Distribution of receptor tyrosine kinase (RTK) nsSNPs in breast cancer (BC) patients (pts) using next-generation sequencing (NGS).

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1080 Background: Non-synonymous SNPs (nsSNPs) discovered by NGS occurring in RTKs’ conserved topology in pts with BC may promote oncogenic signaling and hence may be actionable. Methods: We analyzed BC pts for nsSNPs in 29 RTKs identified by tumor profiling with NGS from Caris during 2013-2015. Mutations were classified by location including the tyrosine kinase domain (TKD), extracellular domain (ECD), transmembrane domain (TM), juxtamembrane domain (JM) and carboxy-terminal (CT) regions. nsSNPs underwent in silico analysis using PolyPhen-2 (Harvard) to determine pathogenicity. Results: 79 pts were identified with a median age of 58 years (range 32-83); 99% female; 60% white, 38% black and 2% other. 77 pts were classifiable with 8 (10%) triple-positive, 35 (46%) ER+/PR+/HER2- (ER/PR+), 10 (13%) ER-/PR-/HER2+ (HER2+) and 24 (31%) triple-negative. 78 nsSNPs and 1 Caris-reported pathogenic substitution of ERBB3 (TKD S846I) were found. 52/79 (66%) pts had ≥1 RTK nsSNP (range 0-4); 28/29 RTKs had ≥1 nsSNP with median of 2 (range 0-15). In 28 pts (35%), 40% of nsSNPs were predicted to be damaging (pnsSNP) and 3 pts had 2 pnsSNPs. 17/29 RTKs had pnsSNPs, median 1 (range 0-9). The most commonly mutated RTKs were ROS1 (9/15 variants were pnsSNPs), ALK (3/4), EPHA5 (3/3), FLT4 (2/5), cKIT (2/4) and ERBB4 (2/3). ROS1 and ALK nsSNPs were most-frequently seen in ER/PR+ (9/15 pnsSNPs), triple-positive (3/3) and HER2+ (0/2) pts; no triple-negative pts had such variants. 100% triple-positive pts (6/8 pnsSNP), 69% ER/PR+ (18/35), 60% HER2+ (2/10) and 58% triple-negative (3/24) had RTK nsSNP. nsSNP were spread in all 5 RTK regions: 58% localized to the ECD (20/45 pnsSNPs), 17% TKD (8/13), 9% CT (2/7), 9% TM (1/7) and 8% JM (1/6) lesions were found. Of 9 ROS1 pnsSNPs, 7 were ECD, 1 CT and 1 TKD. Conclusions: 35% of BC pts had pnsSNP in RTKs across various phenotypes including frequent mutations in potentially actionable genes such as ROS1 and ALK. 26% of ER/PR+ pts had pnsSNPs in ROS1 or ALK. nsSNPs in the ECD or TKD were most likely to be damaging.