RAD51 与同源重组缺陷 (HRD) 及未经治疗的三阴性乳腺癌 (TNBC) 临床结局的关联：GeparSixto 随机临床试验分析。

Association of RAD51 with homologous recombination deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial.

机构信息

Vall d'Hebron Institute of Oncology, Barcelona, Spain.

GBG, Medicine and Research, Neu-Isenburg, Germany.

出版信息

Ann Oncol. 2021 Dec;32(12):1590-1596. doi: 10.1016/j.annonc.2021.09.003. Epub 2021 Sep 11.

DOI:10.1016/j.annonc.2021.09.003

PMID:34520831

Abstract

BACKGROUND

Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum-based neoadjuvant chemotherapy (NACT).

PATIENTS AND METHODS

This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet®-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and γH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were carried out between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (Myriad myChoice®). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low).

RESULTS

Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% [95% confidence interval (CI) 79% to 93%]. In patients with RAD51-high tumors, pCR was similar between treatment arms [PMCb 31% versus PM 39%, odds ratio (OR) 0.71, 0.23-2.24, P = 0.56]. Patients with RAD51-low tumors benefited from PMCb (pCR 66% versus 33%, OR 3.96, 1.56-10.05, P = 0.004; interaction test P = 0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar disease-free survival in the RAD51-high [hazard ratio (HR) 0.40, log-rank P = 0.11] and RAD51-low (0.45, P = 0.11) groups.

CONCLUSIONS

The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making.

摘要

背景

目前用于测量同源重组缺陷（HRD）的遗传和基因组检测的预测价值有限。本研究比较了基于免疫组织化学的 RAD51 检测与遗传/基因组检测，以识别 HRD 原发性三阴性乳腺癌（TNBC）患者，并评估其准确性以选择对铂类新辅助化疗（NACT）敏感的患者。

患者和方法

这是 GeparSixto 随机临床试验的回顾性、盲法生物标志物分析。TNBC 患者接受新辅助紫杉醇加 Myocet®-非聚乙二醇化脂质体多柔比星（PM）或 PM 加卡铂（PMCb）治疗，两个治疗组均联合贝伐珠单抗。福尔马林固定石蜡包埋（FFPE）肿瘤样本铺在组织微阵列上。使用免疫荧光法检测 RAD51、BRCA1 和 γH2AX。通过回归模型评估 RAD51 的预测价值。进行 RAD51 评分与肿瘤 BRCA（tBRCA）状态或基因组 HRD 评分（Myriad myChoice®）之间的一致性分析。研究与病理完全缓解（pCR）和生存的相关性。将功能 HRD 定义为 RAD51 评分≤10%（RAD51-低）。

结果

在 133 个肿瘤中有 81 个（61%）证实存在 RAD51-低功能性 HRD。RAD51 可识别 93%的 tBRCA 突变肿瘤和 45%的非 tBRCA 突变病例为功能性 HRD。RAD51 与基因组 HRD 的一致性为 87%（95%置信区间[CI]79%至 93%）。在 RAD51 高肿瘤患者中，PMCb 组和 PM 组的 pCR 相似[PMCb 为 31%，PM 为 39%，比值比（OR）0.71，0.23-2.24，P=0.56]。RAD51 低肿瘤患者从 PMCb 治疗中获益（pCR 为 66%，PM 为 33%，OR 3.96，1.56-10.05，P=0.004；交互检验 P=0.02）。多变量分析仍保持统计学意义。在 RAD51 高肿瘤患者中，加用卡铂在疾病无进展生存方面显示出相似的效果[风险比（HR）0.40，对数秩检验 P=0.11]，在 RAD51 低肿瘤患者中亦如此（HR 0.45，P=0.11）。