Prognostic Value of Intrinsic Subtypes in Hormone Receptor-Positive Metastatic Breast Cancer Treated With Letrozole With or Without Lapatinib
Prognostic Value of Intrinsic Subtypes in Hormone Receptor-Positive Metastatic Breast Cancer Treated With Letrozole With or Without Lapatinib
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DOI：
10.1001/jamaoncol.2016.0922
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发表时间：
2016-10-01
期刊：
影响因子：
28.4
通讯作者：
Johnston, Stephen
中科院分区：
文献类型：
--
作者：
Prat, Aleix;Cheang, Maggie C. U.;Johnston, Stephen
乳腺癌固有亚型(腔A、腔B、人表皮生长因子受体2[目前称为ERBB2，但在本研究中称为HER2])在转移环境中的价值目前尚不清楚。目的评估乳腺癌固有亚型与激素受体(HR)阳性转移性乳腺癌预后和/或益处的相关性。设计、背景和参与者对来自EGF30008第三阶段临床试验(NCT00073528)的821例肿瘤样本(85.7%原发和14.3%转移)进行计划外回顾分析。在这些研究中，HR阳性的浸润性乳腺癌患者以及没有接受过晚期或转移性疾病治疗的绝经后妇女被随机分成两组：来曲唑加或不加雷帕替尼，后者是一种表皮生长因子受体(EGFR)/HER2酪氨酸激酶抑制剂。使用基于研究的PAM50分类器将肿瘤样本分类为每个亚型。以前的新辅助/辅助抗雌激素治疗是允许的。排除有广泛症状性内脏疾病的患者。治疗效果通过交互作用测试进行评估。主要结果和测量主要和次要终点是无进展生存期和总生存期。结果中位年龄为62岁(31-94岁)。在所有患者以及HER2阴性(n=644)或HER2阳性(n=157)疾病患者中，固有亚型是与无进展生存期和总生存期独立相关的最强预后因素。中位无进展生存期在临床HER2阴性疾病的固有亚型中有所不同：管腔A(16.9[95%CI，14.1-19.9]个月)、管腔B(11.0[95%CI，9.6-13.6]个月)、HER2富集型(4.7[95%CI，2.7-10.8]个月)和基底样(4.1[95%CI，2.5-13.8]个月)。不同内在亚型的中位数OS也不同：管腔A(45[95%CI，41-不适用{NA}]个月)，管腔B(37[95%CI，31-42]个月)，HER2富集型(16[95%CI，10-NA]个月)，和基底样(23[95%CI，12-NA]个月)。HER2阴性/HER2富集症的患者受益于拉帕替尼治疗(中位数PFS6.49vs2.60月；无进展生存风险比0.238[95%CI，0.066-0.863]；交互作用P=0.02)。结论和相关性这是第一项揭示一线HR阳性转移性乳腺癌固有亚型与预后之间关系的研究。HER2富集型HR阳性/HER2阴性疾病的患者可能受益于拉帕替尼联合内分泌治疗。激素受体阳性的转移性乳腺癌的固有亚型的临床价值值得进一步研究，但无论内脏疾病和转移数量如何，腔A/HER2阴性的转移性乳腺癌患者可能是来曲唑一线单一治疗的良好候选者。
IMPORTANCE The value of the intrinsic subtypes of breast cancer (luminal A, luminal B, human epidermal growth factor receptor 2 [currently known as ERBB2, but referred to as HER2 in this study]-enriched, and basal-like) in the metastatic setting is currently unknown.OBJECTIVE To evaluate the association of the intrinsic subtypes of breast cancer with outcome and/or benefit in hormone receptor (HR)-positivemetastatic breast cancer.DESIGN, SETTING, AND PARTICIPANTS Unplanned retrospective analysis of 821 tumor samples (85.7% primary and 14.3% metastatic) from the EGF30008 phase 3 clinical trial (NCT00073528), in which postmenopausal women with HR-positive invasive breast cancer and no prior therapy for advanced or metastatic disease were randomized to letrozole with or without lapatinib, an epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor. Tumor samples were classified into each subtype using the research-based PAM50 classifier. Prior neoadjuvant/adjuvant antiestrogen therapy was allowed. Patients with extensive symptomatic visceral disease were excluded. Treatment effects were evaluated using interaction tests.MAIN OUTCOMES AND MEASURES Primary and secondary end points were progression-free survival and overall survival.RESULTS The median (range) age was 62 (31-94) years. Intrinsic subtype was the strongest prognostic factor independently associated with progression-free survival and overall survival in all patients, and in patients with HER2-negative (n = 644) or HER2-positive (n = 157) diseases. Median progression-free survival differed across the intrinsic subtypes of clinically HER2-negative disease: luminal A (16.9 [95% CI, 14.1-19.9] months), luminal B (11.0 [95% CI, 9.6-13.6] months), HER2-enriched (4.7 [95% CI, 2.7-10.8] months), and basal-like (4.1 [95% CI, 2.5-13.8] months). Median OS also differed across the intrinsic subtypes: luminal A (45 [95% CI, 41-not applicable {NA}] months), luminal B (37 [95% CI, 31-42] months), HER2-enriched (16 [95% CI, 10-NA] months), and basal-like (23 [95% CI, 12-NA] months). Patients with HER2-negative/HER2-enriched disease benefited from lapatinib therapy (median PFS, 6.49 vs 2.60 months; progression-free survival hazard ratio, 0.238 [95% CI, 0.066-0.863]; interaction P =.02).CONCLUSIONS AND RELEVANCE This is the first study to reveal an association between intrinsic subtype and outcome in first-line HR-positivemetastatic breast cancer. Patients with HR-positive/HER2-negative disease with a HER2-enriched profile may benefit from lapatinib in combination with endocrine therapy. The clinical value of intrinsic subtyping in hormone receptor-positive metastatic breast cancer warrants further investigation, but patients with luminal A/HER2-negative metastatic breast cancer might be good candidates for letrozole monotherapy in the first-line setting regardless of visceral disease and number of metastases.