Genomic Characterization and Prognostic Significance of Human Epidermal Growth Factor Receptor 2–Low, Hormone Receptor–Positive, Early Breast Cancers From the BIG 1-98 and SOFT Clinical Trials

PURPOSE To investigate whether hormone receptor–positive, human epidermal growth factor receptor 2–low (HR+HER2-low) versus HR+HER2-zero early breast cancers have distinct genomic and clinical characteristics. METHODS This study included HR+, HER2-negative early breast cancers from patients enrolled in the phase III, randomized BIG 1-98 and SOFT clinical trials that had undergone tumor genomic sequencing. Tumors were classified HR+HER2-low if they had a centrally reviewed HER2 immunohistochemistry (IHC) score of 1+ or 2+ with negative in situ hybridization and HR+HER2-zero if they had an HER2 IHC score of 0. RESULTS A total of 1,795 tumors were evaluable for this study (BIG 1-98 n = 520, SOFT n = 1,275). The frequency of HER2-low tumors was 37% and 21% in the postmenopausal BIG 1-98 and premenopausal SOFT cohorts, respectively. There were no significant differences in clinicopathologic variables between HER2-low and HER2-zero groups which was consistent across both trials. There was no significant difference in risk of distant recurrence for patients with HER2-low tumors versus HER2-zero tumors (5-year % distant recurrence-free 94.0% v 92.8%, P = .61, in BIG 1-98; 89.4% v 92.7%, P = .31, in SOFT, respectively). Somatic genomic profiles were similar with the exception of MAP3K1 mutations which were more frequent in HER2-zero tumors (BIG 1-98 19% v 5%, SOFT 11% v 6%). Both ERBB2 copy number and ERBB2 gene expression abundance were significantly higher in HER2-low tumors compared with HER2-zero tumors; however, the absolute difference was small. Correlation between ERBB2 copy number values and gene expression was modest ( r = 0.17). CONCLUSION In two large clinical trials with centrally reviewed HER2 IHC, our findings do not support HER2-low breast cancer as a distinct clinical or biologic entity among HR+HER2- early breast cancers. Absolute differences in median ERBB2 copy number levels or gene expression are small and of unclear biologic relevance.