Energy balance and reproductive health after early-onset colorectal cancer - Adults diagnosed with colorectal cancer before the age of 50 years (early-onset CRC) are treated with a greater volume of cancer therapies compared to older-age patients with similar tumor features, which could damage reproductive organs and lead to infertility. Although this is a resounding concern for patients of reproductive age, at present there are no prospective data for us to understand whether modifiable behaviors-such as physical activity-can improve fertility after CRC. Given the unexplained rise in early-onset CRC incidence over the last decades, such evidence is now critical to guide clinical care management and surveillance for young CRC patients. Therefore, our proposal is designed to address this unmet, growing care need and achieve its overarching goal: to characterize the link between fertility and energy balance among young patients after CRC. To do so, we will utilize the Preserving Fertility After Colorectal Cancer (PREFACE) Study cohort that is actively enrolling 220 patients between ages 18 and 49 years who have been newlydiagnosed with CRC at Vanderbilt-Ingram Cancer Center. To characterize the potential contributions of physical activity and sedentary behavior on fertility across the CRC care continuum (Aim 1 ), we will prospectively collect physical activity, sedentary behavior and reproductive health validated questionnaires as well as capture one-week of accelerometry-assessed physical activity; at diagnosis, treatment and surveillance study timepoints. This will define whether and how patterns of frequency, duration, bouts, intensity and type of physical activity as well as sedentary behaviors change over time, and will also inform the highest physical activity concerns and needs-specific to reproductive age CRC patients along their cancer care journeys. We will then use fasting blood samples that are collected in parallel from patients at all three, uniform study timepoints to measure 39 circulating inflammatory and immune biomarkers (e.g., CRP, FGF, IL-1~, IL-6/8/10, IL-15, MCP-1/4, PIGF, SAA, TNF-am, VEGF-A/C/D) via validated multiplex assays. These biomarker levels, together with paired blood-based measurements for hormonal markers from our FDA-approved clinical immunoassays (for AMH, estradiol, FSH, SHBG, LH, DHEAS, inhibin B, testosterone, androstenedione, and DHT) and detailed clinical/treatment data, will be analyzed to investigate associations of gonadal function and energy balance in young CRC patients over time (Aim 2). Overall, this cost-efficient proposal augments existing PREFACE Study infrastructure to generate new data that is statistically-powered to inform clinical management guidelines on fertility and physical activity in early-onset CRC and, ultimately, to improve patient care and outcomes. Our findings may also lead to physical activity intervention studies for the design of effective, acceptable exercise prescriptions toward improving fertility after CRC in patients of reproductive age.
