The spectrum of activating EGFR mutations from cell-free DNA (cfDNA) in large pancreatic cancer cohort.

Abstract

237 Background: Metastatic pancreatic cancer (mPC) is one of the deadliest cancers with a < 10% 5-year survival rate. Poor prognosis is well established with lack of response to or rapid progression on existing chemotherapy options. Targeted therapies, like EGFR-TKIs, have been shown to increase survival in other solid tumors like NSCLC with certain oncogenic drivers. Although treatment with the EGFR-TKI erlotinib, in combination with gemcitabine, is available for patients (pts) with mPC, the survival benefit is small in unselected patients. A better understanding of the spectrum of EGFR mutations in mPC may lead to improved therapy selection. Methods: We retrospectively reviewed genomic results from 2,938 consecutive mPC pt samples sent for ctDNA NGS analysis between 7/2014 - 9/2018 (Guardant Health, Inc.). All reported EGFR mutations were reviewed and activating mutations were determined based on literature review. Results: 19 EGFR activating mutations were identified in 16 unique pts (0.66% of total mPC pts with alterations detected). 3 mutations were identified in the extracellular domain and 16 mutations in the tyrosine kinase domain (3 in exon 18, 3 in exon 19, 6 in exon 20, 4 in exon 21). Alterations in exon 20 included 5 T790M mutations; two of these were reported at allelic frequencies suggestive of germline origin. Analysis of co-mutations revealed 7 pts with EGFR mutations that appeared subclonal relative to other potential drivers (4 KRAS, 2 ERBB2, 1 GNAS). The median number of alterations per sample was 4 (range 2-170) with the latter pt exhibiting a hypermutator phenotype. Multiple pts had more than one activating EGFR alteration including one who was found to have 4 EGFR sequence alterations (S768I, L861Q, T790M, p.Val769_Asp770insMet) plus EGFR amplification (plasma copy number 66.8). We will collect and report clinical details to characterize the treatment context for these pts. Conclusions: Activating EGFR mutations in mPC are rare but may present an opportunity for targeted therapy in this population. Further exploration is warranted to better understand the oncogenic activity of less common, subclonal, or co-occurring EGFR mutations and their sensitivity to EGFR-TKIs in mPC.