RB-pathway disruption is associated with improved response to neoadjuvant chemotherapy in breast cancer.
RB-pathway disruption is associated with improved response to neoadjuvant chemotherapy in breast cancer.
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DOI：
10.1158/1078-0432.ccr-12-0903
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发表时间：
2012-09-15
期刊：
影响因子：
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通讯作者：
Knudsen ES
中科院分区：
文献类型：
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作者：
Witkiewicz AK;Ertel A;McFalls J;Valsecchi ME;Schwartz G;Knudsen ES
我们试图确定RB肿瘤抑制通路的失调是否与乳腺癌新辅助化疗反应的改善有关。使用RB-丢失标记来分析包含三种不同新辅助治疗方案的基因表达数据集中通路状态与病理完全应答之间的关联。对治疗前活检标本进行RB通路的平行免疫组化分析，以确定与新辅助化疗病理反应的相关性。在接受FAC（p<0.001）、T/FAC（p <0.001）和TA（p<0.001）新辅助治疗的乳腺癌患者的数据集中，RB缺失基因表达特征与病理学完全缓解增加相关，这些患者大约有1,000例。在ER阳性和ER阴性乳腺癌中，新辅助化疗的反应改善与此相关。p16 ink 4a的高表达与RB信号丢失相关（R=0.493-0.5982），相应地，在分析的相同数据集中，p16 ink 4a mRNA水平与病理完全反应强烈相关。在一个独立的队列中，RB和p16 ink 4a的免疫组化分析显示RB丢失（p=0.0018）或p16 ink 4a升高（p=0.0253）与病理学完全缓解相关。此外，通过Miller-Payne和临床病理学评分（CPS）分析，RB缺陷型肿瘤对新辅助化疗的反应总体改善。通过几种独立的方法测量的RB通路的破坏与新辅助化疗的应答改善相关。RB通路状态与ER阳性和ER阴性乳腺癌的病理学反应相关，在多种化疗方案中观察到相似的结果。综合起来，这些数据表明，RB状态与乳腺癌新辅助化疗的反应有关，并可用于指导治疗。
We sought to determine whether dysregulation of the RB tumor suppressor pathway was associated with improved response to neoadjuvant chemotherapy in breast cancer. An RB-loss signature was used to analyze the association between pathway status and pathological complete response in gene expression datasets encompassing three different neoadjuvant regimens. Parallel immunohistochemical analysis of the RB-pathway was performed on pretreatment biopsies to determine the association with pathological response to neoadjuvant chemotherapy. An RB loss gene expression signature was asssociated with increased pathological complete response in datasets from breast cancer patients treated with FAC (p<0.001), T/FAC (p<0.001) and TA (p<0.001) neoadjuvant therapy encompasssing approximately 1,000 patients. The association with improved response to neoadjuvant chemotherapy was true in both ER-positive and ER-negative breast cancer. Elevated expression of p16ink4a is associated with the RB-loss of signature (R=0.493–0.5982), and correspondingly p16ink4a mRNA levels were strongly associated with pathological complete response in the same data sets analyzed. In an independent cohort, immunohistochemical analyses of RB and p16ink4a revealed an association of RB loss (p=0.0018) or elevated p16ink4a (p=0.0253) with pathological complete response. Additionally, by Miller-Payne and Clinical-Pathologic Scoring (CPS) analyses, RB-deficient tumors experienced an overall improved response to neoadjuvant chemotherapy. Disruption of the RB-pathway as measured by several independent methods was associated with improved response to neoadjuvant chemotherapy. The RB-pathway status was relevant for pathological response in both ER-positive and ER-negative breast cancer with similar results observed with multiple chemotherapy regimens. Combined, these data indicate that RB-status is associated with the response to neoadjuvant chemotherapy in breast cancer and could be employed to inform treatment.