Characterizing clinical outcomes and DNA co-alterations of ERBB2-amplified colorectal cancer.

Abstract

3627 Background: A subset of colorectal cancer (CRC) features amplification (amp) of the ERBB2 gene. The prognostic role and treatment in these patients are poorly understood. This study aims to characterize the clinical outcomes and molecular profiles of ERBB2-amp CRC. Methods: This is a retrospective analysis of clinical outcomes data and next-generation sequencing at MD Anderson from 2006-2025 in patients with ERBB2-amp CRC including all classes of genomic alterations (GA) in other genes. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier, log-rank, and cox regression. Chi square goodness of fit was assessed for the proportion of left versus right sided CRC. Results: 100 pts with ERBB2-amp CRC were identified. Patients (Table) who received ERBB2-directed therapy (n = 36) did not have significantly longer OS compared to those who received other systemic therapy (n = 57) (53.8 vs. 45.5 m, p = 0.35). Patients who underwent surgery (n = 64) (56.8 vs. 23.2 m, p = 0.01) or non-surgical localized therapy (n = 45) had longer OS (64.4 vs 45.5 m, p = 0.01). ERBB2-amp was more associated with left sided CRC (n = 80) than right-sided CRC (n = 19) (X 2 = 39.34, df = 1, p < 0.0001) but there was no significant OS difference (53.8 vs. 45.5 m, p = 0.76). Median PFS (mPFS) for all 1st (n = 93), 2nd (n = 80), and 3rd line (n = 61) systemic therapy was 8.0, 5.1, and 4.9 m, respectively. mPFS for all ERBB-2 directed therapy (n = 59) was 3.5 m. The most common concurrent co-GA were TP53 (90%) and APC (64%) and most common co-amp were CDK12 (31%) and EGFR (23%). Concurrent APC mutation was associated with improved OS (53.8 vs. 26.2 m, p = 0.003). No other co-GA or co-amp, including KRAS, showed significant survival outcome associations. TP53 co-GA was present in 90% of both left and right-sided ERBB-2 CRC and KRAS co-GA in 15% and 32%, respectively. Conclusions: There was no difference in OS in ERBB2 amp CRC in patients who received ERBB2 directed therapy, however patients had improved OS with surgery or localized therapy options and should be offered to eligible patients if possible. Co-GA with APC mutation correlated with improvement in survival outcomes. Baseline data, initial staging, treatments, and mutational profile for ERBB2 co-amp CRC. Age at Diagnosis (median) 55 years Gender – no. M (56), F (44) Stage at Initial Diagnosis – no. I (6), II (6), III (18), IV (69) Location of Primary Tumor – no. R-sided (19), L-sided (80), Cecum (7), Ascending (8), Transverse (5), Descending (7), Sigmoid/Rectum (73) Surgery – no. Primary tumor (55), Liver metastectomy (24), Lung metastectomy (8) Localized Therapy – no. RT (36), Ablation (6), Y90 (4), Cryotherapy (1) ERBB2 Directed Therapy (excluded if n=1) – no. Trastuzumab (TRA) + Pertuzumab (20), ERBB2-directed trial drug (14), Trastuzumab deruxtecan (8), TRA (7), TRA + Tucatinib (4) Mutational Profile Co-GA: TP53 (90%), APC (64%), SMAD4 (18%), KRAS (18%) Co-amp: CDK12 (31%), EGFR (23%), MYC (19%), BRAF (13%)