Abstract PO5-15-05: Clinical and genomic landscape of ERBB2 and ERBB3 mutated breast cancer

Abstract Background: Our understanding of tumorigenesis in ERBB2 (HER2) non-amplified breast cancer has recently evolved through genome sequencing efforts identifying somatic mutations in ERBB2 and its ERBB3 coreceptor (ERBB2/3). These alterations result in upregulation of HER2 activity and have been implicated in resistance to certain targeted therapies. To develop efficacious therapeutic strategies in this context, further delineation of the clinical and genomic landscape of ERBB2/3-mutated (ERBB2/3-mut) breast cancers is paramount. Methods: Patients (pts) with breast cancer who underwent tumor and normal tissue sequencing using the MSK-IMPACT assay between April 2015 to August 2019 were surveyed in this analysis. We performed gene enrichment analyses to assess the frequency, type and pattern of ERBB2/3-mut, and compared demographics and clinicopathologic characteristics of this cohort with those of pts with ERBB2/3-wild-type (wt) tumors. The landscape of co-occurring and mutually exclusive genomic alterations in oncogenic (as per OncoKB) ERBB2/3-mut vs. ERBB2/3-wt was studied in the context of receptor status. Finally, we investigated the association between ERBB2/3-mut status and clinical outcomes in HR+/HER2- pts. Progression free survival (PFS) on first line CDK4/6 inhibitors and endocrine therapy (CDK4/6i-ET) was assessed utilizing Cox proportional hazard models adjusted for endocrine therapy partner. Results: Of 4, 458 evaluable pts with breast cancer, 260 were ERBB2/3-mut (ERBB2 n=182, 4. 1%; ERBB3 n=90, 2. 0%, with both ERBB2/3 n=12, 0. 27%). A total of 368 ERBB2/3 alterations were identified in 321 samples, of which 324 were SNVs (88. 0%) and 44 indels (12. 0%). Of the 256 ERBB2-mut, 185 (72. 3%) were pathogenic variants (PVs), with the most frequent alterations being L755S (28. 6%), V777L (13. 5%), G778P780dup (10. 3%) and S310F (12. 4%). Of the 112 ERBB3-mut, 53 (47. 3%) were PVs; E928G (47. 3%) and G284R (11. 3%) were the most common. ERBB2/3-mut tumors were enriched in lobular (n=72, 13. 3%) over ductal histology (n=164, 4. 6%; Odds ratio OR: 3. 15, 95% confidence interval CI: 2. 31–4. 25; p=8. 2 e-13). When duplicates from each category were excluded, ERBB2/3 variants were more prevalent in metastatic tumors (n=165, 7. 3%) compared to primaries (n=119, 4. 7%; OR: 1. 61, 95% CI: 1. 25–2. 06, p=0. 0001). A similar trend was observed in the HR+/HER2- subgroup (metastatic: 6. 7% vs. primary: 4. 3%; OR: 1. 61, 95% CI: 1. 12–2. 2, p=0. 0024). In the HR+/HER2- subgroup (n=3, 039), ERBB2-mut (4. 0%, PVs: 3. 1%) were significantly co-altered (q 0. 1) with CDH1, TBX3, ERBB3, RUNX1, CBFB, MAP3K1, FOXA1 and NF1 and mutually exclusive with GATA3. In the HER2+ subgroup (n=640), ERBB2-mut (7. 2%, PVs: 4. 7%) were significantly co-altered with CDH1, TBX3, and CDKN2A/B. In the TNBC cohort (n=779), ERBB2-mut (2. 3%, PVs: 1. 7%) were mutually exclusive with TP53, and co-altered with PIK3CA, ARID1A, MAP3K1, CBFB, and CDH1. Overall, the ERBB3-mut were co-altered with ERBB2, CDH1, and CBFB. In HR+/HER2- pts with tumor sequencing performed prior to receiving first-line CDK4/6i-ET (n=468), PFS for ERBB2/3-mut (n=23) was not significantly different than ERBB2/3-wt (hazard ratio: 1. 19, 95% CI: 0. 75–1. 90, p=0. 46). Conclusion: Here we describe the clinical and genomic characteristics of a large cohort of ERBB2/3-mut breast cancers. We identify a notable enrichment of ERBB2/3-mut in lobular histology and metastatic tumors and tendency for co-alteration with CDH1 and multiple transcription factors reflecting the unique biology of ERBB2/3-mut breast cancers. Further analyses on an expanded cohort (n 6000 pts), including outcomes on HER2-directed antibody-drug conjugates (T-DXd) and targeted therapies such as PI3K inhibitors, will be presented at the 2023 SABCS Annual Meeting. Citation Format: Nadeem Bilani, Jacqueline Tao, Anton Safonov, Dana Casey, Joshua Drago, Mehnaj Ahmed, Barbara Acevedo, Komal Jhaveri, Jorge Reis-Filho, Mark Robson, Eneda Toska, Ariella Hanker, Carlos Arteaga, Sarat Chandarlapaty, Hanna Y Wen, Pedram Razavi. Clinical and genomic landscape of ERBB2 and ERBB3 mutated breast cancer abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84 (9 Suppl): Abstract nr PO5-15-05.