Abstract RF4-07: Genomic characteristics of de novo HER2-positive metastatic breast cancer

Abstract Background: Metastatic breast cancers (MBC) can present as either de novo (dn) stage IV disease or metastatic recurrence of prior stage I-III cancers. Historically, 30% of human epidermal growth factor receptor 2-positive (HER2+) MBC was dnMBC; however, due to recent improvements in adjuvant systemic therapy, over 50% of HER2+ MBC now represents dnMBC. We previously reported that 34% of patients with HER2+ dnMBC had local-regional progression only, with sustained systemic control. Although HER2+ dnMBC shows distinct clinical characteristics and a favorable prognosis following anti-HER2 therapy compared to relapsed MBC, genomic features associated with treatment response and patterns of failure remain poorly understood. Methods: Patients with HER2+ dnMBC who received first-line trastuzumab and pertuzumab (HP)-based therapy from May 2011 to February 2023 and had MSK-IMPACT sequencing data were included. Clinicopathologic data were obtained from medical records. Overall survival (OS) was defined from the first dose of therapy to death from any cause. Tumor samples were categorized as breast, axillary lymph node, and distant metastasis pre- and post-HP therapy. Progression patterns were classified as local-only (breast/ipsilateral axillary lymph nodes), systemic (distant ± local), or no progression. Mutational signature was analyzed on samples with ≥5 single-nucleotide variants using SigMA. Results: We identified 162 patients with HER2+ dnMBC treated with first-line HP-based therapy. Median age was 48.5 years; 61.7% were estrogen receptor (ER)-positive. The median follow-up was 51.2 months. Forty-two patients (25.9%) remained on first-line therapy (durable responders), while 114 (70.4%) progressed; 76 had systemic and 45 had local-only progression. In total, 209 tumor samples were analyzed, including 142 pre-treatment samples (61 breast, 6 axillary lymph nodes, 75 distant) and 67 post-treatment samples (29 breast, 38 distant). In pre-treatment samples, ERBB2 amplification, TP53, and PIK3CA mutations were observed in 71.8%, 66.9%, and 21.8%, respectively. There was no difference in TMB and FGA between pre-treatment breast and distant tumors. Alterations in JAK-STAT signaling pathway genes were enriched in pre-treatment breast tumors compared to pre-treatment distant tumors (q .001), and were also enriched in pre-treatment tumors that showed local-only progression compared to those with systemic progression (q = .003). Pre-treatment TP53 and PIK3CA mutations were less common in durable responders compared to non-durable responders (PIK3CA; 9.5% vs. 32.6%, p = .005, TP53; 50% vs. 75%, p = .006). PIK3CA mutations were independently associated with worse OS in a multivariable analysis adjusted for age and ER status (HR 2.29, 95%CI 1.09-4.79, p = .03). Tumors with dominant non-clock-like signatures tended to be more frequent in non-durable responders (75% vs. 56%, p = .068). Post-treatment tumors had higher TMB (p = 0.001) and a lower frequency of ERBB2 amplification (58.2% vs. 77.9%, p = 0.005). Paired analysis of pre- and post-treatment samples showed a decrease in dominant signature 3 tumors (p .001), and an increase in dominant APOBEC signatures tumors (p = .01) after treatment. Conclusions: Pre-treatment breast and metastatic tumors in HER2+ dnMBC exhibited similar genomic characteristics. PIK3CA was an independent prognostic factor in this de novo metastatic setting. JAK-STAT alterations in breast tumors may contribute to local progression. The shift in mutational signatures from signature 3 to APOBEC signature in post-treatment indicates potential mechanisms of acquired resistance. These findings may inform future strategies for tailored treatment in HER2+ dnMBC. Citation Format: S. Yazaki, E. Ferraro, M. Acikel, P. Razavi, S. Shen, X. Pei, S. Modi, S. Chandarlapaty, S. Powell, N. Riaz, A. Khan. Genomic characteristics of de novo HER2-positive metastatic breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF4-07.