分子亚型预测来曲唑±拉帕替尼治疗激素受体阳性转移性乳腺癌的价值

　　乳腺癌分子亚型（管腔A型、管腔B型、ERBB2或称HER2扩增型、基底样型）对于转移性患者的价值目前尚不明确。

　　2016年6月9日，《美国医学会杂志肿瘤学分册》在线发表西班牙瓦尔·德希伯伦肿瘤研究所、西班牙巴塞罗那医院、西班牙奥古斯特·苏涅尔生物医学研究所、英国伦敦癌症研究所、美国南加利福尼亚大学诺里斯综合癌症中心、美国诺华、美国葛兰素史克、英国伦敦皇家马斯登医院的研究报告，探讨了乳腺癌分子亚型与激素受体阳性转移性乳腺癌结局和/或获益的相关性。

　　该研究对Ⅲ期临床试验EGF30008（NCT00073528）821例肿瘤标本（85.7%原发性和14.3%转移性）进行了计划外回顾性分析。在该临床试验中，疾病发生进展或转移后未经治疗的激素受体阳性浸润性乳腺癌绝经后女性随机接受了来曲唑±拉帕替尼（EGFR/HER2酪氨酸激酶抑制剂）治疗，使用研究性PAM50分类法将肿瘤标本分为各亚型，允许在疾病早期使用过新辅助或辅助抗雌激素疗法，排除广泛症状性内脏疾病患者，使用交互检验评价治疗效果，主要和次要试验终点分别为无进展生存和总生存。

　　患者中位年龄为62（范围：31～94）岁。分子亚型为最强预后因素，与所有患者、HER2阴性（644例）或HER2阳性（157例）患者的无进展生存和总生存独立相关。临床HER2阴性疾病各分子亚型的中位无进展生存各不相同：管腔A型16.9个月（95%置信区间：14.1～19.9），管腔B型11.0个月（95%置信区间：9.6～13.6），HER2扩增型4.7个月（95%置信区间：2.7～10.8），基底样型4.1个月（95%置信区间，2.5～13.8）。各分子亚型的中位总生存也不相同：管腔A型45个月（95%置信区间，41～无法获得），管腔B型37个月（95%置信区间：31～42），HER2扩增型16个月（95%置信区间：10～无法获得），基底样型23个月（95%置信区间：12～无法获得）。HER2阴性/HER2扩增型疾病患者可从拉帕替尼疗法获益（中位无进展生存：6.49比2.60个月；无进展生存风险比为0.238，95%置信区间：0.066～0.863；交互P=0.02）。

　　这是揭示分子亚型与激素受体阳性转移性乳腺癌一线治疗结局之间相关性的首项研究。激素受体阳性/HER2阴性的HER2扩增型患者可从拉帕替尼＋内分泌疗法获益。有必要进一步调查激素受体阳性转移性乳腺癌分子亚型的临床价值，但管腔A型/HER2阴性转移性乳腺癌患者可能是一线来曲唑单药疗法不错的候选者，无论内脏疾病及数量转移如何。

　　结合该研究，英国医学科学院院士（研究员）、英国伦敦皇家马斯登医院拉尔夫·劳伦乳腺癌研究中心的米切尔·道塞特博士发表了同期述评：分子亚型或个体生物标记用于预测转移性乳腺癌的结局？

JAMA Oncol. 2016 Jun 9. [Epub ahead of print]

Prognostic Value of Intrinsic Subtypes in Hormone Receptor-Positive Metastatic Breast Cancer Treated With Letrozole With or Without Lapatinib.

Prat A, Cheang MC, Galván P, Nuciforo P, Paré L, Adamo B, Munoz M, Viladot M, Press MF, Gagnon R, Ellis C, Johnston S.

Vall d'Hebron Institute of Oncology, Barcelona, Spain; Hospital Clínic of Barcelona, Barcelona, Spain; August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain; Institute of Cancer Research, London, England; University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California; Novartis, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; GlaxoSmithKline Oncology, Collegeville, Pennsylvania; Royal Marsden Hospital, London, England.

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)-positive metastatic 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-positive metastatic 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.

PMID: 27281556

DOI: 10.1001/jamaoncol.2016.0922

JAMA Oncol. 2016 Jun 9. [Epub ahead of print]

Intrinsic Subgroups or Individual Biomarkers for Predicting Outcome of Metastatic Breast Cancer?

Dowsett M.

The Ralph Lauren Breast Centre for Breast Cancer Research, Royal Marsden NHS Trust, London, England.

PMID: 27281312

DOI: 10.1001/jamaoncol.2016.0983