A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer.
A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer.
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DOI：
10.1158/1078-0432.ccr-10-1027
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发表时间：
2010-12-15
期刊：
影响因子：
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通讯作者：
Turner NC
中科院分区：
文献类型：
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作者：
Graeser M;McCarthy A;Lord CJ;Savage K;Hills M;Salter J;Orr N;Parton M;Smith IE;Reis-Filho JS;Dowsett M;Ashworth A;Turner NC
为了评估散发性原发性乳腺癌中基于同源重组（HR）的DNA修复缺陷的患病率，检查与HR缺陷相关的临床病理学特征以及与新辅助化疗反应的关系。我们研究了一组68例接受新辅助蒽环类药物化疗的散发性原发性乳腺癌患者，在第一个化疗周期后24小时进行了核心活检。我们评估了RAD 51病灶形成，HR能力的标志物，通过免疫荧光在化疗后活检沿着与双生蛋白作为增殖细胞的标志物。我们评估了RAD 51评分为具有RAD 51病灶的增殖细胞的比例。26%的病例（15/57，95% CI，15-40%）存在较低的RAD 51评分。低RAD 51评分与高组织学分级（p=0.031）和高基线Ki 67（p=0.005）相关。与ER和/或HER 2阳性乳腺癌相比，三阴性乳腺癌中低RAD 51评分更常见（分别为67% vs 19%，p=0.0036）。低RAD 51评分强烈预测了对化疗的病理学完全反应，与3%的其他癌症相比，33%的低RAD 51评分癌症实现了病理学完全反应（p=0.011）。我们的研究结果表明，有缺陷的HR，如低RAD 51评分所示，可能是对蒽环类药物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子集中，从而确定可能受益于靶向HR缺陷的治疗（如PARP抑制剂）的乳腺癌。
To assess the prevalence of defective homologous recombination (HR) based DNA repair in sporadic primary breast cancers, examine the clincopathological features that correlate of 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 post chemotherapy 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 histological grade (p=0.031) and high baseline Ki67 (p=0.005). Low RAD51 score was more frequent in triple negative breast cancers compared to ER and/or HER2 positive breast cancer (67% vs 19% respectively, p=0.0036). Low RAD51 score was strongly predictive of pathological complete response to chemotherapy, with 33% low RAD51 score cancers achieving pathological complete response compared to 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 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.