Institute of Pathology, Philipps University Marburg and University Hospital Marburg (UKGM), Marburg, Germany.
F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Clin Cancer Res. 2023 Apr 14;29(8):1569-1581. doi: 10.1158/1078-0432.CCR-22-1989.
In KATHERINE, adjuvant T-DM1 reduced risk of disease recurrence or death by 50% compared with trastuzumab in patients with residual invasive breast cancer after neoadjuvant therapy (NAT) comprised of HER2-targeted therapy and chemotherapy. This analysis aimed to identify biomarkers of response and differences in biomarker expression before and after NAT.
Exploratory analyses investigated the relationship between invasive disease-free survival (IDFS) and HER2 protein expression/gene amplification, PIK3CA hotspot mutations, and gene expression of HER2, PD-L1, CD8, predefined immune signatures, and Prediction Analysis of Microarray 50 intrinsic molecular subtypes, classified by Absolute Intrinsic Molecular Subtyping. HER2 expression on paired pre- and post-NAT samples was examined.
T-DM1 appeared to improve IDFS versus trastuzumab across most biomarker subgroups, except the HER2 focal expression subgroup. High versus low HER2 gene expression in residual disease was associated with worse outcomes with trastuzumab [HR, 2.02; 95% confidence interval (CI), 1.32-3.11], but IDFS with T-DM1 was independent of HER2 expression level (HR, 1.01; 95% CI, 0.56-1.83). Low PD-L1 gene expression in residual disease was associated with worse outcomes with trastuzumab (HR, 0.66; 95% CI, 0.44-1.00), but not T-DM1 (HR, 1.05; 95% CI, 0.59-1.87). PIK3CA mutations were not prognostic. Increased variability in HER2 expression was observed in post-NAT versus paired pre-NAT samples.
T-DM1 appears to overcome HER2 resistance. T-DM1 benefit does not appear dependent on immune activation, but these results do not rule out an influence of the tumor immune microenvironment on the degree of response.
在 KATHERINE 研究中，与曲妥珠单抗相比，在接受曲妥珠单抗为基础的新辅助治疗（NAT）后仍有残余浸润性乳腺癌的患者中，辅助 T-DM1 使疾病复发或死亡风险降低了 50%。本分析旨在鉴定与无病生存（IDFS）相关的生物标志物，并确定 NAT 前后生物标志物表达的差异。
探索性分析调查了无浸润性疾病生存（IDFS）与 HER2 蛋白表达/基因扩增、PIK3CA 热点突变、HER2、PD-L1、CD8、预先定义的免疫特征以及通过绝对内在分子分类法分类的 Prediction Analysis of Microarray 50 固有分子亚型之间的关系。检查了配对的 NAT 前后样本中的 HER2 表达。
T-DM1 似乎改善了 IDFS 对比曲妥珠单抗，除了 HER2 局灶性表达亚组之外，在大多数生物标志物亚组中均如此。残留疾病中高 versus 低 HER2 基因表达与曲妥珠单抗相关的不良结局相关[HR，2.02；95%置信区间（CI），1.32-3.11]，但 T-DM1 与 HER2 表达水平无关（HR，1.01；95%CI，0.56-1.83）。残留疾病中低 PD-L1 基因表达与曲妥珠单抗相关的不良结局相关（HR，0.66；95%CI，0.44-1.00），但与 T-DM1 无关（HR，1.05；95%CI，0.59-1.87）。PIK3CA 突变不是预后因素。与配对的 NAT 前样本相比，NAT 后样本中观察到 HER2 表达的变异性增加。
T-DM1 似乎克服了 HER2 耐药性。T-DM1 获益似乎不依赖于免疫激活，但这些结果并不能排除肿瘤免疫微环境对反应程度的影响。
