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

• Published in: Cancers 2024-03, Vol.16 (5), p.1062
• Main Authors: Tanei, Tomonori, Seno, Shigeto, Sota, Yoshiaki, Hatano, Takaaki, Kitahara, Yuri, Abe, Kaori, Masunaga, Nanae, Tsukabe, Masami, Yoshinami, Tetsuhiro, Miyake, Tomohiro, Shimoda, Masafumi, Matsuda, Hideo, Shimazu, Kenzo
• Format: Article
• Language: English
• Subjects: Adjuvant therapy; Adjuvant treatment; Automation; Breast cancer; Cancer; Cancer therapies; Chemotherapy; Copy number; Epidermal growth factor; ErbB-2 protein; Fluorescence in situ hybridization; Gene amplification; Gene expression; Genes; Health aspects; Histograms; Kinases; Medical prognosis; Medical research; Medicine, Experimental; Metastases; Metastasis; Patients; Pertuzumab; Prognosis; Protein expression; Proteins; Surgery; Survival; Tumors
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers16051062

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. This study included patients with primary breast cancer ( = 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. 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: < 0.001 (HH:63% vs. LH:91% at 10 years) and for the OS: = 0.012 (HH:78% vs. LH:95% at 10 years). 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.