01/22/2023

Genomic and immune landscape of ERBB2/ERBB3 alterations in gastroesophageal adenocarcinoma

ASCO Gastrointestinal Cancers Symposium 2023 PRESENTATION
Authors Sarbajit Mukherjee, Elizabeth Mauer, Karyn Ronski, Manish A. Shah

Background: HER2/ERBB2 is a known therapeutic target in gastroesophageal adenocarcinoma (GEAC). HER3/ERBB3 is an emerging target in a variety of cancers but less defined in GEAC. Insights into the genomic and immunologic landscape of ERBB2/ERBB3 alterations (ERBB2/3-alt) are required to develop effective treatments.

Methods: We analyzed de-identified data from 2,050 GEAC patient tumor samples which underwent next generation sequencing with the Tempus xT assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq). Bivariate analyses were performed to compare demographics, immuno-oncology (IO) biomarkers, and co-mutations between ERBB2/3-alt groups. P-values comparing individual co-mutations between groups were adjusted for false discovery.

Results: Overall, 17.8% (365/2050) of tumors harbored an ERBB2 or ERBB3-alt, 3 of which had both and were excluded from analyses. Alterations were defined as pathogenic/likely pathogenic mutations, copy number amplifications (CN amp), or copy number loss (CN loss). Tumors were divided into ERBB2 CN amp (n=252, 12.3%), ERBB2 other (CN loss/mutation) (n=71, 3.5%), ERBB3 CN amp (n=17, 0.8%), ERBB3 other (n=22, 1%), and WT (n=1685, 82%) for both. No differences were observed between groups regarding baseline demographics (age of onset, race, ethnicity) aside from the percentage of females (p=0.002). Significant differences in IO markers and the co-occurring genetic alterations were seen. ERBB3 other (N = 22 mutations – No CN loss) had increased TMB, microsatellite instability high (MSI-H), and median neoantigen tumor burden.

Conclusions: ERBB2/ERBB3-alt are associated with significant changes in the tumor microenvironment in GEAC. Co-occurring genetic or immunologic alterations can be exploited to develop effective targeted or immune therapies.

Comparison between ERBB2 and ERBB3 groups regarding co-alterations and IO markers.
Overall N = 2,047 ERBB2 CN amp N = 252 ERBB2 other N = 71 ERBB3 CN amp N = 17 ERBB3 other N = 22 ERBB2/ERBB3 WT N = 1,685 p-value/ q-value
TMB^ (N=1880) 3.33 (1.92, 4.99) 3.75 (2.69, 5.00) 3.46 (2.31, 5.76) 1.94 (0.82, 3.26) 5.38 (2.78, 11.72) 3.33 (1.92, 4.96) p = <0.001
TMB-H* (N=1880) 75 (4.0%) 5 (2.2%) 4 (5.8%) 0 (0%) 6 (27%) 60 (3.9%) p = <0.001
MSI-H 63 (3.1%) 1 (0.4%) 2 (2.9%) 0 (0%) 5 (23%) 55 (3.3%) p = <0.001
PDL1+ (N=1316) 751 (57%) 97 (54%) 21 (54%) 7 (64%) 12 (67%) 614 (57%) p = 0.8
Neoantigen Tumor Burden^ (N=1768) 1.46 (0.97, 2.20) 1.46 (0.98, 2.20) 1.46 (0.98, 2.47) 0.49 (0.49, 1.71) 2.44 (1.22, 8.05) 1.46 (0.97, 2.20) p = 0.008
KRAS 380 (19%) 22 (8.7%) 6 (8.5%) 4 (24%) 4 (18%) 344 (20%) q = <0.001
ALK 316 (15%) 28 (11%) 11 (15%) 2 (12%) 8 (36%) 267 (16%) q = 0.064
PIK3CA 142 (7%) 14 (5.6%) 6 (8.5%) 1 (5.9%) 7 (32%) 114 (6.8%) q = 0.023
TP53 1292 (63%) 187 (74%) 48 (68%) 5 (29%) 7 (32%) 1,045 (62%) q = <0.001
TMB=Tumor Mutational Burden (mut/MB), * >=10 mut/MB, PDL1+=PD-L1 positive by internal IHC, ^ Median (Interquartile Range)

 

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