分子亚型和免疫标记预测新辅助化疗＋靶向药物治疗乳腺癌患者效果的整合评价：CherLOB

　　2016年8月2日，欧洲肿瘤内科学会官方期刊、牛津大学出版社旗下《肿瘤学年鉴》在线发表意大利帕多瓦大学、摩德纳-雷焦·艾米里亚大学、摩德纳大学医院、住院与治疗科学研究所、克雷莫纳医院研究所、西班牙巴塞罗那医院、奥古斯特·苏涅尔生物医学研究所的研究报告，评价了HER2阳性病变肿瘤相关和免疫相关多样性对新辅助化疗＋抗HER2药物疗效的的影响以及相关作用。

　　该Ⅱ期研究（CherLOB）将121例HER2阳性乳腺癌患者随机分配接受新辅助化疗＋曲妥珠单抗±拉帕替尼。诊断性空心针穿刺活检肿瘤标本被集中，对苏木素-伊红（H&E）染色涂片评价肿瘤浸润淋巴细胞（TIL），采用微阵列芯片（PAM50）亚型研究性50基因分析进行分子亚型，并评价免疫相关基因特征标记。

　　结果发现，基质肿瘤浸润淋巴细胞（Str-TIL）和肿瘤内肿瘤浸润淋巴细胞（It-TIL）与病理学完全缓解（pCR）有显著相关性（比值比分别为1.03和1.09，95%置信区间分别为：1.02～1.05和1.04～1.15，P值均＜0.001）。

　　根据PAM50，亚型分布为：HER2富集型26.7%、管腔A性25.6%、管腔B型16.3%、基底样细胞型14%、正常细胞样型17.4%。

　　HER2富集型的pCR率最高（50%），随后依次为基底细胞样型、管腔B型、管腔A型（χ2检验，P值为0.026）。

　　经单变量分析发现，免疫基因特征标记与pCR有显著相关性，其中大多数（除了TIL）经多变量分析校正PAM50亚型后仍与pCR有显著相关性。

　　因此，在该研究中，肿瘤相关和免疫相关特征均参与影响新辅助化疗＋抗HER2药物后的pCR。在PAM50分子亚型的基础上，免疫特征标记（除了TIL）提高了pCR预测的显著相关性。

Ann Oncol. 2016 Aug 2. [Epub ahead of print]

Integrated evaluation of PAM50 subtypes and immune modulation of pCR in HER2-positive breast cancer patients treated with chemotherapy and HER2-targeted agents in the CherLOB trial.

Dieci MV, Prat A, Tagliafico E, Paré L, Ficarra G, Bisagni G, Piacentini F, Generali DG, Conte P, Guarneri V.

University of Padua, Padua, Italy; Hospital Clínic of Barcelona, Barcelona, Spain; University of Modena and Reggio Emilia, Modena; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Modena University Hospital, Modena; Azienda Ospedaliera ASMN, IRCCS, Reggio Emilia; Istituti Ospitalieri di Cremona, Cremona, Italy.

BACKGROUND: The aim of this work was to evaluate the impact of (and relative contribution of) tumor-related and immune-related diversity of HER2-positive disease on the response to neoadjuvant chemotherapy plus anti-HER2 agents.

PATIENTS AND METHODS: The CherLOB phase II study randomized 121 HER2-positive breast cancer patients to neoadjuvant chemotherapy plus trastuzumab, lapatinib or both. Tumor samples from diagnostic core biopsy were centralized. Tumor-infiltrating lymphocytes (TILs) were evaluated on H&E slides. Intrinsic subtyping was carried out using the research-based 50-gene prediction analysis of a microarray (PAM50) subtype predictor. Immune-related gene signatures were also evaluated.

RESULTS: Continuous Str-TILs and It-TILs were significantly associated with pCR [OR 1.03, 95% CI 1.02-1.05 (P < 0.001) and OR 1.09, 95% CI 1.04-1.15 (P < 0.001) for Str-TILs and It-TILs, respectively]. According to PAM50, the subtype distribution was as follows: HER2-enriched 26.7%, Luminal A 25.6%, Luminal B 16.3%, Basal-like 14% and Normal-like 17.4%. The highest rate of pCR was observed for the HER2-enriched subtype (50%), followed by Basal-like, Luminal B and Luminal A (χ2 test, P = 0.026). Immune gene signatures significantly associated with pCR in univariate analyses were identified: most of them maintained a significant association with pCR in multivariate analyses corrected for PAM50 subtypes, whereas TILs did not.

CONCLUSIONS: In this study, both tumor-related and immune-related features contribute to the modulation of pCR after neoadjuvant chemotherapy plus anti-HER2 agents. Immune signatures rather than TILs added significant prediction of pCR beyond PAM50 intrinsic subtypes.

KEYWORDS: HER2; PAM50; breast cancer; immune signatures; neoadjuvant; tumor-infiltrating lymphocytes

PMID: 27484801

PII: mdw262

DOI: 10.1093/annonc/mdw262