1、Cancer Biol Med 2023.doi:10.20892/j.issn.2095-3941.2022.0525ORIGINAL ARTICLEAssociation between homologous recombination deficiency and outcomes with platinum and platinum-free chemotherapy in patients with triple-negative breast cancerYimeng Chen1*,Xue Wang2*,Feng Du1,Jian Yue2,Yiran Si1,Xiaochen Z
2、hao3,Lina Cui3,Bei Zhang3,Ting Bei3,Binghe Xu1,Peng Yuan21Department 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;2Department
3、 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;3The Medical Department,3D Medicines Inc.,Shanghai 201114,ChinaABSTRACT Objective:The choice of chemo
4、therapeutic 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 platin
5、um-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 chemothe
6、rapy-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
7、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 0.220.84;P=0.01.Among HRD-pos
8、itive 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;
9、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 gui
10、de decision-making regarding the use of platinum treatment in patients with TNBC in both adjuvant and metastatic settings.KEYWORDS Homologous recombination deficiency;triple-negative breast cancer;platinum;survival;BRCAIntroductionTriple-negative breast cancer(TNBC)is a tumor type that does not expr
11、ess estrogen receptor,progesterone receptor,or human epidermal growth factor receptor 2(HER2)1-3.Effective therapeutic strategies are lacking for TNBC4.In recent years,immune checkpoint inhibitors and anti-angiogenic drugs have shown efficacy in TNBC treatment5-8.However,chemo-therapy remains the ma
12、in treatment for TNBC9,and the opti-mum chemotherapeutic regimen has remained undefined,partially because of the high degree of TNBC heterogeneity.Platinum-based chemotherapy,a first-line treatment option for advanced TNBC,and the neoadjuvant regimen for resecta-ble TNBC9 have shown modest advantage
13、s over platinum-free regimens.A considerable proportion of patients do not respond to platinum10-18.Biomarkers are needed to inform patient selection and allow effective therapy to be provided*These authors contributed equally to this work.Correspondence to:Peng Yuan and Binghe XuEmail: and ORCID ID
14、:https:/orcid.org/0000-0003-4627-8203(P.Yuan)Received August 26,2022;accepted November 28,2022Available at www.cancerbiomed.org2023 Cancer Biology&Medicine.Creative Commons Attribution-NonCommercial 4.0 International License156 Chen et al.HRD for guiding platinum chemotherapy in TNBCto defined respo
15、nding patients while enabling nonresponders to avoid the severe toxicity of ineffective chemotherapeutic regimens.Previous studies have shown that patients with BRCA mutations are platinum-sensitive19-21;on this basis,BRCA mutations have been clinically used as predictors of plati-num therapy effica
16、cy.BRCA1/2 mutation-associated-signa-tures overlap with abnormalities in homologous recombina-tion repair(HRR)genes,which are deficient in a substantial subset of TNBC termed sporadic basal TNBC22,23.The hall-mark aberrations in the BRCA and HR gene pathways are sensitive to DNA crosslinking induced by platinum24-28.Therefore,studies have been conducted to develop meas-ures including HR deficiency(HRD)detection for iden-tifying both BRCA1/2-intact and BRCA1/2-deleterious HR-deficient patients,an
