Majority of B2M -Mutant and -Deficient Colorectal Carcinomas Achieve Clinical Benefit From Immune Checkpoint Inhibitor Therapy and Are Microsatellite Instability-High.

Purpose: Microsatellite instability-high (MSI-H) colorectal carcinomas (CRCs) show high rates of response to immune checkpoint inhibitors (IOs). B2M mutations and protein loss have been proposed as causes of resistance to IOs, yet they are enriched in MSI-H CRC. We aimed to characterize B2M -mutant, IO-naive CRC.
Patients and Methods: All CRCs with results for Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets, a next-generation sequencing assay that interrogates > 400 genes for mutations as well as MSI status, were surveyed for B2M mutations. All B2M -mutant CRCs were assessed for expression of B2M , major histocompatibility complex class I, and programmed death-1 ligand (PD-L1) via immunohistochemistry and average CD3 ⁺ and CD8 ⁺ tumor-infiltrating lymphocyte counts against a control group of MSI-H B2M wild-type CRCs.
Results: Fifty-nine (3.4%) of 1,751 patients with CRC harbored B2M mutations, with 84% (77 of 92) of the mutations predicted to be truncating. B2M mutations were significantly enriched in MSI-H CRCs, with 44 (24%) of 182 MSI-H CRCs harboring B2M mutations ( P < .001). Thirty-two of 44 B2M -mutant CRCs with available material (73%) had complete loss of B2M expression, whereas all 26 CRCs with wild-type B2M retained expression ( P < .001). B2M mutation status was not associated with major histocompatibility complex class I expression, KRAS or BRAF mutation, tumor-infiltrating lymphocyte level, or PD-L1 expression after adjustment for MSI status. Of 13 patients with B2M -mutant CRC who received programmed death-1 or PD-L1 IOs, 11 (85%) achieved clinical benefit, defined as stable disease or partial response using Response Evaluation Criteria in Solid Tumors criteria.
Conclusion: B2M mutations occur in approximately 24% of MSI-H CRCs and are usually associated with loss of B2M expression. Most patients with B2M -mutant MSI-H CRC with loss of protein expression obtain clinical benefit from IOs.
Competing Interests: AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST AND DATA AVAILABILITY STATEMENT The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Rona Yaeger Research Funding: Array BioPharma, GlaxoSmithKline, Novartis Travel, Accommodations, Expenses: Array BioPharma Zsofia K. Stadler Consulting or Advisory Role: Allergan (I), Genentech/Roche (I), Regeneron (I), Optos (I), Adverum (I), Biomarin (I), Alimera Sciences (I), Novartis (I), Spark Therapeutics (I), Fortress Biotech (I), Regenxbio (I) Luis A. Diaz Jr Leadership: Personal Genome Diagnostics, Jounce Therapeutics Stock and Other Ownership Interests: PapGene, Personal Genome Diagnostics, Jounce Therapeutics, Zydecom Consulting or Advisory Role: Merck, Personal Genome Diagnostics, Cell Design Labs, Phoremost, Lyndra, Caris Life Sciences, Genocea Biosciences, Zydecom Research Funding: Merck (Inst) Patents, Royalties, Other Intellectual Property: US-2010041048-A1 Circulating mutant DNA to assess tumor dynamics; US-2015344970-A1 personalized tumor biomarkers; WO-2010118016-A2 digital quantification of DNA methylation; US-2005202465-A1 thymidylate synthase gene and metastasis; US-2014227271-A1 somatic mutations in ATRX in brain cancer; WO-2012094401-A2 genes frequently altered in pancreatic neuroendocrine tumors; US-2013323167-A1 detecting and treating solid tumors through selective disruption of tumor vasculature; EP-2912468-B1 Papanicolaou test for ovarian and endometrial cancers; US-9976184-B2 mutations in pancreatic neoplasms; US-2017267760-A1 checkpoint blockade and microsatellite instability; US-2018171413-A1 head and neck squamous cell carcinoma assays; US-2018086832-A1 HLA-restricted epitopes encoded by somatically mutated genes; US-2018258490-A1 assaying ovarian cyst fluid; US-2016208340-A1 TERT promoter mutations in urothelial neoplasia; US-2015252415-A1 Arid1b and neuroblastoma; WO-2018071796-A2 compositions and methods for identifying functional antitumor T-cell responses; EP-3322824-A1 detection of tumor-derived DNA in cerebrospinal fluid; US-2016273049-A1 systems and methods for analyzing nucleic acid (Inst); US-2018135044-A1 nonunique barcodes in a genotyping assay (Inst); US-2017016075-A1 neoantigen analysis (Inst) Travel, Accommodations, Expenses: Merck Leonard Saltz Consulting or Advisory Role: McNeil (I) Research Funding: Taiho Pharmaceutical Neil Segal Consulting or Advisory Role: Bristol-Myers Squibb, Pfizer, AstraZeneca/ MedImmune, Imugene, Roche/Genentech, Pieris Pharmaceuticals, Synlogic, Aduro Biotech, Kyn Therapeutics, Boehringer Ingelheim, Merck, Puretech, Horizon Pharma, EMD Serono, Gritstone Oncology, Chugai Pharma, TRM Oncology, IFM Therapeutics, PsiOxus Therapeutics Research Funding: MedImmune, Bristol-Myers Squibb, Pfizer, Roche/ Genentech, Merck, Incyte Marc Ladanyi Honoraria: Merck (I) Consulting or Advisory Role: National Comprehensive Cancer Network/ AstraZeneca Tagrisso RFP Advisory Committee, Takeda Pharmaceuticals, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Merck (I) Research Funding: Loxo (Inst), Helsinn Therapeutics Ahmet Zehir No relationship to disclose Jaclyn F. Hechtman Honoraria: Medscape Consulting or Advisory Role: Navigant Consulting, Axiom Biotechnologies Research Funding: Bayer No other potential conflicts of interest were reported.