Abstract GMM-025: ERBB FAMILY GENOMIC ALTERATIONS IN GYNECOLOGICAL MALIGNANCIES
Authors: Gay Laurie M , Vergilio Jo-Anne , Killian J Keith , Ramkissoon Shakti , Severson Eric , Daniel Sugganth , Hemmerich Amanda , Ross Jeffrey S , Elvin Julia A 
Published: June 2021

Abstract
Activation of HER2 or EGFR signaling is a common, targetable oncogenic mechanism in solid tumors such as breast, gastroesophageal, lung and colorectal carcinomas. In addition, ERBB3 activation has been shown to confer sensitivity to HER2-targeted therapies, and ERBB4 mutation is reported a mechanism of resistance. From a database of 14,692 comprehensive genomic profiles for both common and rare gynecological malignancies, we extracted 9,121 ovarian tumor profiles and evaluated the prevalence of genomic alterations (GA) in the ERBB family (EGFR, ERBB2, ERBB3, ERBB4), including base substitutions, small indels, amplification (AMP), and rearrangements (RE).
At least 50ng of DNA was extracted from FFPE specimens and sequenced to high, uniform median coverage (&gt;500X) by hybridization capture of exons from up to 406 cancer-related genes and select introns from up to 31 genes commonly rearranged in cancer. For some samples, RNA sequencing of 265 genes was also performed. Tumor mutational burden (TMB, mutations/Mb [mut/Mb]) was determined on ~1.1 Mbp of sequenced DNA, and microsatellite instability (MSI) and overall genomic loss of heterozygosity was evaluated for subsets of the samples.
Of 9,121 tumors, most were serous carcinomas (n = 6,847). A total of 615 (6.7%) tumors had ≥1 oncogenic GA in an ERBB gene, with 40 (0.4%) having ≥2 ERBB GA. ERBB+ were most often mucinous (15.9%) or clear cell (13.9%) carcinomas. Serous carcinomas were ERBB+ in 4.3-7.1% of samples. Patient age was comparable in both the ERBB+ and ERBB- tumors (median 61 y vs. 61 y, range 19-94 y vs. 2-95 y).
ERBB2 (HER2) AMP was the most common ERBB GA; 2.7% of serous carcinomas had amplified ERBB2. GA distribution by ERBB gene was as follows: ERBB2 4.5% (n=394; of those AMP were 78.4%, n=309), ERBB3 0.8% (n=87; AMP 50.6%, n=44), EGFR 0.9% (n=90; AMP 45.6%, n=41), and ERBB4 0.6% (n=66; AMP 65.1%, n=43). Known or potential oncogenic rearrangements, fusions, and splice site GA were observed in both ERBB2 (n=20) and EGFR (n=10), including a kinase domain duplication in EGFR and exon 16 deletions in ERBB2. Although ERBB2 AMP is concordant with HER2+ by IHC or FISH, 70/615 (11.4%) HER2-driven samples harbored targetable, oncogenic GA that would not be detected by these methods, including the well-characterized A775_G776insYVMA (n=13), S310Y/F (n=10), and V842I (n=8).
In ERBB+ tumors, the most commonly co-occurring GA affected TP53 (76.6%), PIK3CA (19.5%), MYC (15.7%), TERC (14.6%), ARID1A (18.3%), and CCNE1 (20.5%). Pathways likely to confer some level of resistance to ERBB-targeted therapies were often mutated: PI3K-AKT-MTOR 35.0% (n=215), RAS-RAF-MEK 18.2% (n=112), and FGFR 5.5% (n=34). ERBB+ tumors had slightly higher TMB scores: median 3.5 mut/Mb vs 2.6 mut/Mb, and average 6.7 vs 3.7 mut/Mb. Of 502 samples analyzed for microsatellite instability, 12 were MSI high. In conclusion, nearly 7% of ovarian tumors harbor potentially targetable GA in an ERBB family gene, including HER2 and EGFR. Of these, 49.6% of samples would not be positive by HER2 IHC or FISH. Further exploration into the efficacy of HER2- or EGFR-targeted therapies, and the effects of co-altered pathways, in ovarian carcinomas may be promising.
Citation Format: Laurie M Gay, Jo-Anne Vergilio, J Keith Killian, Shakti Ramkissoon, Eric Severson, Sugganth Daniel, Amanda Hemmerich, Jeffrey S Ross, Julia A Elvin. ERBB FAMILY GENOMIC ALTERATIONS IN GYNECOLOGICAL MALIGNANCIES [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-025.