Genomic and immune landscape of ERBB2/ERBB3 alterations in Gastroesophageal Adenocarcinoma
ASCO Gastrointestinal Cancers Symposium 2023
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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