Background: CRC is the 2^nd most common cause of cancer death in the US, and nearly 60% of CRC cases occur among older adults. There is a critical unmet need to understand the underlying cause(s) of observed variability in chemotherapy toxicity (chemotoxicity) outcomes to minimize adverse outcomes and appropriately personalize therapy for older adults. Low muscle mass, known as myopenia, is prevalent in older adults with CRC (̃60%) and is associated with chemotoxicity and decreased overall survival (OS). However, little is known about trajectories of myopenia and underlying mechanisms of increased toxicities and decreased survival in myopenic patients. We address these gaps in a prospective cohort study, with the central goal of examining the role of myopenia in chemotoxicity in older adults with metastatic CRC undergoing 5-Fluouracil (5FU) based chemotherapy, and to explore the mediating influence of germline genetic variants and pharmacokinetics (PKs) in the association between myopenia and chemotherapy toxicity. Methods: This prospective cohort study is accruing through the Wake Forest NCI Community Oncology Research Program Research Base (WF NCORP) and funded by the NCI grants 2UG1CA189824 and K08CA234225. The study examines the impact of myopenia on chemotoxicity and OS in older adults with newly diagnosed metastatic CRC planning to receive systemic 5FU-based chemotherapy (either as monotherapy or in combination with oxaliplatin and/or irinotecan +/- biologics) (NCT03998202). All patients undergo the Cancer & Aging Resilience Evaluation and Life-Space Evaluation at baseline, 3 and 6 months. Standard of care Computed Tomography (CT) images will be obtained to assess muscle measures (skeletal muscle area/density) at the L3 cross-section. The primary outcome is grades 3 to 5 chemotoxicity measured up to 6 months after initiation of chemotherapy using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. We will assess the association of baseline myopenia and trajectories of myopenia with severe chemotherapy toxicities. Secondary outcome measures include OS at 1 year and chemotoxicities using the Patient Reported Outcomes (PRO) version of the CTCAE. The study also explores the mediating/moderating influence of genetic variation and altered PKs (n = 60) in the association between myopenia and chemotherapy toxicity. To date, the study has accrued 73 of the 300 targeted patients from 110 NCORP practices. Clinical trial information: NCT03998202.