Clinically aggressive malignancies associated with STK11 germline mutations (STK11GCa): A comprehensive genomic profiling (CGP) study.

Abstract

3558 Background: Germline mutations in the STK11 ( LKB1) mTOR pathway gene are associated with Peutz-Jehger’s Syndrome and a variety of malignancies of variable clinical aggressiveness. Recent evidence also links STK11 inactivation with failure to benefit from anti-cancer immune checkpoint inhibitor (IO) therapy in NSCLC. Methods: Using hybrid capture based CGP on extracted tumor DNA and a published “somatic-germline-zygosity” SGZ data analysis algorithm on 212,470 samples of clinically advanced malignancies, we identified 103 (0.05%) STK11GCa inactivating base substitutions or indels. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 57 (55%) STK11GCa cases were NSCLC, 7 (7%) STK11GCa cases each were CRC, breast, pancreatic and unknown primary carcinomas, and 3 (3%) were gynecologic cancers. Amongst all samples included in this analysis, STK11 germline alterations were found in 0.15% NSCLC, 0.03% CRC, 0.03% breast, 0.08% pancreas, 0.06% unknown primary carcinoma and 0.03% of gynecologic cancers. Additional malignancies harboring STK11GCa included melanoma, gastroesophageal, HNSCC, bladder, HCC, lymphoma and mesothelioma. In STK11GCa, the median patient age at sequencing was 61 years (range 2 to > 89 years); gender distribution was 52% female and 48% male. STK11GCa cases had a median of 6.5 genomic alterations (GA)/tumor and KEAP1, another IO resistance gene, was co-altered in 10%. Currently untargetable GA were detected in TP53 (50%), KRAS (38% with 9% in potentially targetable G12C), CDKN2A (32%), CDKN2B (22%), SMARCA4 (19%), MYC (11%), and APC (10%). Potentially targetable GA, which have also been linked in some studies to IO efficacy, included GA in BRAF (10%), EGFR (9%) and PBRM1 (4%). No targetable gene rearrangements or fusions were identified. No MSI High cases were identified. The median TMB was 5 mut/Mb with 23 % >10 mut/Mb and 4% >20 mut/Mb. 15% of 20 evaluated STK11GCA cases were PD-L1 high (>50% tumor cell staining). Conclusions: STK11GCa include a wide variety of primary tumors with a paucity of co-occurring targetable GA. Although these tumors have significant PD-L1 staining and a subset harbor other markers of potential IO efficacy, the inactivated STK11 in these tumors may contribute to IO resistance and lack of responsiveness to immunotherapies.