同源重组缺陷生物标志物对接受辅助多柔比星和环磷酰胺治疗的三阴性乳腺癌患者结局的影响（SWOG S9313）。
Impact of homologous recombination deficiency biomarkers on outcomes in patients with triple-negative breast cancer treated with adjuvant doxorubicin and cyclophosphamide (SWOG S9313).
机构信息
Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, USA.
SWOG Statistical Center, Seattle, USA; Cancer, Research and Biostatistics (CRAB), Seattle, USA.
出版信息
Ann Oncol. 2018 Mar 1;29(3):654-660. doi: 10.1093/annonc/mdx821.
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).
背景
同源重组缺陷（HRD）改变已在三阴性乳腺癌（TNBC）中报道。我们假设 HRD 改变的 TNBC 可能对蒽环类药物加环磷酰胺为基础的化疗更敏感，并报告 HRD 状态和 BRCA1 启动子甲基化（PM）作为接受 SWOG9313 辅助多柔比星（A）和环磷酰胺（C）治疗的 TNBC 患者的预后标志物。
方法
从 S9313 中总共鉴定了 425 例 TNBC 患者。对福尔马林固定石蜡包埋组织中分离的 DNA 进行 HRD 评分、肿瘤 BRCA1/2 测序和 BRCA1 PM。阳性 HRD 状态定义为有害肿瘤 BRCA1/2（tBRCA）突变或预定义 HRD 评分≥42。使用 Cox 回归模型，根据治疗分配和淋巴结状态，对疾病无进展生存期（DFS）和总生存期（OS）进行标记物预后价值的检验。
结果
在 425 例病例中，89%（379/425）确定了 HRD 状态。其中，67%为 HRD 阳性（27%有 tBRCA 突变，40% tBRCA 阴性但 HRD 评分≥42）。HRD 阳性状态与更好的 DFS[风险比（HR）0.72；95%置信区间（CI）0.51-1.00；P=0.049]和非显著的 OS 趋势相关（HR=0.71；95%CI 0.48-1.03；P=0.073）。tBRCA 阴性患者（n=274）中高 HRD 评分（≥42）也与更好的 DFS（HR=0.64；95%CI 0.43-0.94；P=0.023）和 OS（HR=0.65；95%CI 0.42-1.00；P=0.049）相关。BRCA1 PM 成功评估了 82%（348/425），并在 32%的病例中检测到。BRCA1 PM 的 DFS HR 与 HRD 相似，但未达到统计学意义（HR=0.79；95%CI 0.54-1.17；P=0.25）。
结论
在接受辅助 AC 治疗的 TNBC 患者中，有三分之二观察到 HRD 阳性，与更好的 DFS 相关。HRD 状态可能识别出从 AC 为基础的化疗中获益更大的 TNBC 患者，应在前瞻性研究中进一步评估。
临床试验编号
Int0137（该试验在 Clinicaltrial.Gov 网站建立之前进行）。
Zotero 插件