A Problem in Breast Cancer Interventional Clinical Trials Funded by the National Institutes of Health (NIH) and other US Federal Agencies

Abstract Background Breast cancer (BCa) is the second leading cause of cancer-related death among women in the United States (US), yet declines in mortality have not been equally experienced across racial and ethnic groups. Although Black women have a 5% lower incidence rate than White women, their mortality rate is 38% higher. This disparity represents a persistent inequity in US cancer outcomes. BCa outcomes are profoundly influenced by type 2 diabetes mellitus (T2D) and obesity, often operating syndemically and adversely impacting prognosis. Despite biological and clinical relevance, federally funded BCa clinical trials seldom adequately account for these metabolic comorbidities. Methods A retrospective analysis was conducted on 90 completed, female-only BCa interventional clinical trials funded by the NIH and other US federal agencies that were registered on ClinicalTrials.gov as of July 25, 2023. Trials were evaluated for explicit or implicit inclusion of T2D and obesity in eligibility criteria using expert pharmacologic review, FDA-labeled and off-label drug indication analysis, and AI-assisted keyword and context recognition to identify direct or indirect metabolic references. Results The study examined 354 conditions across 90 trials. Ten (10) trials explicitly addressed T2D, and only two (2) trials directly addressed obesity. Eight (8) trials indirectly referenced diabetes through glucose-based or metabolic exclusion criteria, and six (6) trials indirectly addressed obesity. Among trials using drugs or behavioral interventions with known metabolic effects, T2D and obesity were rarely considered. Only 3 of these trials addressed both comorbidities and 74.4% did not address either condition. Discussion These findings reveal a persistent disconnect between the biological relevance of metabolic comorbidities and their consideration in clinical trial design, reflecting a reductionist paradigm that overlooks real-world patient complexity, especially for women disproportionately affected by T2D and obesity. Conclusion Federally funded BCa trials in this study were predominantly reductionist in design, with limited consideration of the syndemic interplay between metabolic and oncologic health. Future funding should prioritize trial designs that integrate diabetes, obesity, and metabolic diversity into eligibility, stratification, and analytic frameworks to enhance pathways for implementation, generalizability, and equity in BCa research.