Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua Division of Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
Translational Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona Translational Genomic and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona Department of Medical Oncology, Hospital Clínic of Barcelona, Barcelona, Spain.
Ann Oncol. 2016 Oct;27(10):1867-73. doi: 10.1093/annonc/mdw262. Epub 2016 Aug 2.
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.
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.
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 (χ(2) 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.
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.
本研究旨在评估 HER2 阳性疾病的肿瘤相关和免疫相关多样性对新辅助化疗加抗 HER2 药物治疗反应的影响（及相对贡献）。
CherLOB Ⅱ期研究将 121 例 HER2 阳性乳腺癌患者随机分为新辅助化疗加曲妥珠单抗、拉帕替尼或两者联合组。从诊断性核心活检中采集肿瘤样本，对肿瘤浸润淋巴细胞（TILs）进行苏木精和伊红（H&E）切片评估。采用基于研究的 50 基因微阵列预测分析（PAM50）预测分析进行内在亚型分类。还评估了免疫相关基因特征。
连续的 Str-TILs 和 It-TILs 与 pCR 显著相关[比值比（OR）为 1.03，95%可信区间（CI）为 1.02-1.05（P<0.001）和 OR 为 1.09，95%CI 为 1.04-1.15（P<0.001），分别用于 Str-TILs 和 It-TILs]。根据 PAM50，亚型分布如下：HER2 富集型占 26.7%，Luminal A 型占 25.6%，Luminal B 型占 16.3%，基底样型占 14%，正常样型占 17.4%。pCR 率最高的是 HER2 富集型（50%），其次是基底样型、Luminal B 型和 Luminal A 型（卡方检验，P=0.026）。单变量分析中，与 pCR 显著相关的免疫基因特征在多变量分析中也得到了证实，校正 PAM50 亚型后，这些特征与 pCR 仍具有显著相关性，而 TILs 则没有。
本研究表明，肿瘤相关和免疫相关特征均有助于新辅助化疗加抗 HER2 药物治疗后 pCR 的调节。免疫特征而不是 TILs，除了 PAM50 内在亚型外，还为 pCR 提供了显著的预测。
