5075 - Association of PD-L1 expression with prognosis among patients with 10 select cancers

Background

Oncogenic RET mutations (mut) are well-described in papillary thyroid (thy) carcinomas (ca) and non-small cell lung cancer (NSCLC), and confer sensitivity to therapies such as vandetanib or alectinib. RET mut are also found in other tumor types (OTT). We queried genomic profiles from >400 tumor types to assess RET RE/FN across diverse cancers.

Methods

Comprehensive genomic profiling of DNA (≥50 ng) and/or RNA from 158,360 samples, both solid and hematologic malignancies, was done by hybridization-capture, adaptor ligation-based next-generation sequencing of up to 465 cancer-related genes. Samples were evaluated for base substitutions (subs), small indels, copy number variations and RE/FN, as well as tumor mutational burden and microsatellite stability status.

Results

In all, 603 RE/FN were found in 51 cancer types: 512 FN and 91 non-FN RE retaining the kinase domain. Unlike oncogenic RET subs (n = 590), most often in medullary thy ca (130/163, 79.8%), RE/FN were most often in papillary thy ca (39/550, 7%), salivary gland ca (5/256, 2%) and lung adenocarcinomas (297/19632, 1.5%); 179/603 (29.7%) RE/FN were in OTT. FN partner (ptn) varied by tumor type (Table). NCOA4-RET was in 6/9 (66.7%) salivary gland ca and 49/62 FN ptn were seen only once. Breakpoints in RET were ex12 (88.5%), ex11 (7.6%), ex13 (0.4%), and ex1-10 (3.3%). Like CCDC6, 8 other FN ptn primarily contributed UTR; 5/5 brain tumors had CCDC6-RET FN. A novel CSGALNATCT2-RET was seen in 2/2 bladder urothelial ca. 8 cases had co-occurring RET subs and RE/FN. Common co-altered genes with RET FN in thy, NSCLC, and OTT were TP53 (12.8% vs 42.9% vs 52.9%, p ≪0.01), CDKN2A (12.8% vs 30.4% vs 26.1%; p = 0.03), and CDKN2B (10.6% vs 25.6% vs 18.2%; p = 0.02); TERT promoter mut were common in thy (26.3% vs 2.4% vs 4.8%; p ≪0.01).Table: 58PD

Conclusions

Recurrent, targetable RET RE/FN are found across diverse tumor types and predominant FN ptn varies: KIF5B in NSCLC, CCDC6 and NCOA4 in thy ca and OTT. 49 ptn were observed only once. Nearly 25% of FN are found in OTT.

Clinical trial identification

Legal entity responsible for the study

Foundation Medicine, Inc.

Funding

Foundation Medicine, Inc.

Editorial Acknowledgement

Disclosure

L.M. Gay, D.C. Pavlick, S. Ramkissoon, S. Daniel, J.K. Killian, J-A. Vergilio, E. Severson, G.M. Frampton, J.A. Elvin, J.S. Ross: Employee and shareholder: Foundation Medicine, Inc.