Abstract

Immune checkpoint inhibition (ICI) has fundamentally improved the treatment of advanced melanoma. PD-L1 positivity ≥1% by immunohistochemistry (IHC) has been associated with improved clinical response and patient survival in ICI-treated melanoma. Moreover, there is increasing evidence that some tumor suppressor proteins regulate expression of immune checkpoint proteins. We sought to assess the genomics of a cohort of melanomas, to identify if PD-L1 status is linked to any distinct mutational signatures, particularly in tumor suppressor genes. FFPE tissue from 811 clinically advanced melanomas underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GAs) and tumor mutational burden (TMB, mutations/Mb). PD-L1 status was determined by IHC using DAB chromogen and Dako 22C3 staining kit, with ≥1% tumor proportion score (TPS) defined as positive and <1% defined as negative. PD-L1 IHC status was positive at the 1% cutoff in 346/811 (43%) of our cohort of advanced melanomas. Of the 54 cases sequenced from lung metastases, a significantly higher percentage were PD-L1 positive compared with the remainder of the cohort (63% vs. 41%, p=0.0025). Compared with the PD-L1 negative cases, PD-L1 positive cases showed significantly higher TMB (median 17.5 vs. 9.6, p<.00001), and significantly higher percentages of pathogenic GAs in TERTp (73% vs. 58%, p<.0001), and two key tumor suppressor genes: TP53 (36% vs. 16%, p<.0001) and NF1 (24% vs. 15%, p=.0015). All four cases with amplification of CD274 were PD-L1 positive. PD-L1 positive cases with ≥50% TPS (n=83) showed a higher percentage of GAs in TP53 compared with positive cases with <50% TPS (n=263) (57% vs. 29%, p<.0001). Advanced melanoma shows significant differences in molecular profile depending on PD-L1 IHC status. These results may direct future studies to evaluate if tumor location or PD-L1-associated GAs influence response to anti-PD-1 immunotherapy.

Financial Disclosure: The oral presenter listed below disclosed the following information about their financial interests. The ASDP Ethics Committee has reviewed these disclosures and determined that no conflicts of interest exist between financial relationships and educational content being presented:

Speaker	Company	Affiliation/Relationship
Erik Williams, MD	Foundation Medicine, Inc.	Consultant