Abstract LB328: Smoking and subsequent primary cancer in breast cancer survivors: A case-cohort study

Abstract Introduction: As breast cancer survival has increased with advances in treatment, there is an increasing number of women at risk of developing a second primary cancer. Smoking is a modifiable behavior associated with increased risk of multiple cancers, however the impact of smoking on the risk of second primary cancers has not yet been explored for breast cancer survivors. Here we evaluated the associations between smoking and risk of the four most common second primary cancers in a population-based case-cohort study. Methods: We identified a total of 2630 breast cancer survivors from the Seattle-Puget Sound region including 1930 cases who developed a second primary cancer (602 breast, 621 lung, 300 colorectal, and 307 endometrial) and 800 non-cases who did not develop a second primary cancer. Smoking exposure was assessed by interview at first breast cancer diagnosis and at second cancer diagnosis. Associations between smoking and second primary cancer risk were assessed using multivariable Cox proportional hazards models adjusting for age, year of diagnosis, histology, estrogen receptor status, stage, and confounders that changed estimates by 10%. Results: Smoking at initial breast cancer diagnosis was associated with a second breast cancer, hazard ratio (HR) 2.07 (95% Confidence interval (CI) 1.39 - 3.06); this association did not appear clearly dose dependent. Smoking was associated with subsequent lung cancer, HR 32.69 (21.29 - 50.20). This association was dose-dependent and remained significant after adjusting for radiation treatment for breast cancer HR 1.79 (1.02 - 3.14) for <10 pack-years, HR 10.41 (6.30 - 16.94) for 10-25 pack-years, HR 20.52 (11.75 - 35.83) for 25-40 pack-years, and HR 47.34 (28.37 - 78.99) for 40+ pack-years. Smoking was associated with subsequent colorectal cancer, HR 2.54 (1.42 - 4.54); this association appears to be dose-dependent but did not reach statistical significance due to limited size when dividing by pack-year groups. Smoking appeared to reduce the risk of subsequent endometrial cancer diagnosis, but did not reach statistical significance, HR 0.47 (0.21 - 1.03); this association appears dose-dependent but again did not reach statistical significance with limited subgroup size. Conclusions: These findings suggest that smoking remains an important modifiable risk factor for secondary cancer in breast cancer survivors and have important implications on risk assessment for tailored surveillance and preventative strategies for breast cancer survivors, an estimated 4 million women in the U.S. Citation Format: Asra N. Shaik, David R. Doody, Kathleen E. Malone, Christopher I. Li. Smoking and subsequent primary cancer in breast cancer survivors: A case-cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB328.