Abstract A053: Prevalence of mismatch repair deficiency (dMMR) in the NCI Molecular Analysis for Therapy Choice (NCI-MATCH or EAY131) population

Abstract

Abstract Introduction: NCI-MATCH (EAY131), a national signal-finding trial, assigns targeted treatments to patients (pts) with relapsed/refractory solid tumors, lymphomas and myelomas based on molecular abnormalities in tumors. We screened 4901 pts for dMMR, an eligibility criterion. Methods: Immunohistochemical expression (IHC) of MLH1 and MSH2 was performed at the CLIA-accredited MD Anderson Clinical IHC Laboratory. Loss of nuclear expression of MLH1 or MSH2 predicted microsatellite instability resulting from sporadic alterations or germline mutations. Assays were validated for FFPE tissue and used under an FDA abbreviated investigational device exemption. IHC was performed on 4 μm deparaffinized and rehydrated FFPE tissue sections. Antigen retrieval was performed at 100°C for 20 minutes with Tris-EDTA buffer solution, pH 6.0 & blocking of endogenous peroxidase with 3% peroxide for 5 minutes. Primary MLH1 antibody (Cell MarqueTM, clone G168-728) at 1:300 dilution and primary MSH2 antibody (Calbiochem®, clone FE11) at 1:100 dilution were applied. Primary antibody detection used a commercial polymer system (Bond Polymer Refine Detection, Leica) with stain development using incubation with DAB and DAB Enhancer (Leica). Loss of nuclear expression (required for dMMR eligibility): Complete loss of nuclear expression by tumor cells and retention of staining in non-neoplastic cells (internal control). Intact nuclear expression: Nuclear expression of any intensity within tumor cells. Cannot be determined: Insufficient specimen, technically inadequate IHC assay, or cytoplasmic staining without definite nuclear staining. Results: 4901 pts had MLH1/MSH2 IHC assay, of whom 37 had both MLH1 and MSH2 indeterminate. Of 4864 cases with valid MLH1/MSH2 results, 2% had dMMR (Table–histologies combined to fit allowed space). The most frequent dMMR was in the few thyroid/parathyroid tumors, followed by various gynecologic tumors. Conclusion: 2% of 4864 cases with valid MLH1/MSH2 results in NCI-MATCH had dMMR by IHC; prevalence varied across histologies. Many tumors lacking expression of MLH1 or MSH2 are not prominently associated with Lynch syndrome or frequent somatic dMMR. The NCI-MATCH screen for dMMR adds to information on the potential benefit of screening advanced/refractory tumor types for this abnormality as a standard practice for determining eligibility for PD-1 inhibitors. Pecent tumor categories lacking MLH1/MSH2 expressionHistologyLoss of nuclear MLH1 expressionLoss of nuclear MSH2 expression# screenedPercent of screenedGastrointestinal cancer29413252.5%Gynecological cancer28330110.3%Brain cancer02523.8%Sarcoma (various)601065.7%Thyroid/Parathyroid02366.7%Prostate071225.7%Breast715661.4%Neuroendocrine231922.6%Other303260.9% Citation Format: Barbara A. Conley, Stanley R. Hamilton, Shuli Li, Robert J. Gray, David R. Patton, Peter J. O'Dwyer, Robert L. Comis, Jeffrey S. Abrams, Nilofer S. Azad, Michael J. Overman, Jonathan D. Schoenfeld, Paul M. Williams, James V. Tricoli, Elad Sharon, Howard Streicher, Lyndsay N. Harris, Alice P. Chen, Keith T. Flaherty. Prevalence of mismatch repair deficiency (dMMR) in the NCI Molecular Analysis for Therapy Choice (NCI-MATCH or EAY131) population [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A053.