and IgκC-Positive Tumor-Infiltrating Plasma Cells in Triple-Negative Breast Cancer. Int J Mol Sci 2023; 24:15219. [PMID: 37894900 PMCID: PMC10607675 DOI: 10.3390/ijms242015219] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 10/12/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
Due to a higher mutational load, triple-negative breast cancer (TNBC) is characterized by a higher immunogenicity compared to other subtypes. In this context, we analyzed the prognostic significance of tumor-infiltrating plasma cells in a cohort of 107 triple-negative breast cancer patients. Tumor-infiltrating plasma cells were analyzed via immunohistochemistry using the plasma cell markers CD38 and IgκC. The prognostic impact of the CD38 and IgκC expression was evaluated using the Kaplan-Meier plots and Cox regression analyses. A Spearman-Rho correlation coefficient was used to evaluate a possible association between plasma cell infiltration and the BRCA mutation status. The study cohort consisted of 107 patients with early-stage TNBC, who were treated between 2009 and 2016 at the Department of Gynecology and Obstetrics, University Medical Center Mainz, Germany. The median follow-up was five years. The Kaplan-Meier survival analysis showed that higher tumor infiltration with CD38-positive plasma cells was associated with significantly longer metastasis-free survival (MFS) (p = 0.039 Log Rank). In the multivariate Cox regression analysis for metastasis-free survival, in which additional clinicopathological factors (age, tumor size, nodal status, and grading) were considered, CD38 was identified as an independent prognostic factor within the analyzed cohort (HR 0.438, 95% CI 0.195-0.983; p = 0.045). In addition to the CD38 expression, the nodal status was also identified as an independent prognostic factor in multivariate Cox regression. Regarding the IgκC expression, a higher IgκC expression was shown to be associated with a better outcome, although this effect was not statistically significant. Furthermore, we were able to show a significant correlation between plasma cell infiltration and the BRCA mutation status. A favorable prognostic significance of tumor-infiltrating plasma cells could be demonstrated in triple-negative breast cancer immunohistochemically analyzed for the CD38 and IgκC expression. CD38 was identified as an independent prognostic factor via multivariate Cox regression.
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Affiliation(s)
- Anne-Sophie Heimes
- Department of Obstetrics and Gynecology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany; (N.R.); (K.A.); (S.K.); (R.S.); (K.S.); (A.L.); (M.J.B.); (W.B.); (A.H.); (M.S.)
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Ye S, Wu J, Yao L, He J. Clinicopathological characteristics and genetic variations of uterine tumours resembling ovarian sex cord tumours. J Clin Pathol 2022; 75:776-781. [PMID: 34348985 PMCID: PMC9606539 DOI: 10.1136/jclinpath-2021-207441] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 07/03/2021] [Indexed: 12/29/2022]
Abstract
AIMS To investigate the clinicopathological and molecular characteristics of uterine tumours resembling ovarian sex cord tumours (UTROSCTs) and the value of molecular diversity in the clinical diagnosis and treatment. METHODS Five patients with UTROSCT were enrolled, and their clinical data, pathological morphologies, immunophenotypes and molecular features were analysed. Fluorescence in situ hybridisation for NCOA1, NCOA2, NCOA3, JAZF1 and PHF1 and next-generation sequencing for 27 homologous recombination/repair (HRR) pathway genes were performed on five and three UTROSCT specimens, respectively. RESULTS All five patients were treated for abnormal uterine bleeding and grossly presented with intrauterine polyps. Under a microscope, tumour cells grew diffusely and presented a cordlike arrangement and glandular duct-like structures, with nuclei ranging from round to oval, vesicular chromatin and visible nucleoli in some cases. The mitotic count was less than 3/10 high-power fields. Immunohistochemistry showed sex cord, epithelial cell and smooth muscle cell biomarkers and diffuse, strong staining for B cell lymphoma-2 (BCL-2). NCOA1 and NCOA3 rearrangements were identified in 80% (4/5) of the cases. JAZF1 and PHF1 rearrangements were not detected in any of five patients. HRR pathway gene mutations were detected in all three patients, including FANCE, ATR and ARID1A mutations in one case each. CONCLUSION UTROSCT is a rare mesenchymal tumour, and biopsy specimens are easily misdiagnosed. UTROSCT diagnosis requires the combined use of biomarkers and molecular detection. BCL-2 has potential diagnostic value as a marker. UTROSCT can have mutations related to the HRR pathway, suggesting that this tumour type may be sensitive to platinum/poly (ADP-ribose) polymerase inhibitors.
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Affiliation(s)
- Shan Ye
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China,Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China,Department of Pathology, Anhui Provincial Cancer Hospital, Hefei, Anhui, China
| | - Jing Wu
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China,Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China,Department of Pathology, Anhui Provincial Cancer Hospital, Hefei, Anhui, China
| | - Lingli Yao
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China,Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Jie He
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China,Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China,Department of Pathology, Anhui Provincial Cancer Hospital, Hefei, Anhui, China
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9
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Kolberg-Liedtke C, Feuerhake F, Garke M, Christgen M, Kates R, Grischke EM, Forstbauer H, Braun M, Warm M, Hackmann J, Uleer C, Aktas B, Schumacher C, Kuemmel S, Wuerstlein R, Graeser M, Nitz U, Kreipe H, Gluz O, Harbeck N. Impact of stromal tumor-infiltrating lymphocytes (sTILs) on response to neoadjuvant chemotherapy in triple-negative early breast cancer in the WSG-ADAPT TN trial. Breast Cancer Res 2022; 24:58. [PMID: 36056374 PMCID: PMC9438265 DOI: 10.1186/s13058-022-01552-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 07/25/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Higher density of stromal tumor-infiltrating lymphocytes (sTILs) at baseline has been associated with increased rates of pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) in triple-negative breast cancer (TNBC). While evidence supports favorable association of pCR with survival in TNBC, an independent impact of sTILs (after adjustment for pCR) on survival is not yet established. Moreover, the impact of sTIL dynamics during NACT on pCR and survival in TNBC is unknown. METHODS The randomized WSG-ADAPT TN phase II trial compared efficacy of 12-week nab-paclitaxel with gemcitabine versus carboplatin. This preplanned translational analysis assessed impacts of sTIL measurements at baseline (sTIL-0) and after 3 weeks of chemotherapy (sTIL-3) on pCR and invasive disease-free survival (iDFS). Predictive performance of sTIL-0 and sTIL-3 for pCR was quantified by ROC analysis and logistic regression; Kaplan-Meier estimation and Cox regression (with mediation analysis) were used to determine their impact on iDFS. RESULTS For prediction of pCR, the AUC statistics for sTIL-0 and sTIL-3 were 0.60 and 0.63, respectively, in all patients; AUC for sTIL-3 was higher in NP/G. The positive predictive value (PPV) of "lymphocyte-predominant" status (sTIL-0 ≥ 60%) at baseline was 59.3%, though only 13.0% of patients had this status. To predict non-pCR, the cut point sTIL-0 ≤ 10% yielded PPV = 69.5% while addressing 33.8% of patients. Higher sTIL levels (particularly at 3 weeks) were independently and favorably associated with better iDFS, even after adjusting for pCR. For example, the adjusted hazard ratio for 3-week sTILs ≥ 60% (vs. < 60%) was 0.48 [0.23-0.99]. Low cellularity in 3-week biopsies was the strongest individual predictor for pCR (in both therapy arms), but not for iDFS. CONCLUSION The independent impact of sTILs on iDFS suggests that favorable immune response can influence key tumor biological processes for long-term survival. The results suggest that the reliability of pCR following neoadjuvant therapy as a surrogate for survival could vary among subgroups in TNBC defined by immune response or other factors. Dynamic measurements of sTILs under NACT could support immune response-guided patient selection for individualized therapy approaches for both very low levels (more effective therapies) and very high levels (de-escalation concepts). TRIAL REGISTRATION Clinical trials No: NCT01815242, retrospectively registered January 25, 2013.
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Affiliation(s)
- Cornelia Kolberg-Liedtke
- Department of Gynecology and Obstetrics, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany.
| | | | | | | | - Ronald Kates
- West German Study Group, Mönchengladbach, Germany
| | | | | | - Michael Braun
- Breast Center, Rotkreuz Clinics Munich, Munich, Germany
| | - Mathias Warm
- Breast Center, City Hospital Holweide, Cologne, Germany
| | | | | | - Bahriye Aktas
- Department of Gynecology, University Hospital Leipzig, Leipzig, 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
| | - Rachel Wuerstlein
- West German Study Group, Mönchengladbach, Germany
- Breast Center, LMU University Hospital, Munich, Germany
| | - Monika Graeser
- West German Study Group, Mönchengladbach, Germany
- University Hospital Hamburg-Eppendorf, Hamburg, Germany
- Breast Center Niederrhein, Ev. Hospital Bethesda, Mönchengladbach, Germany
| | - Ulrike Nitz
- West German Study Group, Mönchengladbach, Germany
- Breast Center Niederrhein, Ev. Hospital Bethesda, Mönchengladbach, Germany
| | - Hans Kreipe
- Institute of Pathology, Medical School Hannover, Hannover, Germany
| | - Oleg Gluz
- West German Study Group, Mönchengladbach, Germany
- Breast Center Niederrhein, Ev. Hospital Bethesda, Mönchengladbach, Germany
| | - Nadia Harbeck
- West German Study Group, Mönchengladbach, Germany
- Breast Center, LMU University Hospital, Munich, Germany
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10
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Yamashita N, Kufe D. Addiction of Cancer Stem Cells to MUC1-C in Triple-Negative Breast Cancer Progression. Int J Mol Sci 2022; 23:8219. [PMID: 35897789 PMCID: PMC9331006 DOI: 10.3390/ijms23158219] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 02/01/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options. TNBC progression is associated with expansion of cancer stem cells (CSCs). Few insights are available regarding druggable targets that drive the TNBC CSC state. This review summarizes the literature on TNBC CSCs and the compelling evidence that they are addicted to the MUC1-C transmembrane protein. In normal epithelia, MUC1-C is activated by loss of homeostasis and induces reversible wound-healing responses of inflammation and repair. However, in settings of chronic inflammation, MUC1-C promotes carcinogenesis. MUC1-C induces EMT, epigenetic reprogramming and chromatin remodeling in TNBC CSCs, which are dependent on MUC1-C for self-renewal and tumorigenicity. MUC1-C-induced lineage plasticity in TNBC CSCs confers DNA damage resistance and immune evasion by chronic activation of inflammatory pathways and global changes in chromatin architecture. Of therapeutic significance, an antibody generated against the MUC1-C extracellular domain has been advanced in a clinical trial of anti-MUC1-C CAR T cells and in IND-enabling studies for development as an antibody-drug conjugate (ADC). Agents targeting the MUC1-C cytoplasmic domain have also entered the clinic and are undergoing further development as candidates for advancing TNBC treatment. Eliminating TNBC CSCs will be necessary for curing this recalcitrant cancer and MUC1-C represents a promising druggable target for achieving that goal.
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Affiliation(s)
- Nami Yamashita
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Donald Kufe
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
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11
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Zeng L, Li SH, Xu SY, Chen K, Qin LJ, Liu XY, Wang F, Fu S, Deng L, Wang FH, Miao L, Li L, Liu N, Wang R, Wang HY. Clinical Significance of a CD3/CD8-Based Immunoscore in Neuroblastoma Patients Using Digital Pathology. Front Immunol 2022; 13:878457. [PMID: 35619699 PMCID: PMC9128405 DOI: 10.3389/fimmu.2022.878457] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
Background Infiltrating immune cells have been reported as prognostic markers in many cancer types. We aimed to evaluate the prognostic role of tumor-infiltrating lymphocytes, namely CD3+ T cells, CD8+ cytotoxic T cells and memory T cells (CD45RO+), in neuroblastoma. Patients and Methods Immunohistochemistry was used to determine the expression of CD3, CD8 and CD45RO in the tumor samples of 244 neuroblastoma patients. We then used digital pathology to calculate the densities of these markers and derived an immunoscore based on such densities. Results Densities of CD3+ and CD8+ T cells in tumor were positively associated with the overall survival (OS) and event-free survival (EFS), whereas density of CD45RO+ T cells in tumor was negatively associated with OS but not EFS. An immunoscore with low density of CD3 and CD8 (CD3-CD8-) was indictive of a greater risk of death (hazard ratio 6.39, 95% confidence interval 3.09-13.20) and any event (i.e., relapse at any site, progressive disease, second malignancy, or death) (hazard ratio 4.65, 95% confidence interval 2.73-7.93). Multivariable analysis revealed that the CD3-CD8- immunoscore was an independent prognostic indicator for OS, even after adjusting for other known prognostic indicators. Conclusions The new immunoscore based on digital pathology evaluated densities of tumor-infiltrating CD3+ and CD8+ T cells contributes to the prediction of prognosis in neuroblastoma patients.
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Affiliation(s)
- Liang Zeng
- Department of Pathology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, National Children's Medical Center for South Central Region, Guangzhou, China
| | - Shu-Hua Li
- Molecular Diagnosis and Gene Testing Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Shuo-Yu Xu
- Bio-totem Pte. Ltd., Foshan, China.,Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Kai Chen
- Department of Pathology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, National Children's Medical Center for South Central Region, Guangzhou, China
| | - Liang-Jun Qin
- Department of Pathology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, National Children's Medical Center for South Central Region, Guangzhou, China
| | - Xiao-Yun Liu
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Fang Wang
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Sha Fu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Cellular & Molecular Diagnostics Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ling Deng
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Feng-Hua Wang
- Departments of Thoracic Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, National Children's Medical Center for South Central Region, Guangzhou, China
| | - Lei Miao
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, National Children's Medical Center for South Central Region, Guangzhou, China
| | - Le Li
- Departments of Thoracic Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, National Children's Medical Center for South Central Region, Guangzhou, China
| | - Na Liu
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Ran Wang
- Department of Pathology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Hai-Yun Wang
- Department of Pathology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, National Children's Medical Center for South Central Region, Guangzhou, China.,Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, National Children's Medical Center for South Central Region, Guangzhou, China
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12
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Immune microenvironment, homologous recombination deficiency, and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: Japan Breast Cancer Research Group (JBCRG)22 TR. BMC Med 2022; 20:136. [PMID: 35462552 PMCID: PMC9036790 DOI: 10.1186/s12916-022-02332-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/10/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is a biologically diverse disease, with characteristics such as homologous recombination deficiency (HRD), gene mutation, and immune reactions. Japan Breast Cancer Research Group 22 is a multicenter trial examining TNBC's response to neoadjuvant chemotherapy (NAC) according to the HRD status. This translational research investigated the clinical significance of the immune microenvironment of TNBC in association with HRD, tumor BRCA1/2 (tBRCA1/2) mutation, and response to NAC. METHODS Patients aged below 65 years with high HRD or germline BRCA1/2 (gBRCA1/2) mutation randomly received paclitaxel + carboplatin (group A1) or eribulin + carboplatin (A2), followed by anthracycline. Patients aged below 65 years with low HRD or those aged 65 years or older without gBRCA1/2 mutation randomly received eribulin + cyclophosphamide (B1) or eribulin + capecitabine (B2); nonresponders to the first four cycles of the therapy received anthracycline. A pathological complete response (pCR) was defined as the absence of residual cancer cells in the tissues. Pretreatment biopsy specimens were stained by multiplexed fluorescent immunohistochemistry using antibodies against CD3, CD4, CD8, Foxp3, CD204, and pan-cytokeratin. Immune cells with specific phenotypes were counted per mm2 in cancer cell nests (intratumor) and stromal regions. The immune cell densities were compared with clinicopathological and genetic factors including tumor response. RESULTS This study analyzed 66 samples. T1 tumors had a significantly higher density of intratumoral CD8+ T cells than T2 or larger tumors. The tBRCA1/2 mutation or HRD status was not associated with the density of any immune cell. The density of intratumoral and stromal CD4+ T cells was higher in patients showing pCR than in those without pCR. In a multivariate analysis, intratumoral and stromal CD4+ T cell density significantly predicted pCR independent of age, chemotherapy dose, HRD status, and treatment groups (P = 0.009 and 0.0057, respectively). In a subgroup analysis, the predictive value of intratumoral and stromal CD4+ T cell density persisted in the platinum-containing chemotherapy group (A1+A2) but not in the non-platinum-containing group (B1+B2). CONCLUSIONS Intratumoral and stromal CD4+ T cell density was an independent predictor of pCR in patients with TNBC. A larger study is warranted to confirm the results. TRIAL REGISTRATION UMIN000023162.
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13
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Mamdani H, Matosevic S, Khalid AB, Durm G, Jalal SI. Immunotherapy in Lung Cancer: Current Landscape and Future Directions. Front Immunol 2022; 13:823618. [PMID: 35222404 PMCID: PMC8864096 DOI: 10.3389/fimmu.2022.823618] [Citation(s) in RCA: 191] [Impact Index Per Article: 63.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 01/20/2022] [Indexed: 12/11/2022] Open
Abstract
Over the past decade, lung cancer treatment has undergone a major paradigm shift. A greater understanding of lung cancer biology has led to the development of many effective targeted therapies as well as of immunotherapy. Immune checkpoint inhibitors (ICIs) have shown tremendous benefit in the treatment of non-small cell lung cancer (NSCLC) and are now being used as first-line therapies in metastatic disease, consolidation therapy following chemoradiation in unresectable locally advanced disease, and adjuvant therapy following surgical resection and chemotherapy in resectable disease. Despite these benefits, predicting who will respond to ICIs has proven to be difficult and there remains a need to discover new predictive immunotherapy biomarkers. Furthermore, resistance to ICIs in lung cancer is frequent either because of a lack of response or disease progression after an initial response. The utility of ICIs in the treatment of small cell lung cancer (SCLC) remains limited to first-line treatment of extensive stage disease in combination with chemotherapy with modest impact on overall survival. It is thus important to explore and exploit additional targets to reap the full benefits of immunotherapy in the treatment of lung cancer. Here, we will summarize the current state of immunotherapy in lung cancer, discuss novel targets, and explore the intersection between DNA repair defects and immunotherapy.
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Affiliation(s)
- Hirva Mamdani
- Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States
| | - Sandro Matosevic
- Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, United States
| | - Ahmed Bilal Khalid
- Department of Internal Medicine, Indiana University, Indianapolis, IN, United States
| | - Gregory Durm
- Department of Internal Medicine, Division of Hematology/Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Shadia I. Jalal
- Department of Internal Medicine, Division of Hematology/Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United States
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14
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Zhou Q, Dong J, Sun Q, Lu N, Pan Y, Han X. Role of neutrophil-to-lymphocyte ratio as a prognostic biomarker in patients with breast cancer receiving neoadjuvant chemotherapy: a meta-analysis. BMJ Open 2021; 11:e047957. [PMID: 34561257 PMCID: PMC8475153 DOI: 10.1136/bmjopen-2020-047957] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 09/06/2021] [Indexed: 01/04/2023] Open
Abstract
OBJECTIVE The neutrophil-to-lymphocyte ratio (NLR) is recognised as a suitable prognostic biomarker in patients with breast cancer. Nevertheless, the efficacy of this biomarker in predicting the pathological complete response (pCR) and survival in patients with breast cancer receiving neoadjuvant chemotherapy (NACT) is still controversial. This meta-analysis aimed to identify the association between baseline NLR and the prognosis of patients with breast cancer treated with NACT. DESIGN Meta-analysis. DATA SOURCES Relevant literature published before 1 May 2021 was searched using the Cochrane Library, Embase, PubMed and the Web of Science databases. ELIGIBILITY CRITERIA All studies involving patients with breast cancer treated with NACT and peripheral blood pretreatment NLR recorded as a dichotomous variable were included. DATA EXTRACTION AND SYNTHESIS Two researchers independently extracted and evaluated OR/HR and its 95% CIs of survival outcomes and clinicopathological parameters. RESULTS A total of 19 studies were identified. From each study, the impact of NLR on the pCR, OR and HR, with their 95% CIs were extracted and combined using either a random or fixed-effects model. The results indicate that a higher pCR in patients with a low NLR (OR 1.620, 95% CI 1.209 to 2.169, p＜0.001). In addition, an elevated NLR predicted lower disease-free survival (HR 2.269, 95% CI 1.557 to 3.307, p<0.001) and overall survival (HR 1.691, 95% CI 1.365 to 2.096, p<0.001) in patients with breast cancer treated with NACT. CONCLUSIONS NLR is a suitable biomarker for predicting pCR and survival in patients with breast cancer receiving NACT.
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Affiliation(s)
- Qiong Zhou
- Department of Oncology, Provincial Hospital Affiliated to Anhui Medical University, Hefei, China
| | - Jie Dong
- Department of Oncology, Provincial Hospital Affiliated to Anhui Medical University, Hefei, China
| | - Qingqing Sun
- Department of Oncology, Provincial Hospital Affiliated to Anhui Medical University, Hefei, China
| | - Nannan Lu
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, Hefei, Anhui, China
| | - Yueyin Pan
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, Hefei, Anhui, China
| | - Xinghua Han
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, Hefei, Anhui, China
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15
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Clark CA, Yang ES. Harnessing DNA Repair Defects to Augment Immune-Based Therapies in Triple-Negative Breast Cancer. Front Oncol 2021; 11:703802. [PMID: 34631532 PMCID: PMC8497895 DOI: 10.3389/fonc.2021.703802] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 08/23/2021] [Indexed: 12/13/2022] Open
Abstract
Triple-negative breast cancer (TNBC) has poor prognosis with limited treatment options, with little therapeutic progress made during the past several decades. DNA damage response (DDR) associated therapies, including radiation and inhibitors of DDR, demonstrate potential efficacy against TNBC, especially under the guidance of genomic subtype-directed treatment. The tumor immune microenvironment also contributes greatly to TNBC malignancy and response to conventional and targeted therapies. Immunotherapy represents a developing trend in targeted therapies directed against TNBC and strategies combining immunotherapy and modulators of the DDR pathways are being pursued. There is increasing understanding of the potential interplay between DDR pathways and immune-associated signaling. As such, the question of how we treat TNBC regarding novel immuno-molecular strategies is continually evolving. In this review, we explore the current and upcoming treatment options of TNBC in the context of DNA repair mechanisms and immune-based therapies, with a focus on implications of recent genomic analyses and clinical trial findings.
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Affiliation(s)
- Curtis A. Clark
- Department of Radiation Oncology, University of Alabama at Birmingham (UAB) School of Medicine, Birmingham, AL, United States
| | - Eddy S. Yang
- Department of Radiation Oncology, University of Alabama at Birmingham (UAB) School of Medicine, Birmingham, AL, United States
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham (UAB) School of Medicine, Birmingham, AL, United States
- Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham (UAB) School of Medicine, Birmingham, AL, United States
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16
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Perkhofer L, Golan T, Cuyle PJ, Matysiak-Budnik T, Van Laethem JL, Macarulla T, Cauchin E, Kleger A, Beutel AK, Gout J, Stenzinger A, Van Cutsem E, Bellmunt J, Hammel P, O’Reilly EM, Seufferlein T. Targeting DNA Damage Repair Mechanisms in Pancreas Cancer. Cancers (Basel) 2021; 13:4259. [PMID: 34503069 PMCID: PMC8428219 DOI: 10.3390/cancers13174259] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 08/06/2021] [Indexed: 12/14/2022] Open
Abstract
Impaired DNA damage repair (DDR) is increasingly recognised as a hallmark in pancreatic ductal adenocarcinoma (PDAC). It is estimated that around 14% of human PDACs harbour mutations in genes involved in DDR, including, amongst others, BRCA1/2, PALB2, ATM, MSH2, MSH6 and MLH1. Recently, DDR intervention by PARP inhibitor therapy has demonstrated effectiveness in germline BRCA1/2-mutated PDAC. Extending this outcome to the significant proportion of human PDACs with somatic or germline mutations in DDR genes beyond BRCA1/2 might be beneficial, but there is a lack of data, and consequently, no clear recommendations are provided in the field. Therefore, an expert panel was invited by the European Society of Digestive Oncology (ESDO) to assess the current knowledge and significance of DDR as a target in PDAC treatment. The aim of this virtual, international expert meeting was to elaborate a set of consensus recommendations on testing, diagnosis and treatment of PDAC patients with alterations in DDR pathways. Ahead of the meeting, experts completed a 27-question survey evaluating the key issues. The final recommendations herein should aid in facilitating clinical practice decisions on the management of DDR-deficient PDAC.
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Affiliation(s)
- Lukas Perkhofer
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany; (L.P.); (A.K.); (A.K.B.); (J.G.)
| | - Talia Golan
- Oncology Institute, Sheba Medical Center, Tel Aviv University, Tel Aviv 52621, Israel;
| | - Pieter-Jan Cuyle
- Digestive Oncology Department, Imelda General Hospital, 2820 Bonheiden, Belgium;
- University Hospitals Gasthuisberg Leuven and KU Leuven, 3000 Leuven, Belgium;
| | - Tamara Matysiak-Budnik
- IMAD, Department of Gastroenterology and Digestive Oncology, Hôtel Dieu, CHU de Nantes, 44000 Nantes, France; (T.M.-B.); (E.C.)
| | - Jean-Luc Van Laethem
- GI Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium;
| | - Teresa Macarulla
- Vall d’Hebrón University Hospital and Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain;
| | - Estelle Cauchin
- IMAD, Department of Gastroenterology and Digestive Oncology, Hôtel Dieu, CHU de Nantes, 44000 Nantes, France; (T.M.-B.); (E.C.)
| | - Alexander Kleger
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany; (L.P.); (A.K.); (A.K.B.); (J.G.)
| | - Alica K. Beutel
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany; (L.P.); (A.K.); (A.K.B.); (J.G.)
| | - Johann Gout
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany; (L.P.); (A.K.); (A.K.B.); (J.G.)
| | - Albrecht Stenzinger
- Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Eric Van Cutsem
- University Hospitals Gasthuisberg Leuven and KU Leuven, 3000 Leuven, Belgium;
| | - Joaquim Bellmunt
- Medical Oncology, University Hospital del Mar, 08003 Barcelona, Spain;
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | | | - Eileen M. O’Reilly
- Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
- Department of Medicine, David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Thomas Seufferlein
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany; (L.P.); (A.K.); (A.K.B.); (J.G.)
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Alkassis S, Yazdanpanah O, Philip PA. BRCA mutations in pancreatic cancer and progress in their targeting. Expert Opin Ther Targets 2021; 25:547-557. [PMID: 34289788 DOI: 10.1080/14728222.2021.1957462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Introduction: Genomic instability resulting from DNA damage repair (DDR) deficiencies is a hallmark of cancer and offers treatment opportunities. Homologous recombination DDR defect is a result of multiple critical gene mutations, including BRCA1/2. Targeting DNA DDR defects in pancreatic cancer (PC) is emerging as a potential treatment strategy with current focus on BRCA mutations.Areas covered: Challenges in treating patients with PC are explained. We review DDR defects as a treatment target in PC, specifically, germline BRCA mutation and sensitivity to platinum compounds and exploiting the strategy of synthetic lethality using poly (ADP-ribose) polymerase (PARP) inhibition. Literature review was undertaken through PubMed, Google Scholar, and Clinicaltrials.gov website.Expert opinion: DDR defects are promising targets for novel therapies in PC. Early application of such strategy is in patient subgroup with BRCA germline mutation, which is seen in only 5-7% of the PC population. The oral PARP inhibitor olaparib in the maintenance setting represents the first targeted therapy in metastatic PC based on a phase 3 study. There is a very modest benefit for patients with PC using PARP inhibitors. Future work must improve our understanding of mechanisms of sensitivity and resistance to PARP inhibitors in PC and enhance the molecular selection of patients for such therapy.
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Affiliation(s)
- Samer Alkassis
- Internal Medicine Department, Wayne State University/Detroit Medical Center, Detroit, MI, USA
| | - Omid Yazdanpanah
- Internal Medicine Department, Wayne State University/Detroit Medical Center, Detroit, MI, USA
| | - Philip Agop Philip
- Division of Hematology/Oncology, Karmanos Cancer Institute, Detroit, MI, USA
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Sarradin V, Lusque A, Filleron T, Dalenc F, Franchet C. Immune microenvironment changes induced by neoadjuvant chemotherapy in triple-negative breast cancers: the MIMOSA-1 study. Breast Cancer Res 2021; 23:61. [PMID: 34039396 PMCID: PMC8157437 DOI: 10.1186/s13058-021-01437-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 05/12/2021] [Indexed: 02/06/2023] Open
Abstract
Background The immune microenvironment (IME) of triple-negative breast cancers (TNBCs) and its modulation by neoadjuvant chemotherapy (NACT) remain to be fully characterized. Our current study aims to evaluate NACT-induced IME changes and assess the prognostic value of specific immune biomarkers. Methods Tumor-infiltrating lymphocytes (TILs) were identified from hematoxylin-eosin-stained sections of paired pre- and post-NACT tumor samples from a TNBC cohort (n = 66) and expression of PD-L1, TIM-3, and LAG-3 evaluated by immunohistochemistry. Results Overall TIL counts and PD-L1 expression did not differ pre- and post-NACT, but there was a response-specific statistically significant difference. TIL counts decreased in 65.5% of patients who achieved a pathological complete response (pCR) and increased in 56.8% of no-pCR patients (p = 0.0092). PD-L1 expression was significantly more frequently lost after NACT in pCR than in no-pCR patients (41.4% vs 16.2%, p = 0.0020). TIM-3 positivity (≥ 1%) was significantly more frequent after NACT (p < 0.0001) with increases in expression levels occurring more frequently in no-pCR than in pCR patients (51.4% vs 31%). LAG-3 expression significantly decreased after NACT, but there was no difference between response groups. Before NACT, a high TIL count (> 10%) was significantly associated with better overall survival (OS), p = 0.0112. After NACT, PD-L1 positivity and strong TIM-3 positivity (≥ 5%) were both associated with significantly worse OS (p = 0.0055 and p = 0.0274, respectively). Patients positive for both PD-L1 and TIM-3 had the worst prognosis (p = 0.0020), even when only considering patients who failed to achieve a pCR, p = 0.0479. Conclusions NACT induces significant IME changes in TNBCs. PD-L1 and TIM-3 expression post-NACT may yield important prognostic information for TNBC patients. Supplementary Information The online version contains supplementary material available at 10.1186/s13058-021-01437-4.
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Affiliation(s)
- Victor Sarradin
- Department of Medical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, IUCT-Oncopole, 1 avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France.
| | - Amélie Lusque
- Department of Biostatistics, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, IUCT-Oncopole, Toulouse, France
| | - Thomas Filleron
- Department of Biostatistics, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, IUCT-Oncopole, Toulouse, France
| | - Florence Dalenc
- Department of Medical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, IUCT-Oncopole, 1 avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France
| | - Camille Franchet
- Department of Pathology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, IUCT-Oncopole, Toulouse, France
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Yamashita N, Long M, Fushimi A, Yamamoto M, Hata T, Hagiwara M, Bhattacharya A, Hu Q, Wong KK, Liu S, Kufe D. MUC1-C integrates activation of the IFN-γ pathway with suppression of the tumor immune microenvironment in triple-negative breast cancer. J Immunother Cancer 2021; 9:jitc-2020-002115. [PMID: 33495298 PMCID: PMC7839859 DOI: 10.1136/jitc-2020-002115] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2020] [Indexed: 01/09/2023] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) have had a profound impact on the treatment of many tumors; however, their effectiveness against triple-negative breast cancers (TNBCs) has been limited. One factor limiting responsiveness of TNBCs to ICIs is a lack of functional tumor-infiltrating lymphocytes (TILs) in ‘non-inflamed’ or ‘cold’ tumor immune microenvironments (TIMEs), although by unknown mechanisms. Targeting MUC1-C in a mouse transgenic TNBC tumor model increases cytotoxic tumor-infiltrating CD8+ T cells (CTLs), supporting a role for MUC1-C in immune evasion. The basis for these findings and whether they extend to human TNBCs are not known. Methods Human TNBC cells silenced for MUC1-C using short hairpin RNAs (shRNAs) were analyzed for the effects of MUC1-C on global transcriptional profiles. Differential expression and rank order analysis was used for gene set enrichment analysis (GSEA). Gene expression was confirmed by quantitative reverse-transcription PCR and immunoblotting. The The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets were analyzed for effects of MUC1 on GSEA, cell-type enrichment, and tumor immune dysfunction and exclusion. Single-cell scRNA-seq datasets of TNBC samples were analyzed for normalized expression associations between MUC1 and selected genes within tumor cells. Results Our results demonstrate that MUC1-C is a master regulator of the TNBC transcriptome and that MUC1-C-induced gene expression is driven by STAT1 and IRF1. We found that MUC1-C activates the inflammatory interferon (IFN)-γ-driven JAK1→STAT1→IRF1 pathway and induces the IDO1 and COX2/PTGS2 effectors, which play key roles in immunosuppression. Involvement of MUC1-C in activating the immunosuppressive IFN-γ pathway was extended by analysis of human bulk and scRNA-seq datasets. We further demonstrate that MUC1 associates with the depletion and dysfunction of CD8+ T cells in the TNBC TIME. Conclusions These findings demonstrate that MUC1-C integrates activation of the immunosuppressive IFN-γ pathway with depletion of TILs in the TNBC TIME and provide support for MUC1-C as a potential target for improving TNBC treatment alone and in combination with ICIs. Of translational significance, MUC1-C is a druggable target with chimeric antigen receptor (CAR) T cells, antibody-drug conjugates (ADCs) and a functional inhibitor that are under clinical development.
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Affiliation(s)
- Nami Yamashita
- Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Mark Long
- Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Atsushi Fushimi
- Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Masaaki Yamamoto
- Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Tsuyoshi Hata
- Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Masayuki Hagiwara
- Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | | | - Qiang Hu
- Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Kwok-Kin Wong
- Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA
| | - Song Liu
- Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Donald Kufe
- Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
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20
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Grandal B, Evrevin C, Laas E, Jardin I, Rozette S, Laot L, Dumas E, Coussy F, Pierga JY, Brain E, Saule C, Stoppa-Lyonnet D, Frank S, Sénéchal C, Lae M, De Croze D, Bataillon G, Guerin J, Reyal F, Hamy AS. Impact of BRCA Mutation Status on Tumor Infiltrating Lymphocytes (TILs), Response to Treatment, and Prognosis in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy. Cancers (Basel) 2020; 12:cancers12123681. [PMID: 33302444 PMCID: PMC7764707 DOI: 10.3390/cancers12123681] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/01/2020] [Accepted: 12/03/2020] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Five to 10% of breast cancers (BCs) occur in a genetic predisposition context (mainly BRCA pathogenic variant). Nevertheless, little is known about immune tumor infiltration, response to neoadjuvant chemotherapy (NAC), pathologic complete response (pCR) and adverse events according to BRCA status. MATERIAL AND METHODS Out of 1199 invasive BC patients treated with NAC between 2002 and 2012, we identified 267 patients tested for a germline BRCA pathogenic variant. We evaluated pre-NAC and post-NAC immune infiltration (TILs). Response to chemotherapy was assessed by pCR rates. Association of clinical and pathological factors with TILs, pCR and survival was assessed by univariate and multivariate analyses. RESULTS Among 1199 BC patients: 46 were BRCA-deficient and 221 BRCA-proficient or wild type (WT). At NAC completion, pCR was observed in 84/266 (31%) patients and pCR rates were significantly higher in BRCA-deficient BC (p = 0.001), and this association remained statistically significant only in the luminal BC subtype (p = 0.006). The interaction test between BC subtype and BRCA status was nearly significant (Pinteraction = 0.056). Pre and post-NAC TILs were not significantly different between BRCA-deficient and BRCA-proficient carriers; however, in the luminal BC group, post-NAC TILs were significantly higher in BRCA-deficient BC. Survival analysis were not different between BRCA-carriers and non-carriers. CONCLUSIONS BRCA mutation status is associated with higher pCR rates and post-NAC TILs in patients with luminal BC. BRCA-carriers with luminal BCs may represent a subset of patients deriving higher benefit from NAC. Second line therapies, including immunotherapy after NAC, could be of interest in non-responders to NAC.
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Affiliation(s)
- Beatriz Grandal
- Department of Surgery, Institut Curie, University Paris, 75005 Paris, France; (B.G.); (C.E.); (E.L.); (I.J.); (S.R.); (L.L.)
- Residual Tumor & Response to Treatment Laboratory, RT2Lab, Translational Research Department, INSERM, U932 Immunity and Cancer, Institut Curie, 26 rue d’Ulm, 75005 Paris, France; (E.D.); (A.-S.H.)
| | - Clémence Evrevin
- Department of Surgery, Institut Curie, University Paris, 75005 Paris, France; (B.G.); (C.E.); (E.L.); (I.J.); (S.R.); (L.L.)
| | - Enora Laas
- Department of Surgery, Institut Curie, University Paris, 75005 Paris, France; (B.G.); (C.E.); (E.L.); (I.J.); (S.R.); (L.L.)
| | - Isabelle Jardin
- Department of Surgery, Institut Curie, University Paris, 75005 Paris, France; (B.G.); (C.E.); (E.L.); (I.J.); (S.R.); (L.L.)
| | - Sonia Rozette
- Department of Surgery, Institut Curie, University Paris, 75005 Paris, France; (B.G.); (C.E.); (E.L.); (I.J.); (S.R.); (L.L.)
| | - Lucie Laot
- Department of Surgery, Institut Curie, University Paris, 75005 Paris, France; (B.G.); (C.E.); (E.L.); (I.J.); (S.R.); (L.L.)
| | - Elise Dumas
- Residual Tumor & Response to Treatment Laboratory, RT2Lab, Translational Research Department, INSERM, U932 Immunity and Cancer, Institut Curie, 26 rue d’Ulm, 75005 Paris, France; (E.D.); (A.-S.H.)
| | - Florence Coussy
- Department of Oncology, Institut Curie, 26 rue d’Ulm, 75005 Paris, France; (F.C.); (J.-Y.P.)
| | - Jean-Yves Pierga
- Department of Oncology, Institut Curie, 26 rue d’Ulm, 75005 Paris, France; (F.C.); (J.-Y.P.)
| | - Etienne Brain
- Department of Oncology, Centre René Huguenin, Institut Curie, 35 rue Dailly, 92210 St Cloud, France;
| | - Claire Saule
- Department of Genetics, Institut Curie, 26 rue d’Ulm, 75005 Paris, France; (C.S.); (D.S.-L.); (S.F.)
| | - Dominique Stoppa-Lyonnet
- Department of Genetics, Institut Curie, 26 rue d’Ulm, 75005 Paris, France; (C.S.); (D.S.-L.); (S.F.)
| | - Sophie Frank
- Department of Genetics, Institut Curie, 26 rue d’Ulm, 75005 Paris, France; (C.S.); (D.S.-L.); (S.F.)
| | - Claire Sénéchal
- Department of Genetics, Institut Bergonié, 229 Cours de l’Argonne, 33000 Bordeaux, France;
| | - Marick Lae
- Department of Pathology, Centre René Huguenin, Institut Curie, 35 rue Dailly, 92210 St Cloud, France; (M.L.); (D.D.C.)
- Department of Pathology, Centre Henri Becquerel, INSERM U1245, UNIROUEN, University of Normandie, 76038 Rouen, France
| | - Diane De Croze
- Department of Pathology, Centre René Huguenin, Institut Curie, 35 rue Dailly, 92210 St Cloud, France; (M.L.); (D.D.C.)
| | | | - Julien Guerin
- Data Office, Institut Curie, 25 rue d’Ulm, 75005 Paris, France;
| | - Fabien Reyal
- Department of Surgery, Institut Curie, University Paris, 75005 Paris, France; (B.G.); (C.E.); (E.L.); (I.J.); (S.R.); (L.L.)
- Residual Tumor & Response to Treatment Laboratory, RT2Lab, Translational Research Department, INSERM, U932 Immunity and Cancer, Institut Curie, 26 rue d’Ulm, 75005 Paris, France; (E.D.); (A.-S.H.)
- Correspondence: ; Tel.: +33-144324660; Fax: +33-153104037
| | - Anne-Sophie Hamy
- Residual Tumor & Response to Treatment Laboratory, RT2Lab, Translational Research Department, INSERM, U932 Immunity and Cancer, Institut Curie, 26 rue d’Ulm, 75005 Paris, France; (E.D.); (A.-S.H.)
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Gou R, Dong H, Lin B. Application and reflection of genomic scar assays in evaluating the efficacy of platinum salts and PARP inhibitors in cancer therapy. Life Sci 2020; 261:118434. [PMID: 32941897 DOI: 10.1016/j.lfs.2020.118434] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 09/05/2020] [Accepted: 09/11/2020] [Indexed: 12/24/2022]
Abstract
Defective DNA repair is one of the most important features of tumors. BRCA1/2 participates in homologous recombination repair as a key tumor suppressor gene. BRCA1/2 mutation is an important biomarker for predicting the sensitivity of platinum salts and Poly (ADP-ribose) polymerase (PARP) inhibitors in breast cancer, ovarian cancer, and other cancers. However, epigenetic modifications and other mutations in homologous recombination repair (HRR) genes can also cause homologous recombination deficiency (HRD). Patients with no BRCA1/2 mutations, but bearing similar molecular phenotypes (BRCAness) can still obtain clinical benefits from treatment with platinum salts or PARP inhibitors. Therefore, an accurate assessment of HRD is essential for the formulation of personalized treatments. However, methods to identify HRD in tumors vary and are controversial. Currently, genomic scar assays have been used in multiple clinical trials to assess patient clinical benefit. This review summarizes the therapeutic effects of platinum salts and PARP inhibitors in breast and ovarian cancer, clarifies the predictive value of genomic scar assays in evaluating the clinical benefit of different patient groups and treatment options, and proposes the limitations and optimization of current HRD scoring methods. Using and optimizing genomic scar assays can help to accurately screen the population with the most benefit, expand the scope of drug application, and make the most suitable clinical decision based on individual differences.
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Affiliation(s)
- Rui Gou
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Hui Dong
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Bei Lin
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China.
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Zhang J, Shih DJH, Lin SY. Role of DNA repair defects in predicting immunotherapy response. Biomark Res 2020; 8:23. [PMID: 32612833 PMCID: PMC7325270 DOI: 10.1186/s40364-020-00202-7] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 06/22/2020] [Indexed: 12/31/2022] Open
Abstract
Defect in DNA damage response (DDR) is a common feature of cancer cells, which regulates tumor growth and therapeutic response. Recently, the approval of immune checkpoint blockade (ICB) for tumors with defective mismatch repair has paved the way for investigating the role of other DDR defects in sensitizing cancer to ICB therapy. Despite great progress in understanding DDR pathways, the mechanisms that link DDR defects and ICB response remain incompletely understood. Further, the clinical activity of ICB in patients with DDR defective tumors has not been well described. Here, we discuss recent studies demonstrating that biomarkers in DDR pathways may serve as potential predictors to guide the selection of patients for ICB therapy. A better understanding of the relationship between deficiency in DDR and response to ICB would facilitate efforts in optimizing the efficacy of immunotherapy.
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Affiliation(s)
- Jing Zhang
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - David J H Shih
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Shiaw-Yih Lin
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
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Tung N, Arun B, Hacker MR, Hofstatter E, Toppmeyer DL, Isakoff SJ, Borges V, Legare RD, Isaacs C, Wolff AC, Marcom PK, Mayer EL, Lange PB, Goss AJ, Jenkins C, Krop IE, Winer EP, Schnitt SJ, Garber JE. TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline BRCA Carriers With HER2-Negative Breast Cancer (the INFORM trial). J Clin Oncol 2020; 38:1539-1548. [PMID: 32097092 PMCID: PMC8462533 DOI: 10.1200/jco.19.03292] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
PURPOSE Platinum compounds have activity in triple-negative breast cancer (TNBC) in germline BRCA mutation carriers (BRCA carriers). Limited data exist for estrogen receptor (ER)-positive (+) breast cancer among BRCA carriers. INFORM is a randomized, multicenter, phase II trial comparing pathologic complete response (pCR) rates (ypT0/is, N0) after neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin-cyclophosphamide (AC) in BRCA carriers with stage I-III human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Secondary objectives included residual cancer burden scores (RCB) of 0 or 1 (combined) and toxicity. The goal was to determine whether pCR was ≥ 20% higher with CDDP than AC. PATIENTS AND METHODS BRCA carriers with cT1-3 (≥ 1.5 cm), cN0-3 HER2-negative breast cancer were randomly assigned to preoperative CDDP (75 mg/m2 every 3 weeks × 4 doses) or AC (doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2 every 2-3 weeks × 4 doses) followed by surgery. Pathologic responses were confirmed by central review. RESULTS A total of 118 patients were randomly assigned; 117 were included in outcome analyses. Mean age was 42 years (range, 24-73 years); 69% were BRCA1+, 30% were BRCA2+, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% had nodal involvement at baseline. Seventy percent had TNBC. Clinical and tumor characteristics were well matched between treatment arms. The pCR rate was 18% with CDDP and 26% with AC, yielding a risk ratio (RR) of 0.70 (90% CI, 0.39 to 1.2). The risk of RCB 0 or 1 (RCB 0/1) was 33% with CDDP and 46% with AC (RR, 0.73; 90% CI, 0.50 to 1.1). Both regimens were generally well tolerated without unexpected toxicities. CONCLUSION pCR or RCB 0/1 is not significantly higher with CDDP than with AC in BRCA carriers with stage I-III HER2-negative breast cancer for both TNBC and ER+/HER2-negative disease.
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Affiliation(s)
- Nadine Tung
- Beth Israel Deaconess Medical Center, Boston, MA,Nadine Tung, MD, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Shapiro 9, Boston, MA 02215; e-mail:
| | - Banu Arun
- The University of Texas MD Anderson Cancer Center, Houston, TX
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