Abstract 3736: Persistent threat: The role of modifiable risk factors in US cancer mortality

Objectives: Cancer is the second leading cause of death globally, with many cases linked to modifiable risk factors. It is crucial to improve our preventive strategies and screening guidelines to reduce preventable cancer. Our study analyzes trends in modifiable risk factors linked to cancer-related mortality in the US over past 30 years. Methods: The Global Burden of Disease (GBD) database was utilized to extract the overall and risk factor-associated Age-Standardized Mortality Rate (ASMR) for all cancers, as well as for 23 specific cancer in the US, from 1990 - 2021. Our analysis involves the stratification and sub-stratification of modifiable risk factors, encompassing behavioral, environmental/occupational, and metabolic categories, to define risk factor-outcome pairs. Joinpoint Trends were analyzed. Results: In 2021, 44.1% of cancer-related deaths (315,572) in the US were due to risk factors, with the top five proportional risk factors being smoking (21.4%), high BMI (6.6%), high plasma glucose (6%), occupational carcinogens (5.1%), and high alcohol use (3.4%). From 1990-2019, metabolic risk factors saw the highest associated increase in cancer mortality (+66.4%), especially plasma-glucose (+87.2%) and high BMI (+At 51.5%), contributing to 9 of top 10 increases in ASMR for risk factor-outcome pairs. The greatest reduction was from household air pollution (-81.9%). The highest ASMR among risk factor-outcome pairs was for smoking- trachea-bronchi-lung cancer (TBLC) overall (17.2), in males (21.6), and in females (13.8). Other common pairs included dietary risks (low whole grain, high red meat) - colorectal cancer (CRC), asbestos-TBLC, high fasting glucose-pancreatic cancer, and high BMI-CRC. For males, the top five remained the same except for smoking-esophageal cancer, while for females, the top five also included unsafe sex-cervical cancer and dietary risks-breast cancer replacing asbestos-TLBC and high BMI-CRC. The highest proportional ASMR for risk factor-outcomes pairs included unsafe sex-cervical cancer (99%), occupational carcinogens-mesothelioma (m:96.1%; f:89%), smoking-larynx (m: 72%; f:67%), smoking-TBLC (m;62%; f:56%). Conclusions: A substantial proportion of cancer-related mortality in the US is linked to modifiable risk factors, particularly smoking, high BMI, and high plasma glucose. Notably, over 50% of the mortality in cancers like cervical, mesothelioma, larynx, TBLC, and liver is associated with modifiable risk factors. Despite a significant decline, smoking remains the leading risk factor for cancer mortality. While mortality associated with environmental and occupational risk factors has improved, that linked to metabolic risk factors has increased both proportionally and absolutely for certain cancers. These findings underscore the urgent need for targeted prevention and screening strategies to address these risk factors and reduce preventable cancer mortality. Citation Format: Chinmay Jani, Aysswarya Manoharan, Furkan Bahar, Samuel Kareff, Gilberto Lopes. Persistent threat: The role of modifiable risk factors in US cancer mortality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3736.