HER2 intratumoral heterogeneity analyses by concurrent HER2 gene and protein assessment for the prognosis of HER2 negative invasive breast cancer patients

Abstract

HER2 gene-protein assay (GPA) is a new method for the simultaneous evaluation of HER2 immunohistochemistry (IHC) and HER2 dual in situ hybridization (DISH) on single tissue sections of breast cancer. We investigated the presence of HER2 gene and protein discrepancy and HER2-heterogeneity using HER2-GPA. HER2 status was analyzed for the correlation between the presence of HER2-heterogeneity and patient prognosis. Consecutive 280 invasive breast cancer were examined. Statuses of HER2 protein and gene were evaluated in whole tumor sections of HER2 GPA slides. HER2 protein and gene combination patterns were classified to six phenotypic and genotypic types for each case, as well as at individual cell levels: (A) IHC and DISH positive; (B) IHC positive and DISH negative; (C) IHC equivocal and DISH positive; (D) IHC equivocal and DISH negative; (E) IHC negative and DISH positive; and (F) IHC and DISH negative. The presence of HER2-heterogeneity was determined by the existence of at least two of six types within one tumor. HER2-IHC positive patients had significantly worse survival than IHC negative patients and HER2-DISH positive patients had significantly worse survival than DISH negative patients. HER2 IHC negative and DISH positive patients had significantly worse recurrence-free survival than IHC and DISH negative patients. In the HER2 IHC and DISH negative group, the HER2 heterogeneous group had significantly worse survival than the nonheterogeneous group. Notably, among triple negative breast cancer (TNBC), the HER2 heterogeneous group had significantly worse survival than the nonheterogeneous group. Our study suggests that the presence of HER2-heterogeneity might be a prognostic factor in HER2 negative breast cancer patients, especially in TNBC.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-016-3856-2) contains supplementary material, which is available to authorized users.

Intratumor heterogeneity defines treatment‐resistant HER2+ breast tumors

“…Kurozumi et al . studied variation in both HER2 copy number and HER2 protein expression within tumors using a semi‐objective analysis (with visual scoring) and found that regional variation of HER2 CN reflected a worse prognosis particularly in ER‐negative disease (Kurozumi et al ., ). Unfortunately, these patients had not received anti‐HER2 therapy, so neither the predictive value nor the impact of dynamics during therapy could be addressed.…”

“…The study by Lee et al (2014) also found patients with both regional and genomic heterogeneity of HER2 amplification to have decreased disease-free survival, but neither of these two study cohorts had uniform treatment regimens (Seol et al, 2012). Kurozumi et al studied variation in both HER2 copy number and HER2 protein expression within tumors using a semi-objective analysis (with visual scoring) and found that regional variation of HER2 CN reflected a worse prognosis particularly in ER-negative disease (Kurozumi et al, 2016). Unfortunately, these patients had not received anti-HER2 therapy, so neither the predictive value nor the impact of dynamics during therapy could be addressed.…”

Functional and genomic characterization of three novel cell lines derived from a metastatic gallbladder cancer tumor

“…ERBB2 was particularly highly expressed in PUC-GBC1 and PUC-GBC2, and showed a somewhat lower expression in PUC-GBC3. This is not an unexpected finding considering that intratumor heterogeneity is a common event in cancer, and genetic heterogeneity of HER2 has been reported for other tumors [82][83][84][85][86][87][88]. For instance, focal or patchy positivity of HER2 is a pattern encountered in primary gastric tumors, which is consequence of the intratumor heterogeneity and could explain discordances observed in HER2 status between the primary tumor and metastatic sites [82,85].…”

Dynamic Phenotypic Transition of Breast Cancer Cells In Vitro Revealed by Self-floating Cell Culture

“…Trastuzumab can inhibit their CSC-like properties (10). Heterogeneous expression of HER2 in HER2 amplification-negative breast cancer is associated with poor prognosis (17). Indeed a population of patients with low HER2 still benefits from trastuzumab (18).…”