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PURPOSE Programmed cell death protein-1 (PD-1) receptor and ligand interactions are the target of immunotherapies for more than 20 cancer types. Biomarkers that predict response to immunotherapy are microsatellite instability, tumor mutational burden, and programmed death ligand-1 (PD-L1) immunohistochemistry. Structural variations (SVs) in PD-L1 ( CD274) and PD-L2 ( PDCD1LG2) have been observed in cancer, but the comprehensive landscape is unknown. Here, we describe the genomic landscape of PD-L1 and PD-L2 SVs, their potential impact on the tumor microenvironment, and evidence that patients with these alterations can benefit from immunotherapy. METHODS We analyzed sequencing data from cancer cases with PD-L1 and PD-L2 SVs across 22 publications and four data sets, including Foundation Medicine Inc, The Cancer Genome Atlas, International Cancer Genome Consortium, and the Oncology Research Information Exchange Network. We leveraged RNA sequencing to evaluate immune signatures. We curated literature reporting clinical outcomes of patients harboring PD-L1 or PD-L2 SVs. RESULTS Using data sets encompassing 300,000 tumors, we curated 486 cases with SVs in PD-L1 and PD-L2 and observed consistent breakpoint patterns, or hotspots. Leveraging The Cancer Genome Atlas, we observed significant upregulation in PD-L1 expression and signatures for interferon signaling, macrophages, T cells, and immune cell proliferation in samples harboring PD-L1 or PD-L2 SVs. Retrospective review of 12 studies that identified patients with SVs in PD-L1 or PD-L2 revealed > 50% (52/71) response rate to PD-1 immunotherapy with durable responses. CONCLUSION Our findings show that the 3′-UTR is frequently affected, and that SVs are associated with increased expression of ligands and immune signatures. Retrospective evidence from curated studies suggests this genomic alteration could help identify candidates for PD-1/PD-L1 immunotherapy. We expect these findings will better define PD-L1 and PD-L2 SVs in cancer and lend support for prospective clinical trials to target these alterations.

Objectives: Here we describe the durable clinical outcomes of four FGFR2 fusion positive pancreatic cancer patients treated with FGFR inhibitors as well as a pancreatic specific analysis of FGFR alterations through our collaboration with Foundation Medicine, Inc. (FMI). Methods: We identified four patients with FGFR2 fusion positive metastatic pancreatic cancer through tumor RNAseq (OSU-SpARKFuse) which identifies gene fusions from cell free DNA (cfDNA). We assessed two tumor markers (Ca19-9 and FGFRDx, an FGFR-focused cell free DNA liquid biopsy assay) and various clinical outcomes (Best overall response, duration, and side effects to their treatments). Additionally, 10,146 tumor-tissue clinical cases of pancreatic cancers were assayed by hybrid-capture based comprehensive genomic profiling (Foundation Medicine, Inc.) to identify genomic alterations in >300 cancer-associated genes, MSI, and tumor mutation burden (TMB). Results: All four patients demonstrated durable clinical responses to various FGFR inhibitors. Patient 1 harbored an FGFR2-USP33 fusion and exhibited a partial response to pemigatinib for 25 months following progression on gemcitabine/abraxane and FOLFIRI chemotherapy. Patient 2 harbored an FGFR2-INA fusion with 12 months of stable disease to pazopanib after experiencing progression from chemotherapy. Patient 3 harbored an FGFR2-INA fusion and exhibited a 12+ month on-going, partial response to pemigatinib. Patient 4 harbored an FGFR2-CEP55 fusion and demonstrated stable disease on ponatinib for 15 months, a 24-month response to gemcitabine/platinum chemotherapy, and a 7+ month on-going partial response to infigratinib.  Through the genomic profiling of 10,146 tumor-tissue clinical cases of pancreatic cancer, we identified 108 FGFR fusions resulting in a prevalence of 1%. We are currently investigating co-occurring and mutually-exclusive genomic alterations, including TMB and MSI-H status, for pancreatic cancer patients harboring FGFR alterations. Conclusions: This retrospective analysis provides clinical evidence that there is a subpopulation of KRAS wild-type FGFR2 fusion positive pancreatic patients who can have beneficial and lasting responses to FGFR inhibitors further suggesting a need to investigate and expand the availability of FGFR inhibitors to more cancer types. Citation Format: Leah Stein, Julie W. Reeser, Michele R. Wing, Karthikeyan Murugesan, Anoosha Paruchuri, Zachary Risch, Eric Samorodnitsky, Emily L. Hoskins, Amy Smith, Thuy Dao, Melissa Babcook, Muhammad Imam, Aharon Freud, Sameek Roychowdhury. Clinical impact of FGFR inhibitors on FGFR2 positive pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3395.

Purpose PD-1 receptor and ligand interactions are the target of immunotherapies across 16 cancer types. Biomarkers that predict response to immunotherapy are microsatellite instability, tumor mutational burden and PD-L1 immunohistochemistry. Structural variations in PD-L1 (CD274) and PD-L2 (PDCD1LG2) have been observed across cancer, but the full landscape is unknown. Here we describe the genomic landscape of PD-L1 and PD-L2 structural variation, their potential impact on the tumor microenvironment and evidence that patients with these alterations can benefit from immunotherapy. Methods We analyzed sequencing data from cancer cases with PD-L1 (CD274) and PD-L2 (PDCD1LG2) structural variations across published data, The Cancer Genome Atlas (TCGA) and the Oncology Research Information Exchange Network. From TCGA we obtained copy number status through cBioPortal, gene expression using TCGABiolinks and PD-L1 structural variations identified by Kataoka et al. Gene fusions were detected in ORIEN using STAR-Fusion and Arriba. To evaluate immune signature enrichment we ran software ImSig on gene expression data, using Mann-Whitney tests to determine significant results. We curated literature of patients with structural variations in PD-L1 or PD-L2 receiving PD-1 immunotherapy. Findings From 18 studies and datasets we curated 319 cases with structural variations in PD-L1 and PD-L2. We observed breakpoint ‘hotspots’ in the untranslated regions (UTRs) of both genes including 70 duplications, 48 deletions, 78 inversions and 106 translocations. Leveraging TCGA, we found that PD-L1 amplified tumors had significantly upregulated PD-L1 expression and signatures for interferon signaling and immune cell proliferation, compared to PD-L1 copy neutral tumors, each p < 0.001. Similarly, in PD-L1 rearranged tumors we observed upregulation in PD-L1 expression and signatures for interferon signaling, macrophages, monocytes, T cells and immune cell proliferation, all p < 0.001 compared to PD-L1 copy neutral tumors. Further, retrospective review of 7 studies including patients with structural variations in PD-L1 or PD-L2 revealed >50% (43/77) response rate to immunotherapy. Implications Our evaluation of PD-L1 and PD-L2 structural variations show that the 3’ UTR is affected in hotspots involving a variety of structural variations. Our findings from TCGA suggest PD-L1 structural variation may play a role in driving expression of PD-L1 and immune dysregulation. Enriched interferon signaling in PD-L1 rearranged tumors is of interest as interferon exposure is known to drive PD-L1 and PD-L2 expression. Retrospective evidence from curated studies suggest that this genomic alteration could help identify candidates for PD-1 inhibitors. Based on these findings we propose further study to optimize detection of PD-L1 and PD-L2 structural variation in cancer and design of a pan-cancer prospective clinical trial to target these alterations. Citation Format: Emily L. Hoskins, Eric Samorodnitsky, Michele R. Wing, Julie W. Reeser, Julia Hopkins, Karthikeyan Murugesan, Zheng Kuang, Leah Stein, Zach Risch, Raven Vella, Serifat Adebola, Lianbo Yu, Anoosha Paruchuri, Richard S. Huang, Lee A. Albacker, Sameek Roychowdhury. Pan-cancer landscape and impact of PD-L1 and PD-L2 structural variation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 761.