Examining Health-Related Quality of Life in Cancer Survivors: Cross-Sectional Associations with Comorbidities, Navigation Services Use, and Perceived Social Support

<b>Background/Objectives:</b> Cancer is the second leading cause of death in Puerto Rico, its impact worsened by an aging population. Many survivors experience long-term effects that reduce health-related quality of life (HRQoL). Chronic comorbidities are common in Puerto Rico, yet cancer survivors remain underrepresented in HRQoL research, raising concern about their impact on survivorship. This study examined whether comorbidity burden was associated with HRQoL and if patient navigation services or perceived social support moderated this association. <b>Methods:</b> This cross-sectional analysis included 643 cancer survivors from the START-PR study (November 2023-August 2025). HRQoL was measured using the Functional Assessment of Cancer Therapy-General (FACT-G) and dichotomized at the sample median (≤71 = poor; >71 = non-poor). Comorbidity burden was grouped as 0, 1, or ≥2 conditions. Patient navigation was assessed by self-reported service use in the past year. Perceived social support was measured using an adapted Multidimensional Scale of Perceived Social Support and dichotomized at the sample median (≤40 = low; >40 = high). Logistic regression estimated odds ratios (OR; 95% CI), adjusting for covariates. Interaction terms tested effect modification. <b>Results:</b> Participants with one (OR = 1.85; 95% CI: 1.15-2.97) or ≥2 comorbidities (OR = 2.95; 95% CI: 1.88-4.61) had significantly higher odds of poor HRQoL than those without comorbidities. Hypertension, depression, diabetes, arthritis, and asthma were more common among participants with poor HRQoL. Neither patient navigation nor perceived social support significantly moderated the comorbidity burden-HRQoL association. <b>Conclusions:</b> Greater comorbidity burden was associated with poor HRQoL. These findings underscore the need for survivorship care models that integrate chronic disease management, including mental health, to improve outcomes in underserved populations.