Background Homologous recombination deficiency (HRD)-causing alterations have been reported in triple-negative breast cancer (TNBC). We hypothesized that TNBCs with HRD alterations might be more sensitive to anthracycline plus cyclophosphamide-based chemotherapy and report on HRD status and BRCA1 promoter methylation (PM) as prognostic markers in TNBC patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG9313. Patients and methods In total, 425 TNBC patients were identified from S9313. HRD score, tumor BRCA1/2 sequencing, and BRCA1 PM were carried out on DNA isolated from formalin-fixed paraffin-embedded tissue. Positive HRD status was defined as either a deleterious tumor BRCA1/2 (tBRCA) mutation or a pre-defined HRD score ≥42. Markers were tested for prognostic value on disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment and nodal status. Results HRD status was determined in 89% (379/425) of cases. Of these, 67% were HRD positive (27% with tBRCA mutation, 40% tBRCA-negative but HRD score ≥42). HRD-positive status was associated with a better DFS [hazard ratio (HR) 0.72; 95% confidence interval (CI) 0.51-1.00; P = 0.049] and non-significant trend toward better OS (HR = 0.71; 95% CI 0.48-1.03; P = 0.073). High HRD score (≥42) in tBRCA-negative patients (n = 274) was also associated with better DFS (HR = 0.64; 95% CI 0.43-0.94; P = 0.023) and OS (HR = 0.65; 95% CI 0.42-1.00; P = 0.049). BRCA1 PM was evaluated successfully in 82% (348/425) and detected in 32% of cases. The DFS HR for BRCA1 PM was similar to that for HRD but did not reach statistical significance (HR = 0.79; 95% CI 0.54-1.17; P = 0.25). Conclusions HRD positivity was observed in two-thirds of TNBC patients receiving adjuvant AC and was associated with better DFS. HRD status may identify TNBC patients who receive greater benefit from AC-based chemotherapy and should be evaluated further in prospective studies. Clinical Trials Number Int0137 (The trial pre-dates Clinicaltrial.Gov website establishment).

中文翻译：

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同源重组缺陷生物标记物对阿霉素和环磷酰胺辅助治疗的三阴性乳腺癌患者预后的影响（SWOG S9313）。

背景技术在三阴性乳腺癌（TNBC）中，已经报道了引起同源重组缺陷（HRD）的改变。我们假设具有HRD改变的TNBC对蒽环类加环磷酰胺为基础的化疗可能更敏感，并在SWOG9313中报告了HRD状态和BRCA1启动子甲基化（PM）作为用辅助阿霉素（A）和环磷酰胺（C）治疗的TNBC患者的预后标志物。患者和方法从S9313中总共鉴定出425名TNBC患者。对从福尔马林固定石蜡包埋的组织中分离的DNA进行HRD评分，肿瘤BRCA1 / 2测序和BRCA1 PM。阳性HRD状态定义为有害的肿瘤BRCA1 / 2（tBRCA）突变或预定义的HRD得分≥42。使用针对治疗分配和淋巴结状态进行了调整的Cox回归模型，测试了标志物的无病生存期（DFS）和总体生存期（OS）的预后价值。结果在89％（379/425）的病例中确定了HRD状态。其中67％是HRD阳性（tBRCA突变为27％，tBRCA阴性为40％，但HRD评分≥42）。HRD阳性状态与更好的DFS相关[危险比（HR）0.72；95％置信区间（CI）0.51-1.00；P = 0.049]和OS改善的趋势不明显（HR = 0.71; 95％CI 0.48-1.03; P = 0.073）。tBRCA阴性患者（n = 274）的高HRD评分（≥42）也与DFS（HR = 0.64; 95％CI 0.43-0.94; P = 0.023）和OS（HR = 0.65; 95％CI 0.42）更好相关-1.00； P = 0.049）。在82％（348/425）中成功评估了BRCA1 PM，并在32％的病例中发现了BRCA1 PM。BRCA1 PM的DFS HR与HRD相似，但未达到统计学显着性（HR = 0.79； 95％CI 0.54-1.17； P = 0.25）。结论在接受辅助性AC的TNBC患者中，三分之二观察到HRD阳性，并与DFS改善有关。HRD状态可能会识别出从基于AC的化疗中受益更大的TNBC患者，应在前瞻性研究中进行进一步评估。临床试验编号Int0137（该试验早于Clinicaltrial.Gov网站建立）。HRD状态可能会识别出从基于AC的化疗中受益更大的TNBC患者，应在前瞻性研究中进行进一步评估。临床试验编号Int0137（该试验早于Clinicaltrial.Gov网站建立）。HRD状态可能会识别出从基于AC的化疗中受益更大的TNBC患者，应在前瞻性研究中进行进一步评估。临床试验编号Int0137（该试验早于Clinicaltrial.Gov网站建立）。