Department of Pathology, Wexner Medical Center at The Ohio State University, 410 W. 10th Ave, Columbus, OH, 43210, USA.
Ventana Medical Systems, Inc., 1910 E. Innovation Park Drive, Tucson, AZ, 85755, USA.
Breast Cancer Res Treat. 2017 Nov;166(2):447-457. doi: 10.1007/s10549-017-4453-8. Epub 2017 Aug 10.
Anti-HER2 neoadjuvant chemotherapy has been widely used in HER2-positive breast cancer patients; however, pathologic complete response (pCR) is achieved in only 40-50% of patients. The aim of this study was to investigate the association of HER2 intratumoral heterogeneity (ITH) with response to anti-HER2 neoadjuvant chemotherapy.
Assessment of HER2 ITH was performed on whole tissue sections of pre-treatment samples from a cohort of 64 invasive breast carcinoma cases originally considered positive for HER2 and treated with anti-HER2 neoadjuvant chemotherapy. Both HER2 gene signal and protein expression were simultaneously evaluated by means of a single-slide dual assay, designated as a HER2 gene-protein assay (GPA). HER2 GPA was carried out as well on surgical resection tissues from 25 cases with incomplete therapeutic response.
Nineteen of 64 cases (30%) showed HER2 ITH. Significantly more cases with HER2 ITH were found in the incomplete response group (56%, 14/25) than in the pCR group (13%, 5/39). Patients without ITH detectable by GPA had a 76% pCR outcome (34/45), as compared to 26% (5/19) for those with detectable ITH. Multivariate analysis demonstrated HER2 ITH, progesterone receptor positivity, and relatively low HER2/chromosome 17 centromere ratio to be significantly associated with incomplete response.
HER2 ITH analyses conducted with GPA method revealed that HER2 ITH is an independent factor predicting incomplete response to anti-HER2 neoadjuvant chemotherapy.
抗 HER2 新辅助化疗已广泛用于 HER2 阳性乳腺癌患者；然而，仅约 40-50%的患者达到病理完全缓解（pCR）。本研究旨在探讨 HER2 肿瘤内异质性（ITH）与抗 HER2 新辅助化疗反应的关系。
对最初被认为 HER2 阳性并接受抗 HER2 新辅助化疗的 64 例浸润性乳腺癌病例的治疗前样本的全组织切片进行 HER2 ITH 评估。采用单幻灯片双检测方法（称为 HER2 基因-蛋白检测（GPA））同时评估 HER2 基因信号和蛋白表达。对 25 例治疗反应不完全的病例，也在手术切除组织上进行了 HER2 GPA。
在 64 例病例中有 19 例（30%）出现 HER2 ITH。在不完全反应组（56%，14/25）中发现更多的具有 HER2 ITH 的病例，而在 pCR 组（13%，5/39）中发现较少的病例。通过 GPA 检测不到 ITH 的患者 pCR 率为 76%（34/45），而检测到 ITH 的患者 pCR 率为 26%（5/19）。多变量分析表明，HER2 ITH、孕激素受体阳性和相对较低的 HER2/17 号染色体着丝粒比值与不完全反应显著相关。
采用 GPA 方法进行的 HER2 ITH 分析表明，HER2 ITH 是预测抗 HER2 新辅助化疗不完全反应的独立因素。
