Department of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Department of Oncogenetics, MRC Holland, Amsterdam, The Netherlands.
Breast Cancer Res. 2020 Jul 25;22(1):79. doi: 10.1186/s13058-020-01313-7.
We previously showed that BRCA-like profiles can be used to preselect individuals with the highest risk of carrying BRCA mutations but could also indicate which patients would benefit from double-strand break inducing chemotherapy. A simple, robust, and reliable assay for clinical use that utilizes limited amounts of formalin-fixed, paraffin-embedded tumor tissue to assess BRCAness status in both ER-positive and ER-negative breast cancer (BC) is currently lacking.
A digital multiplex ligation-dependent probe amplification (digitalMLPA) assay was designed to detect copy number alterations required for the classification of BRCA1-like and BRCA2-like BC. The BRCA1-like classifier was trained on 71 tumors, enriched for triple-negative BC; the BRCA2-like classifier was trained on 55 tumors, enriched for luminal-type BC. A shrunken centroid-based classifier was developed and applied on an independent validation cohort. A total of 114 cases of a randomized controlled trial were analyzed, and the association of the classifier result with intensified platinum-based chemotherapy response was assessed.
The digitalMLPA BRCA1-like classifier correctly classified 91% of the BRCA1-like samples and 82% of the BRCA2-like samples. Patients with a BRCA-like tumor derived significant benefit of high-dose chemotherapy (adjusted hazard ratio (HR) 0.12, 95% CI 0.04-0.44) which was not observed in non-BRCA-like patients (HR 0.9, 95% CI 0.37-2.18) (p = 0.01). Analysis stratified for ER status showed borderline significance.
The digitalMLPA is a reliable method to detect a BRCA1- and BRCA2-like pattern on clinical samples and predicts platinum-based chemotherapy benefit in both triple-negative and luminal-type BC.
我们之前的研究表明，BRCA 样特征可用于预先选择携带 BRCA 突变风险最高的个体，也可以指示哪些患者将从双链断裂诱导化疗中获益。目前缺乏一种简单、稳健且可靠的临床检测方法，该方法利用有限量的福尔马林固定、石蜡包埋肿瘤组织，同时评估 ER 阳性和 ER 阴性乳腺癌（BC）的 BRCA 状态。
设计了一种数字多重连接探针扩增（digitalMLPA）检测方法，用于检测 BRCA1 样和 BRCA2 样 BC 分类所需的拷贝数改变。BRCA1 样分类器是在 71 个富含三阴性 BC 的肿瘤中进行训练的；BRCA2 样分类器是在 55 个富含 luminal 型 BC 的肿瘤中进行训练的。开发了基于收缩质心的分类器，并应用于独立的验证队列。分析了一项随机对照试验的 114 例病例，评估了分类器结果与强化铂类化疗反应的相关性。
digitalMLPA BRCA1 样分类器正确分类了 91%的 BRCA1 样样本和 82%的 BRCA2 样样本。具有 BRCA 样肿瘤的患者从高剂量化疗中获益显著（调整后的危险比（HR）0.12，95%CI 0.04-0.44），而非 BRCA 样患者未观察到获益（HR 0.9，95%CI 0.37-2.18）（p=0.01）。按 ER 状态分层分析显示具有边缘意义。
digitalMLPA 是一种可靠的方法，可用于检测临床样本中的 BRCA1 和 BRCA2 样模式，并预测铂类化疗在三阴性和 luminal 型 BC 中的获益。
