Myopenia and Mechanisms of Chemotherapy Toxicity in Older Adults with Colorectal Cancer: The M&M Study

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Abstract Colorectal Cancer (CRC) is the 2nd most common cause of cancer death in the US with the majority of diagnoses occurring in older adults (≥65y). Older adults with CRC are at increased risk for severe treatment- related toxicities and other adverse outcomes. The heterogeneous aging process evident in older adults complicates the treatment of CRC and results in significant variability in outcomes. Understanding the variability in chemotherapy toxicity in older adults with CRC is necessary to personalize treatments and improve outcomes. Low muscle mass, known as myopenia, is highly prevalent in older adults. Losses in skeletal muscle mass are apparent as early as the 4th decade of life and progress linearly with increasing age. In CRC, low muscle mass is associated with increased chemotherapy-related toxicities and decreased survival. Most studies to date on myopenia in CRC have been retrospective and have failed to comprehensively assess myopenia, thus limiting our understanding of the underlying mechanisms associated with increased adverse outcomes. Furthermore, conventional chemotherapy dosing by body surface area (BSA) ignores the variability in body composition demonstrated in adults with cancer. As myopenia frequently results in lower lean body mass (LBM) relative to BSA, myopenic patients receive higher effective doses of chemotherapy relative to their LBM, likely resulting in increased chemotoxicity. Prospective evaluation of myopenia in older adults with CRC is critically needed to better understand the association of myopenia with adverse outcomes and to develop precise and personalized interventions to improve outcomes. The central goal of our prospective longitudinal study is to better understand myopenia and its association with chemotherapy toxicity and overall survival in older adults with metastatic CRC. We will leverage the routine clinical use of Computed Tomography (CT) imaging to assess muscle mass at baseline and evaluate trajectories over time during treatment with chemotherapy. In addition, we will explore genetic variation in telomere homeostasis, DNA damage response/repair (DDR), inflammation, and myostatin as well as altered pharmacokinetics (PKs) of oxaliplatin (in a subset of patients) to explore their mediation of the association between myopenia and grades 3-5 chemotoxicity. This study will further promote my long-term goal of optimizing the treatment of older adults with cancer and provide additional training in clinical trial design, advanced quantitative analysis, body composition methods, PK measurement/interpretation, and molecular epidemiology. My results will inform future studies including the development of chemotoxicity prediction tools specific to older adults with CRC, interventional trials combating myopenia, and the potential development of alternative dosing strategies in myopenic patients that incorporate LBM to augment chemotherapy dosing in order avoid unnecessary toxicities while maintaining and/or improving efficacy. My proposed research experience coupled with my career development plan and mentorship will provide the necessary catalyst for me to develop an independent research career focused on improving the outcomes of older adults with CRC.