Background & Aims-Mutations in the DNA mismatch repair (MMR) gene MSH2 cause Lynch Syndromes I & II, and sporadic colorectal cancers (CRCs). Msh2 null mice predominantly develop lymphoma and do not accurately recapitulate the CRC phenotype.

Background. Racial disparities among clinical trial participants present a challenge to assess whether trial results can be generalized into patients representing diverse races and ethnicities. The objective of this study is to evaluate the impact of race and ethnicity on treatment response in advanced non-small cell lung cancer (aNSCLC) patients treated with PD-1 or PD-L1 inhibitors through analysis of real-world data (RWD). Materials and Methods. A retrospective cohort study of 11,138 lung cancer patients treated at hospitals within the Mount Sinai Health System was performed. Patients with confirmed aNSCLC who received anti-PD1/PD-L1 treatment were analyzed for clinical outcomes. Our cohort included 249 aNSCLC patients who began nivolumab, pembrolizumab, or atezolizumab treatment between November 2014 and December 2018. Time-to-treatment discontinuation (TTD) and overall survival (OS) were the analyzed clinical endpoints. Results. After a median follow-up of 14.8 months, median TTD was 7.8 months (95% confidence interval 5.4not estimable [NE]) in 75 African American patients vs. 4.6 (2.4 -7.2) in 110 White patients (hazard ratio [HR] 0.63). Median OS was not reached (18.4 -NE) in African Americans vs. 11.6 months (9.7 -NE) in Whites (HR 0.58). Multivariable cox regression conducted with potential confounders confirmed longer TTD (adjusted HR 0.65) and OS (adjusted HR 0.60) in African American vs. White patients. Similar real-world response rate (42.6% vs. 43.5%) and disease control rate (59.6% vs. 56.5%) were observed in the African American and White patient populations. Further investigation revealed the African American group had lower incidence (14.7%) of putative hyperprogressive diseases (HPD) upon anti-PD1/PD-L1 treatment than the White patient group (24.5%). Conclusions. Analysis of RWD showed longer TTD and OS in African American aNSCLC patients treated with anti-PD1/PD-L1 inhibitors. Lower incidence of putative HPD is a possible reason for the favorable outcomes in this patient population. The Oncologist 2021;9999:• • Implications for Practice: There is a significant underrepresentation of minority patients in randomized clinical trials, and this study demonstrates we can use real world data to investigate the impact of race and ethnicity on treatment response. In retrospective analysis of advanced non-small cell lung cancer patients treated with PD-1 or PD-L1 inhibitors, African American patients had significantly longer time-to-treatment discontinuation and longer overall survival. Analysis of realworld data can yield clinical insights and establish a more complete picture of medical interventions in routine clinical practice.

Background Immune checkpoint inhibitors (ICIs) have been incorporated into various clinical oncology guidelines for systemic treatment of advanced non-small cell lung cancers (aNSCLC). However, less than 50% (and 20%) of the patients responded to the therapy as a first (or second) line of therapy. PD-L1 immunohistochemistry (IHC) is an extensively studied biomarker of response to ICI, but results from this test have equivocal predictive power. In order to identify other biomarkers that support clinical decision-making around whether to treat with ICIs or not, we performed a retrospective study of patients with aNSCLC who underwent ICI-based therapy in the Mount Sinai Health System between 2014 and 2019. Methods We analyzed data from standard laboratory tests performed in patients as a part of the routine clinical workup during treatment, including complete blood counts (CBC) and a comprehensive metabolic panel (CMP), to correlate test results with clinical response and survival. Results Of 11,138 NSCLC patients identified, 249 had been treated with ICIs. We found associations between high neutrophil-to-lymphocyte ratio (NLR ≥ 5) and poor survival in ICI-treated NSCLC. We further observed that sustained high NLR after initiation of treatment had a more profound impact on survival than baseline NLR, regardless of PD-L1 status. Hazard ratios when comparing patients with NLR ≥ 5 vs. NLR < 5 are 1.7 (p = 0.02), 3.4 (p = 4.2 × 10− 8), and 3.9 (p = 1.4 × 10− 6) at baseline, 2–8 weeks, and 8–14 weeks after treatment start, respectively. Mild anemia, defined as hemoglobin (HGB) less than 12 g/dL was correlated with survival independently of NLR. Finally, we developed a composite NLR and HGB biomarker. Patients with pretreatment NLR ≥ 5 and HGB < 12 g/dL had a median overall survival (OS) of 8.0 months (95% CI 4.5–11.5) compared to the rest of the cohort with a median OS not reached (95% CI 15.9-NE, p = 1.8 × 10− 5), and a hazard ratio of 2.6 (95% CI 1.7–4.1, p = 3.5 × 10− 5). Conclusions We developed a novel composite biomarker for ICI-based therapy in NSCLC based on routine CBC tests, which may provide meaningful clinical utility to guide treatment decision. The results suggest that treatment of anemia to elevate HGB before initiation of ICI therapy may improve patient outcomes or the use of alternative non-chemotherapy containing regimens.

Inflammation predisposes to tumorigenesis in various organs by potentiating a susceptibility to genetic aberrations. The mechanism underlying the enhanced genetic instability through chronic inflammation, however, is not clear. Here, we demonstrated that TNFa stimulation induced transcriptional downregulation of MSH2, a member of the mismatch repair family, via NF-kBdependent miR-21 expression in hepatocytes. Liver cancers developed in ALB-MSH2 À/À AID þ , ALB-MSH2

Germline mutations in DNA mismatch repair (MMR) genes are the cause of hereditary non-polyposis colorectal cancer/Lynch syndrome (HNPCC/LS) one of the most common cancer predisposition syndromes, and defects in MMR are also prevalent in sporadic colorectal cancers. In the past, the generation and analysis of mouse lines with knockout mutations in all of the known MMR genes has provided insight into how loss of individual MMR genes affects genome stability and contributes to cancer susceptibility. These studies also revealed essential functions for some of the MMR genes in B cell maturation and fertility. In this review, we will provide a brief overview of the cancer predisposition phenotypes of recently developed mouse models with targeted mutations in MutS and MutL homologs (Msh and Mlh, respectively) and their utility as preclinical models. The focus will be on mouse lines with conditional MMR mutations that have allowed more accurate modeling of human cancer syndromes in mice and that together with new technologies in gene targeting, hold great promise for the analysis of MMR-deficient intestinal tumors and other cancers which will drive the development of preventive and therapeutic treatment strategies.