High HER2 Intratumoral Heterogeneity Is a Predictive Factor for Poor Prognosis in Early-Stage and Locally Advanced HER2-Positive Breast Cancer.

Simple Summary: Breast cancer tumors are considered to have intratumoral, as well as human epidermal growth factor receptor 2 (HER2), heterogeneity. Tumors with high intratumoral heterogeneity (ITH) have demonstrated therapeutic resistance. However, studies on cancer heterogeneity as a prognostic factor in breast cancer have been limited. Therefore, we evaluated HER2 ITH, which was manifested by the shape of HER2 fluorescence in situ hybridization amplification distributed histograms (HER2 FISH distributions) with the HER2 gene copy number within a tumor sample. We aimed to determine whether high HER2 heterogeneity is clinically significant for poor prognosis due to resistance to postoperative adjuvant therapy with HER2-targeted agents in primary breast cancer. Indeed, we were able to show herein that high HER2 heterogeneity is significantly associated with poorer prognosis in patients with HER2-positive breast cancer. These results indicated that high HER2 heterogeneity is a factor predicting poor prognosis in patients with HER2-positive breast cancer. Our present observation seemed to be clinically important, because it is expected that our HER2 FISH distribution analysis of heterogeneity might be a convenient and clinically useful method for the prognosis prediction of patients after HER2 adjuvant therapy. Purpose: Breast cancer tumors frequently have intratumoral heterogeneity (ITH). Tumors with high ITH cause therapeutic resistance and have human epidermal growth factor receptor 2 (HER2) heterogeneity in response to HER2-targeted therapies. This study aimed to investigate whether high HER2 heterogeneity levels were clinically related to a poor prognosis for HER2-targeted adjuvant therapy resistance in primary breast cancers. Methods: This study included patients with primary breast cancer (n = 251) treated with adjuvant HER2-targeted therapies. HER2 heterogeneity was manifested by the shape of HER2 fluorescence in situ hybridization amplification (FISH) distributed histograms with the HER2 gene copy number within a tumor sample. Each tumor was classified into a biphasic grade graph (high heterogeneity [HH]) group or a monophasic grade graph (low heterogeneity [LH]) group based on heterogeneity. Both groups were evaluated for disease-free survival (DFS) and overall survival (OS) for a median of ten years of annual follow-up. Results: Of 251 patients with HER2-positive breast cancer, 46 (18.3%) and 205 (81.7%) were classified into the HH and LH groups, respectively. The HH group had more distant metastases and a poorer prognosis than the LH group (DFS: p < 0.001 (HH:63% vs. LH:91% at 10 years) and for the OS: p = 0.012 (HH:78% vs. LH:95% at 10 years). Conclusions: High HER2 heterogeneity is a poor prognostic factor in patients with HER2-positive breast cancer. A novel approach to heterogeneity, which is manifested by the shape of HER2 FISH distributions, might be clinically useful in the prognosis prediction of patients after HER2 adjuvant therapy. [ABSTRACT FROM AUTHOR]