Maggie Fox

e14520 Background: Mismatch repair deficient (MMRd) tumors are highly sensitive to checkpoint blockade (CPB) in patients with metastatic disease regardless of tumor type. However, the efficacy of CPB in the adjuvant setting is unknown, especially since MMRd is considered a favorable biomarker for most resected tumor types. Circulating tumor DNA (ctDNA) could be used to screen for patients at high risk for recurrence following surgery or adjuvant chemotherapy and identify patients (pts) that would most benefit from CPB. Methods: To assess the frequency of ctDNA in the resected MMRd population, we prospectively screened pts with MMRd tumors who completed standard perioperative chemotherapy and surgery (NCT03832569). DNA from resected tumors and matched postoperative plasma was sequenced for the presence of somatic mutations. Patients were considered to have minimal residual disease (MRD) when mutations were identified in tumor and found to be identical to those in matched plasma DNA. Somatic tissue mutations were assessed using MSK-IMPACT and ctDNA was assessed using FoundationOne, Guardant360 or MSK-ACCESS. Results: A total of 86 pts were screened for the presence of MRD. These represented 7 tumor types with colorectal (63%), endometrial (16%) and esophagogastric (13%) being the most common. The majority of pts were stage III (49%). MRD was detected in 18% of cases (14 of 79). Among the MRD negative group (n=62), only one pt developed disease recurrence. Three samples failed ctDNA analysis for technical reasons. Conclusions: MRD was identified in 18% of resected MMRd tumors using ctDNA analysis, suggesting this to be a feasible tumor agnostic approach to test the efficacy of CPB in a pts at high-risk for recurrence. Future studies will assess the impact of CPB in MRD positive MMRd tumors.[Table: see text]

Abstract Background: The incidence of early onset (EO) colorectal cancer (CRC) (age <50) is rising with a left-sided predominance. Response to chemotherapy and anti-EGFR therapies differ in left- and right-sided colon cancers after accounting for genomic differences. The intestinal microbiome may contribute to CRC pathogenesis and response to therapy; how organisms drive metastasis and treatment resistance is not known. Purpose: To define the microbiome contribution to EO-CRC and response to treatment by analyzing longitudinal samples from previously untreated patients with CRC. Methods: We designed a prospective biospecimen collection platform and selected patients with previously untreated CRC. We collected stool, biopsy or surgical tissue, and peripheral blood mononuclear cells at baseline and serially throughout treatment. Stool samples were analyzed using shotgun sequencing. Alpha diversity was calculated using the inverse Simpson index and compared between groups using the Wilcoxon signed-rank test. Beta diversity was analyzed using the Bray-Curtis dissimilarity matrix and compared using PERMANOVA. Multivariate associations between species abundance, metabolic pathway abundance and clinical covariates were performed using MaAsLin2 R package. Results: We analyzed a total of 132 stool samples from 65 patients with CRC including up to 5 samples from a single patient over time. Mean alpha diversity did not differ significantly by primary site, stage or age at diagnosis. Beta diversity was significantly different between samples from right- compared with left-sided CRC (P=.011) and pre- and post-surgery (P=.001). Beta diversity also differed significantly by diagnosis age (<50 vs. > 50) (P=.001 all samples, P=.032 baseline samples). When CRC baseline samples were examined at the species level, Blautia glucerasea was associated with right-sided primary (P<.001, Q=.1). Considering non-metastatic cases, recurrence was associated with increased Enteroscipio rubneri, Actinomyces oral taxon 448, Bacteroidales sp. and Lancefieldella parvula (P<.01, Q>0.1). We further investigated metabolic pathway associations. The superpathway of L-threonine metabolism was significantly increased in samples from patients with right-sided colon cancer at baseline (P<.001, Q=.03). Considering samples across all time points, right-sided colon cancer was associated with increased abundance of pathways associated with propanoate degradation, L-threonine metabolism, yeast NADPH production, and hydroxyphenylacetate degradation (all P<.001, Q<.05). Conclusions: The functional effects of the intestinal microbiome may underlie the distinct biology of right-sided colon cancer. Composition of the intestinal microbiome differs by age at diagnosis. Updated recurrence data will be presented. Citation Format: Melissa Lumish, Nicholas Waters, Joshua Leinwand, Asha Saxena, Anqi Dai, Teng Fei, Maggie Fox, Andre Chavez, Jonathan Bermeo, Dorina Ismailgeci, Elizabeth Benitez, Christopher Cowley, Julio Garcia-Aguilar, Martin Weiser, Andrea Cercek, Luis A. Diaz, Marcel van den Brink, Jonathan Peled, Karuna Ganesh. Shotgun sequencing of serial fecal microbiome samples in patients with colorectal cancer reveals distinct bacterial species and metabolic pathways associated with tumor sidedness and age at diagnosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2805.