The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Academic Department of Biochemistry, and Breast Unit, Royal Marsden Hospital, London, United Kingdom.
Clin Cancer Res. 2010 Dec 15;16(24):6159-68. doi: 10.1158/1078-0432.CCR-10-1027. Epub 2010 Aug 27.
To assess the prevalence of defective homologous recombination (HR)-based DNA repair in sporadic primary breast cancers, examine the clincopathologic features that correlate with defective HR and the relationship with neoadjuvant chemotherapy response.
We examined a cohort of 68 patients with sporadic primary breast cancer who received neoadjuvant anthracylcine-based chemotherapy, with core biopsies taken 24 hours after the first cycle of chemotherapy. We assessed RAD51 focus formation, a marker of HR competence, by immunofluorescence in postchemotherapy biopsies along with geminin as a marker of proliferative cells. We assessed the RAD51 score as the proportion of proliferative cells with RAD51 foci.
A low RAD51 score was present in 26% of cases (15/57, 95% CI: 15%-40%). Low RAD51 score correlated with high histologic grade (P = 0.031) and high baseline Ki67 (P = 0.005). Low RAD51 score was more frequent in triple-negative breast cancers than in ER- and/or HER2-positive breast cancer (67% vs. 19% respectively; P = 0.0036). Low RAD51 score was strongly predictive of pathologic complete response (pathCR) to chemotherapy, with 33% low RAD51 score cancers achieving pathCR compared with 3% of other cancers (P = 0.011).
Our results suggest that defective HR, as indicated by low RAD51 score, may be one of the factors that underlie sensitivity to anthracycline-based chemotherapy. Defective HR is frequent in triple-negative breast cancer, but it is also present in a subset of other subtypes, identifying breast cancers that may benefit from therapies that target defective HR such as PARP inhibitors.
评估散发性原发性乳腺癌中同源重组（HR）缺陷的流行率，研究与 HR 缺陷相关的临床病理特征及其与新辅助化疗反应的关系。
我们对 68 例接受蒽环类新辅助化疗的散发性原发性乳腺癌患者进行了研究，在第一周期化疗后 24 小时对其进行了核心活检。我们通过免疫荧光法检测了化疗后活检中的 RAD51 焦点形成，这是 HR 功能的标志物，同时使用增殖细胞标志物 geminin 进行检测。我们评估了 RAD51 评分，即具有 RAD51 焦点的增殖细胞的比例。
在 26%的病例（57 例中的 15 例，95%CI：15%-40%）中存在低 RAD51 评分。低 RAD51 评分与高组织学分级（P = 0.031）和高基线 Ki67 相关（P = 0.005）。低 RAD51 评分在三阴性乳腺癌中比在 ER 和/或 HER2 阳性乳腺癌中更为常见（分别为 67%和 19%；P = 0.0036）。低 RAD51 评分强烈预测化疗的病理完全缓解（pathCR），低 RAD51 评分的癌症中有 33%达到 pathCR，而其他癌症只有 3%（P = 0.011）。
我们的结果表明，RAD51 评分低表明 HR 缺陷，可能是对蒽环类化疗敏感的因素之一。HR 缺陷在三阴性乳腺癌中很常见，但也存在于其他亚型的亚组中，这可以识别出可能受益于靶向 HR 缺陷的治疗方法（如 PARP 抑制剂）的乳腺癌。
