AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home Cancer Biology & Medicine Article
PDF (390.4 KB)
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript AI Chat Paper
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Original Article | Open Access

Association between homologous recombination deficiency and outcomes with platinum and platinum-free chemotherapy in patients with triple-negative breast cancer

Yimeng Chen1,*, Xue Wang2,*, Feng Du1, Jian Yue2, Yiran Si1, Xiaochen Zhao3, Lina Cui3, Bei Zhang3, Ting Bei3, Binghe Xu1( ), Peng Yuan2 ( )
Department of Medical Oncology and Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
The Medical Department, 3D Medicines Inc., Shanghai 201114, China

*These authors contributed equally to this work.

Show Author Information

Abstract

Objective

The choice of chemotherapeutic regimen for triple-negative breast cancer (TNBC) remains controversial. Homologous recombination deficiency (HRD) has attracted increasing attention in informing chemotherapy treatment. This study was aimed at investigating the feasibility of HRD as a clinically actionable biomarker for platinum-containing and platinum-free therapy.

Methods

Chinese patients with TNBC who received chemotherapy between May 1, 2008 and March 31, 2020 were retrospectively analyzed with a customized 3D-HRD panel. HRD positivity was defined by an HRD score ≥ 30 or deleterious BRCA1/2 mutation. A total of 386 chemotherapy-treated patients with TNBC were screened from a surgical cohort (NCT01150513) and a metastatic cohort, and 189 patients with available clinical and tumor sequencing data were included.

Results

In the entire cohort, 49.2% (93/189) of patients were identified as HRD positive (40 with deleterious BRCA1/2 mutations and 53 with BRCA1/2 intact with an HRD score of ≥ 30). In the first-line metastatic setting, platinum therapy was associated with longer median progression-free survival (mPFS) than platinum-free therapy [9.1 vs. 3.0 months; hazard ratio (HR), 0.43; 95% confidence interval 0.22–0.84; P = 0.01]. Among HRD-positive patients, the mPFS was significantly longer in those treated with platinum rather than platinum-free therapy (13.6 vs. 2.0 months; HR, 0.11; P = 0.001). Among patients administered a platinum-free regimen, HRD-negative patients showed a PFS significantly superior to that of HRD-positive patients (P = 0.02; treatment-biomarker P-interaction = 0.001). Similar results were observed in the BRCA1/2-intact subset. In the adjuvant setting, HRD-positive patients tended to benefit more from platinum chemotherapy than from platinum-free chemotherapy (P = 0.05, P-interaction = 0.02).

Conclusions

HRD characterization may guide decision-making regarding the use of platinum treatment in patients with TNBC in both adjuvant and metastatic settings.

Keywords

platinumtriple-negative breast cancersurvivalHomologous recombination deficiencyBRCA

Electronic Supplementary Material

Download File(s)
cbm-20-2-155_ESM.docx (767.8 KB)

References

1

Jiang YZ, Liu Y, Xiao Y, Hu X, Jiang L, Zuo WJ, et al. Molecular subtyping and genomic profiling expand precision medicine in refractory metastatic triple-negative breast cancer: the future trial. Cell Res. 2021; 31: 178-86.
Crossref Google Scholar
2

Borri F, Granaglia A. Pathology of triple negative breast cancer. Semin Cancer Biol. 2021; 72: 136-45.
Crossref Google Scholar
3

Criscitiello C, Azim HA, Schouten PC, Linn SC, Sotiriou C. Understanding the biology of triple-negative breast cancer. Ann Oncol. 2012; 23: vi13-8.
Crossref Google Scholar
4

Ge J, Zuo W, Chen Y, Shao Z, Yu K. The advance of adjuvant treatment for triple-negative breast cancer. Cancer Biol Med. 2021; 19: 187-201.
Crossref Google Scholar
5

Schmid P, Cortes J, Pusztai L, McArthur H, Kummel S, Bergh J, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020; 382: 810-21.
Crossref Google Scholar
6

Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020; 396: 1817-28.
Crossref Google Scholar
7

Hu N, Si Y, Yue J, Sun T, Wang X, Jia Z, et al. Anlotinib has good efficacy and low toxicity: a phase Ⅱ study of anlotinib in pre-treated HER-2 negative metastatic breast cancer. Cancer Biol Med. 2021; 18: 849-59.
Crossref Google Scholar
8

Zhu A, Yuan P, Hu N, Li M, Wang W, Wang X, et al. Phase Ⅱ study of apatinib in combination with oral vinorelbine in heavily pretreated HER2-negative metastatic breast cancer and clinical implications of monitoring ctDNA. Cancer Biol Med. 2021; 18: 875-87.
Crossref Google Scholar
9
National Comprehensive Cancer Network. NCCN clinical practice guidelines in Oncology. Breast Cancer. Version 5. 2021.
10

Mayer IA, Zhao F, Arteaga CL, Symmans WF, Park BH, Burnette BL, et al. Randomized phase Ⅲ postoperative trial of platinum-based chemotherapy versus capecitabine in patients with residual triple-negative breast cancer following neoadjuvant chemotherapy: ECOG-ACRIN EA1131. J Clin Oncol. 2021; 39: 2539-51.
Crossref Google Scholar
11

Chen Y, Guan Y, Wang J, Ma F, Luo Y, Chen S, et al. Platinum-based chemotherapy in advanced triple-negative breast cancer: a multicenter real-world study in china. Int J Cancer. 2020; 147: 3490-9.
Crossref Google Scholar
12

Hu X, Wang B, Zhang J, Wang Z, Sun T, Wang S, et al. 282MO Abraxane plus cisplatin compared with gemcitabine plus cisplatin as first-line treatment in patients with metastatic triple-negative breast cancer (GAP): a multicenter, randomized, open-label, phase Ⅲ trial. Ann Oncol. 2020; 31: S354.
Crossref Google Scholar
13

Hu XC, Zhang J, Xu BH, Cai L, Ragaz J, Wang ZH, et al. Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2015; 16: 436-46.
Crossref Google Scholar
14

Fan Y, Xu BH, Yuan P, Ma F, Wang JY, Ding XY, et al. Docetaxel-cisplatin might be superior to docetaxel-capecitabine in the first-line treatment of metastatic triple-negative breast cancer. Ann Oncol. 2013; 24: 1219-25.
Crossref Google Scholar
15

Tutt A, Tovey H, Cheang MCU, Kernaghan S, Kilburn L, Gazinska P, et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT trial. Nat Med. 2018; 24: 628-37.
Crossref Google Scholar
16

Li Q, Zhang P, Yuan P, Wang J, Ma F, Luo Y, et al. A phase Ⅱ study of capecitabine plus cisplatin in metastatic triple-negative breast cancer patients pretreated with anthracyclines and taxanes. Cancer Biol Ther. 2015; 16: 1746-53.
Crossref Google Scholar
17

O’Shaughnessy J, Schwartzberg L, Danso MA, Miller KD, Rugo HS, Neubauer M, et al. Phase Ⅲ study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol. 2014; 32: 3840-7.
Crossref Google Scholar
18

Zhu Y, Hu Y, Tang C, Guan X, Zhang W. Platinum-based systematic therapy in triple-negative breast cancer. Biochim Biophys Acta Rev Cancer. 2022; 1877: 188678.
Crossref Google Scholar
19

Isakoff SJ, Mayer EL, He L, Traina TA, Carey LA, Krag KJ, et al. TBCRC009: a multicenter phase Ⅱ clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer. J Clin Oncol. 2015; 33: 1902-9.
Crossref Google Scholar
20

Byrski T, Gronwald J, Huzarski T, Grzybowska E, Budryk M, Stawicka M, et al. Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol. 2010; 28: 375-9.
Crossref Google Scholar
21

Arun B, Bayraktar S, Liu DD, Gutierrez Barrera AM, Atchley D, Pusztai L, et al. Response to neoadjuvant systemic therapy for breast cancer in brca mutation carriers and noncarriers: a single-institution experience. J Clin Oncol. 2011; 29: 3739-46.
Crossref Google Scholar
22

Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer. 2016; 16: 110-20.
Crossref Google Scholar
23

Davies H, Glodzik D, Morganella S, Yates LR, Staaf J, Zou X, et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med. 2017; 23: 517-25.
Crossref Google Scholar
24

Muggia F, Safra T. ‘BRCAness’ and its implications for platinum action in gynecologic cancer. Anticancer Res. 2014; 34: 551-6.
Google Scholar
25

Tutt AN, Lord CJ, McCabe N, Farmer H, Turner N, Martin NM, et al. Exploiting the DNA repair defect in BRCA mutant cells in the design of new therapeutic strategies for cancer. Cold Spring Harb Symp Quant Biol. 2005; 70: 139-48.
Crossref Google Scholar
26

Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature. 2012; 481: 287-94.
Crossref Google Scholar
27

Taniguchi T, D’Andrea AD. Molecular pathogenesis of fanconi anemia: recent progress. Blood. 2006; 107: 4223-33.
Crossref Google Scholar
28

Venkitaraman AR. Tracing the network connecting brca and fanconi anaemia proteins. Nat Rev Cancer. 2004; 4: 266-76.
Crossref Google Scholar
29

Timms KM, Abkevich V, Hughes E, Neff C, Reid J, Morris B, et al. Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. Breast Cancer Res. 2014; 16: 475.
Crossref Google Scholar
30

Sipos O, Tovey H, Quist J, Haider S, Nowinski S, Gazinska P, et al. Assessment of structural chromosomal instability phenotypes as biomarkers of carboplatin response in triple negative breast cancer: the TNT trial. Ann Oncol. 2021; 32: 58-65.
Crossref Google Scholar
31

Lips EH, Mulder L, Oonk A, van der Kolk LE, Hogervorst FB, Imholz AL, et al. Triple-negative breast cancer: BRCAness and concordance of clinical features with BRCA1-mutation carriers. Br J Cancer. 2013; 108: 2172-7.
Crossref Google Scholar
32

Popova T, Manie E, Rieunier G, Caux-Moncoutier V, Tirapo C, Dubois T, et al. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res. 2012; 72: 5454-62.
Crossref Google Scholar
33

Birkbak NJ, Wang ZC, Kim JY, Eklund AC, Li Q, Tian R, et al. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov. 2012; 2: 366-75.
Crossref Google Scholar
34

Abkevich V, Timms KM, Hennessy BT, Potter J, Carey MS, Meyer LA, et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer. 2012; 107: 1776-82.
Crossref Google Scholar
35

Moore KN, Secord AA, Geller MA, Miller DS, Cloven N, Fleming GF, et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019; 20: 636-48.
Crossref Google Scholar
36

Telli ML, Timms KM, Reid J, Hennessy B, Mills GB, Jensen KC, et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin Cancer Res. 2016; 22:3764-73.
Crossref Google Scholar
37

Telli ML, Chu C, Badve SS, Vinayak S, Silver DP, Isakoff SJ, et al. Association of tumor-infiltrating lymphocytes with homologous recombination deficiency and BRCA1/2 status in patients with early triple-negative breast cancer: a pooled analysis. Clin Cancer Res. 2020; 26: 2704-10.
Crossref Google Scholar
38

Loibl S, Weber KE, Timms KM, Elkin EP, Hahnen E, Fasching PA, et al. Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response-final results from GeparSixto. Ann Oncol. 2018; 29: 2341-7.
Crossref Google Scholar
39

Chai Y, Chen Y, Zhang D, Wei Y, Li Z, Li Q, et al. Homologous recombination deficiency (HRD) and BRCA 1/2 gene mutation for predicting the effect of platinum-based neoadjuvant chemotherapy of early-stage triple-negative breast cancer (TNBC): a systematic review and meta-analysis. J Pers Med. 2022; 12: 323.
Crossref Google Scholar
40

Mayer EL, Abramson V, Jankowitz R, Falkson C, Marcom PK, Traina T, et al. TBCRC 030: a phase Ⅱ study of preoperative cisplatin versus paclitaxel in triple-negative breast cancer: evaluating the homologous recombination deficiency (HRD) biomarker. Ann Oncol. 2020; 31: 1518-25.
Crossref Google Scholar
41

Zhang L, Chen Y, Cheng MY, Zhuang X, Zou J, Wei D, et al. Homologous recombination deficiency predicts the response to platinum-based neoadjuvant chemotherapy in early-stage triple-negative breast cancer patients: a systematic review and meta-analysis. Ther Adv Med Oncol. 2022; 14: 17588359221096253.
Crossref Google Scholar
42

Ueno T, Kitano S, Masuda N, Ikarashi D, Yamashita M, Chiba T, et al. 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.
Crossref Google Scholar
43

Vetter M, Fokas S, Biskup E, Schmid T, Schwab F, Schoetzau A, et al. Efficacy of adjuvant chemotherapy with carboplatin for early triple negative breast cancer: a single center experience. Oncotarget. 2017; 8: 75617-26.
Crossref Google Scholar
44

Yu KD, Ye FG, He M, Fan L, Ma D, Mo M, et al. Effect of adjuvant paclitaxel and carboplatin on survival in women with triple-negative breast cancer: a phase 3 randomized clinical trial. JAMA Oncol. 2020; 6: 1390-6.
Crossref Google Scholar
45

Zhao EY, Shen Y, Pleasance E, Kasaian K, Leelakumari S, Jones M, et al. Homologous recombination deficiency and platinum-based therapy outcomes in advanced breast cancer. Clin Cancer Res. 2017; 23: 7521-30.
Crossref Google Scholar
46

Du F, Wang W, Wang Y, Li M, Zhu A, Wang J, et al. Carboplatin plus taxanes are non-inferior to epirubicin plus cyclophosphamide followed by taxanes as adjuvant chemotherapy for early triple-negative breast cancer. Breast Cancer Res Treat. 2020; 182: 67-77.
Crossref Google Scholar
47

Hong R, Ma F, Xu B, Li Q, Zhang P, Yuan P, et al. Efficacy of platinum-based chemotherapy in triple-negative breast cancer patients with metastases confined to the lungs: a single-institute experience. Anticancer Drugs. 2014; 25: 1089-94.
Crossref Google Scholar
48

Lheureux S, Lai Z, Dougherty BA, Runswick S, Hodgson DR, Timms KM, et al. Long-term responders on olaparib maintenance in high-grade serous ovarian cancer: clinical and molecular characterization. Clin Cancer Res. 2017; 23: 4086-94.
Crossref Google Scholar
49

Sokol ES, Pavlick D, Khiabanian H, Frampton GM, Ross JS, Gregg JP, et al. Pan-cancer analysis of BRCA1 and BRCA2 genomic alterations and their association with genomic instability as measured by genome-wide loss of heterozygosity. JCO Precis Oncol. 2020; 4: 442-65.
Crossref Google Scholar
50

Priestley P, Baber J, Lolkema MP, Steeghs N, de Bruijn E, Shale C, et al. Pan-cancer whole-genome analyses of metastatic solid tumours. Nature. 2019; 575: 210-6.
Crossref Google Scholar
51

Knijnenburg TA, Wang L, Zimmermann MT, Chambwe N, Gao GF, Cherniack AD, et al. Genomic and molecular landscape of DNA damage repair deficiency across The Cancer Genome Atlas. Cell Rep. 2018; 23: 239-54.
Crossref Google Scholar
52

Menghi F, Banda K, Kumar P, Straub R, Dobrolecki L, Rodriguez IV, et al. Genomic and epigenomic BRCA alterations predict adaptive resistance and response to platinum-based therapy in patients with triple-negative breast and ovarian carcinomas. Sci Transl Med. 2022; 14: eabn1926.
Crossref Google Scholar
Cancer Biology & Medicine
Volume 20 Issue 2,
February 2023
Pages 155-168
DOI: 10.20892/j.issn.2095-3941.2022.0525
Cite this article:
Chen Y, Wang X, Du F, et al. Association between homologous recombination deficiency and outcomes with platinum and platinum-free chemotherapy in patients with triple-negative breast cancer. Cancer Biology & Medicine, 2023, 20(2): 155-168. https://doi.org/10.20892/j.issn.2095-3941.2022.0525

177

Views

4

Downloads

5

Crossref

3

Web of Science

4

Scopus

Altmetrics
Received: 26 August 2022
Accepted: 28 November 2022
Published: 02 March 2023
©2023 Cancer Biology & Medicine.

Creative Commons Attribution-NonCommercial 4.0 International License
Return