Responsiveness of intrinsic subtypes to adjuvant anthracycline substitution in the NCIC.CTG MA.5 randomized trial.
Responsiveness of intrinsic subtypes to adjuvant anthracycline substitution in the NCIC.CTG MA.5 randomized trial.
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DOI：
10.1158/1078-0432.ccr-11-2956
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发表时间：
2012-04-15
期刊：
影响因子：
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通讯作者：
Nielsen TO
中科院分区：
文献类型：
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作者：
Cheang MC;Voduc KD;Tu D;Jiang S;Leung S;Chia SK;Shepherd LE;Levine MN;Pritchard KI;Davies S;Stijleman IJ;Davis C;Ebbert MT;Parker JS;Ellis MJ;Bernard PS;Perou CM;Nielsen TO
最近的研究表明，固有乳腺癌亚型对特定化疗方案的反应可能不同。我们在NCIC.CTG MA.5上检验了这一假设，这是一项临床试验，将患有结节阳性乳腺癌的绝经前妇女随机接受CMF(环磷酰胺-甲氨蝶呤-氟尿嘧啶)辅助化疗与CEF(环磷酰胺-表阿霉素-氟尿嘧啶)化疗。用定量逆转录聚合酶链式反应PAM50基因表达试验确定476例肿瘤的固有亚型。腔A、腔B、HER2富集型(HER2-E)和基底样亚型与无复发生存期(RFS)和总生存期(OS)相关，采用Kaplan-Meier曲线图和对数等级检验。多变量COX回归分析确定了治疗和固有亚型之间交互作用的意义。在合并队列中，固有亚型与RFS(P=0.005)和OS(P<；0.0001)相关。HER2-E从CEF和CMF中获益最大，5年RFS和OS的绝对差异超过20%，而非HER2-E肿瘤的差异不到2%(相互作用测试，RFS和OS的P=0.03)。在临床明确的Her2+肿瘤中，根据基因表达将79%(72/91)归类为HER2-E亚型，这一亚型与CEF和CMF的疗效密切相关(62%比22%，P=0.0006)。对于基底细胞样瘤，两组疗效无显著差异[n=94；HR，1.1；95%可信区间(CI)，0.6−1，HR 1.3；95%CI，0.7−2.5，OS]。HER2-E基因强烈预测了对蒽环类药物的敏感性。对化疗敏感的基底细胞样瘤显示CEF比CMF没有额外的益处，这表明尽管还需要进一步的研究，非蒽环类药物在这一亚型中可能是足够的。
Recent studies suggest that intrinsic breast cancer subtypes may differ in their responsiveness to specific chemotherapy regimens. We examined this hypothesis on NCIC.CTG MA.5, a clinical trial randomizing premenopausal women with node-positive breast cancer to adjuvant CMF (cyclophosphamide-methotrexate-fluorouracil) versus CEF (cyclophosphamide-epirubicin-fluorouracil) chemotherapy. Intrinsic subtype was determined for 476 tumors using the quantitative reverse transcriptase PCR PAM50 gene expression test. Luminal A, luminal B, HER2-enriched (HER2-E), and basal-like subtypes were correlated with relapse-free survival (RFS) and overall survival (OS), estimated using Kaplan-Meier plots and log-rank testing. Multivariable Cox regression analyses determined significance of interaction between treatment and intrinsic subtypes. Intrinsic subtypes were associated with RFS (P = 0005) and OS (P < 0.0001) on the combined cohort. The HER2-E showed the greatest benefit from CEF versus CMF, with absolute 5-year RFS and OS differences exceeding 20%, whereas there was a less than 2% difference for non-HER2-E tumors (interaction test P = 0.03 for RFS and 0.03 for OS). Within clinically defined Her2+ tumors, 79% (72 of 91) were classified as the HER2-E subtype by gene expression and this subset was strongly associated with better response to CEF versus CMF (62% vs. 22%, P = 0.0006). There was no significant difference in benefit between CEF and CMF in basal-like tumors [n = 94; HR, 1.1; 95% confidence interval (CI), 0.6−.1 for RFS and HR, 1.3; 95% CI, 0.7−2.5 for OS]. HER2-E strongly predicted anthracycline sensitivity. The chemotherapy-sensitive basal- like tumors showed no added benefit for CEF over CMF, suggesting that nonanthracycline regimens may be adequate in this subtype although further investigation is required.