Data from Genetic Alterations Detected by Circulating Tumor DNA in HER2-Low Metastatic Breast Cancer

Abstract

<div>AbstractPurpose:<p>About 50% of breast cancers are defined as HER2-low and may benefit from HER2-directed antibody–drug conjugates. While tissue sequencing has evaluated potential differences in genomic profiles for patients with HER2-low breast cancer, genetic alterations in circulating tumor DNA (ctDNA) have not been well described.</p>Experimental Design:<p>We retrospectively analyzed 749 patients with metastatic breast cancer (MBC) and ctDNA evaluation by Guardant360 from three academic medical centers. Tumors were classified as HER2-low, HER2-0 (IHC 0) or HER2-positive. Single-nucleotide variants, copy-number variants, and oncogenic pathways were compared across the spectrum of HER2 expression. Overall survival (OS) was evaluated by HER2 status and according to oncogenic pathways.</p>Results:<p>Patients with HER2-low had higher rates of <i>PIK3CA</i> mutations [relative risk ratio (RRR), 1.57; <i>P</i> = 0.024] compared with HER2-0 MBC. There were no differences in <i>ERBB2</i> alterations or oncogenic pathways between HER2-low and HER2-0 MBC. Patients with HER2-positive MBC had more <i>ERBB2</i> alterations (RRR, 12.43; <i>P</i> = 0.002 for amplification; RRR, 3.22; <i>P</i> = 0.047 for mutations, in the hormone receptor–positive cohort), fewer <i>ERS1</i> mutations (RRR, 0.458; <i>P</i> = 0.029), and fewer ER pathway alterations (RRR, 0.321; <i>P</i> < 0.001). There was no difference in OS for HER2-low and HER2-0 MBC [HR, 1.01; 95% confidence interval (CI), 0.79–1.29], while OS was improved in HER2-positive MBC (HR, 0.32; 95% CI, 0.21–0.49; <i>P</i> < 0.001).</p>Conclusions:<p>We observed a higher rate of <i>PIK3CA</i> mutations, but no significant difference in <i>ERBB2</i> alterations, oncogenic pathways, or prognosis, between patients with HER2-low and HER2-0 MBC. If validated, our findings support the conclusion that HER2-low MBC does not represent a unique biological subtype.</p></div>