The status of homologous recombination deficiency is a potential biomarker for platinum-based chemotherapy in triple-negative breast cancer

Abstract BackgroundTriple-negative breast cancer (TNBC) is a subtype of breast cancer that is highly susceptible to recurrence and metastasis. The therapeutic drugs are limited due to the lack of effective biomarkers predicting the therapeutic efficacy and prognosis of disease. Previous studies have shown that platinum-containing regimens are effective for both early and advanced TNBC, therefore, it is particularly important to explore biomarkers for predicting the efficacy of platinum drugs and to screen the population sensitive to platinum drugs. Methods All patients with available tumor specimens from National Cancer Center in China were eligible for this prospective-retrospective study (n=189), including 149 patients with early TNBC (NCT01150513, CH-BC-007) and 40 patients with advanced TNBC (12-123/657, CH-BC-018) who are treated with or without platinum. The primary endpoint is disease-free survival (DFS) for early TNBC and progression free survival (PFS) for advanced TNBC. For HRD status and genomic signatures, indexed libraries were subjected to probe-based hybridization with a customized NGS panel targeting 733 cancer-related genes. 3DMed-HRD algorithm was evaluated based on loss of heterozygosity score (LOH), telomeric allelic imbalance score (TAI) and large-scale state transition score (LST) to characterize genomic instability using over 10,000 single-nucleotide polymorphisms distributed across human genome, adjusted by tumor ploidy and purity. HRD positive is defined by HRD score above the threshold (cut-off ≥30) and/or deleterious mutation in BRCA1/2. ResultsDeleterious BRCA1/2 mutations were detected in 21.2% (40/189) of TNBC patients and 48.1% (91/189) were defined as HRD positive. In advanced TNBC cohort, 21 patients received platinum-containing and 19 received platinum-free chemotherapy regimens for first-line chemotherapy. The progression-free survival (PFS) of the platinum-containing group was longer than that of the platinum-free group (median PFS 9.13 vs 2.97 months, HR 0.39, 95%CI, 0.19-0.81, P=0.011), and the PFS of patients with HRD positive was significantly longer than HRD negative patients (median PFS 13.6 vs 6.80 months, HR 0.38, 95%CI, 0.15-0.99, P=0.048) in platinum-containing group. Interestingly, HRD-positive patients have a significantly shorter PFS than HRD-negative in platinum-free group (median PFS 1.97 vs 4.52 months, HR 3.67, 95%CI, 1.20-11.22, P=0.023). For the HRD-positive patients, median PFS was significantly better in platinum-based group than platinum-free group (median PFS 13.6 vs 1.97 months, HR 0.12, 95%CI, 0.03-0.43, P=0.001). In early-stage TNBC cohort (n=149), 74 patients received platinum-containing and 75 received platinum-free chemotherapy regimens for adjuvant chemotherapy. In platinum-containing group, no statistically significant difference was found in DFS between HRD-positive and HRD-negative patients (P=0.118). High-risk TNBC group (Ki-67 ≥ 15%) analysis revealed that HRD-positive patients had a numerical better DFS than HRD-negative patients (HR 0.43, 95%CI, 0.12-1.50, P=0.180). Among patients with HRD-positive, patients in platinum-containing group had a tendency to benefit more than those in platinum-free group (HR 0.35, 95%CI, 0.11-1.10, P=0.062). Conclusions: We developed a novel algorithm to evaluate 3DMed-HRD status and highlights the potential utility of HRD in guiding chemotherapy for TNBC patients in this retrospective analysis. In comparison to platinum-free chemotherapy, the advanced TNBC HRD positive patients with advanced TNBC receiving platinum-based chemotherapy is a preferable regimen, and the HRD negative patients might be on the contrary. Prospective validation with larger sample size is needed. Citation Format: Yimeng Chen, Xue Wang, Feng Du, Jian Yue, Yiran Si, Lina Cui, Bei Zhang, Binghe Xu, Peng Yuan. The status of homologous recombination deficiency is a potential biomarker for platinum-based chemotherapy in triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-12.