Single nucleotide polymorphisms (SNPs) in MHC class I and II genes to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3, MAVERICC, and TRIBE trials.

person Pooja Mittal Division of Medical Oncology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA info_outline Pooja Mittal, Francesca Battaglin, Yan Yang, Joshua Millstein, Sebastian Stintzing, Aparna Raj Parikh, Shivani Soni, Jae Ho Lo, Lesly Torres-Gonzalez, Sandra Algaze, Priya Jayachandran, Karam Ashouri, Alexandra Wong, Wu Zhang, Christoph Mancao, Chiara Cremolini, Volker Heinemann, Heinz-Josef Lenz

Authors person Pooja Mittal Division of Medical Oncology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA info_outline Pooja Mittal, Francesca Battaglin, Yan Yang, Joshua Millstein, Sebastian Stintzing, Aparna Raj Parikh, Shivani Soni, Jae Ho Lo, Lesly Torres-Gonzalez, Sandra Algaze, Priya Jayachandran, Karam Ashouri, Alexandra Wong, Wu Zhang, Christoph Mancao, Chiara Cremolini, Volker Heinemann, Heinz-Josef Lenz Organizations Division of Medical Oncology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, University of Southern California, Los Angeles, CA, Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, Charité - Universitätsmedizin Berlin, Berlin, Germany, Department of Medicine, Division of Hematology & Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, Bayer AG, Leverkusen, Germany, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa & Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy, Italy, University of Munich, Munich, Germany, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA Abstract Disclosures Research Funding Other Foundation National Cancer Institute, Gloria Borges WunderGlo, Dhont Family, San Pedro Peninsula Cancer Guild, Daniel Butler Research Fund, Victoria and Philip Wilson Research Fund, Fong research project, Ming Hsieh research fund Background: The immune system is alerted for virally infected cells in the body by the antigen presentation pathway, which is in turn mediated by the major histocompatibility complex (MHC) class I and II molecules. Cancer cells overcome immune evasion as a major hallmark by downregulation of antigen presentation pathway molecules. Therefore, the present study aimed to explore the effect of genetic variants in MHC class I and II pathways on first-line treatment outcome in mCRC pts. Methods: Genomic DNA from blood samples of 775 pts enrolled in three independent, randomized, first-line trials: TRIBE (FOLFIRI-bevacizumab [bev], N = 215), FIRE-3 (FOLFIRI-bev, N = 107; FOLFIRI-cetuximab [cet], N = 129) and MAVERICC (FOLFIRI-bev, N = 163; FOLFOX-bev, N = 161) was genotyped through OncoArray, a custom array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 40 selected SNPs in 22 genes of MHC class I and II pathways ( ERAP1, ERAP2, TAP1, TAP2, TAPBP, B2M, HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, HLA-G, CIITA, HLA-DMA, HLA-DMB, HLA-DOA, HLA-DOB, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1 and HLA-DRA ) was analyzed. Results: We identified several SNPs in multiple genes associated with targeted treatment benefit across different treatment arms in our study population ( P < .05). Germline variants in ERAP1 rs2287987 were associated with worse PFS in pts receiving FOLFIRI-bev in TRIBE (10.4 vs 8.8 months, HR 1.48, 95%CI 1.04-2.12, P = .035) and FIRE-3 trials (11.1 vs 9.9 months, HR 3.46, 95%CI 1.18-10.12, P = .049), while rs26653 SNP in the same gene was associated with better PFS in MAVERICC (10.1 vs 14.5 months, HR 0.54, 95%CI 0.35-0.84, P = .0062). TAP1 rs1135216, TAP2 rs1800454 and rs1044043, HLA-B rs2770, HLA-G rs1610696, CIITA rs4774, HLA-DRA rs7192 were associated with longer OS and/or PFS in cet-treated pts in FIRE-3; whereas TAP2 rs241447, TAPBP rs3106191, HLA-DMB rs10751, HLA-DOB rs11244, HLA-DPB1 rs3097671 showed worse PFS and/or OS. SNPs in TAP2 (rs1800454), HLA-C (rs1049281), HLA-G (rs1063320), CIITA (rs1139564), HLA-DMB (rs1042337), HLA-DOA (rs375256, rs3129303), HLA-DPA1 (rs1042190) and HLA-DRA (rs7192) were specifically associated with clinical outcomes in the FOLFOX-bev arm of MAVERICC but not in control cohorts of pts treated with FOLFIRI-bev. Treatment-SNP interaction analyses with targeted agents (bev vs cet) and chemotherapy backbone (FOLFIRI vs FOLFOX) confirmed a significant treatment interaction for HLA-G, TAP2 , CIITA , and HLA-DMB SNPs ( P < .05). Conclusions: Our results highlight an important role for MHC SNPs as prognostic and predictive biomarkers for first-line treatment in mCRC, with differential effects based on biologic agent and chemotherapy backbone. These biomarkers, when further validated, may contribute to personalized treatment strategies for mCRC patients.