Abstract LB-29: Hormonal risk factors and breast cancer prognosis and survival by PAM50 molecular subtype.
Authors: Kwan Marilyn L. , Sweeney Carol , Habel Laurel A. , Weltzien Erin , Castillo Adrienne , Davis Carole , Factor Rachel E. , Kroenke Candyce H. , Shakespear Kaylynn , Quesenberry Charles P. , Stijleman Inge J. , Bernard Philip S. , Kushi Lawrence H. , Caan Bette J. 
Published: August 2014

Background: Lifestyle and reproductive factors known to influence estrogen levels have been associated with breast cancer (BC) risk and prognosis. However, it is unknown whether associations vary by tumor molecular subtype at diagnosis.

Methods: A case-cohort study population of 1,439 women with invasive BC was sampled from two prospective cohort studies: LACE (AJCC stage I (≥1 cm), II, IIIA diagnosed 1997-2000), and Pathways (any invasive stage ≥0.5 cm diagnosed 2006-2008). Molecular subtype (luminal A, luminal B, HER2-enriched, basal-like) was determined by RT-PCR of RNA extracted from samples from formalin-fixed, paraffin-embedded primary tumor blocks and assayed for expression of PAM50 genes. Information on hormone replacement therapy (HRT), oral contraceptive use (OC), reproductive factors (age at menarche, parity, age at first birth, breastfeeding), alcohol intake, and body mass index (BMI) were obtained from baseline participant questionnaires, and an index of lifetime hormonal exposure [low (0-1, reference), medium (2-4), high (5-6)] was created based on their expected influence on circulating estrogen. Specifically, any factor associated with more estrogen exposure was assigned a score of 1 (e.g., HRT yes, OC no, BMI≥25 kg/m2) while less exposure was assigned a score of 0 (e.g., HRT no, OC yes, BMI&lt;25 kg/m2). Tumor and treatment information were obtained from the KPNC Cancer Registry and clinical databases. Recurrence and mortality outcomes were ascertained by questionnaire and electronic medical record review. We estimated hazard ratios (HR) and associated 95% confidence intervals (CI) using Cox proportional hazards regression within subtype, adjusting for covariates such as age at diagnosis, race/ethnicity, stage, surgery, and treatment.

Results: There were 370 recurrences and 501 total deaths (269 BC-related) over a median 6.6±3.9 years. In the overall study population, a higher hormonal exposure index was associated with an increased risk of breast cancer death (p for trend=0.02). By molecular subtype, the highest tertile of the hormonal index was associated with both recurrence (HR=3.8; 95% CI: 1.0, 14.5) and BC-specific death (HR=7.3; 95% CI: 1.7, 31.7), compared with a low hormonal index, among the luminal A subtype. In contrast, no associations of the hormonal index with recurrence and BC-specific death were observed in the luminal B, HER2-enriched, or basal-like subtypes (p for homogeneity=0.01). A high hormonal index was not associated with all-cause mortality overall and by subtype.

Discussion: Traditional hormonal risk factors for BC showed differing associations with prognosis and survival depending on tumor molecular subtype of the primary BC. Subtypes that are treated similar based on conventional prognostic indicators such as ER status (luminal A and luminal B) may have differing associations between risk factors and prognosis.

Funded by NCI R01 CA129059.

Citation Format: Marilyn L. Kwan, Carol Sweeney, Laurel A. Habel, Erin Weltzien, Adrienne Castillo, Carole Davis, Rachel E. Factor, Candyce H. Kroenke, Kaylynn Shakespear, Charles P. Quesenberry, Inge J. Stijleman, Philip S. Bernard, Lawrence H. Kushi, Bette J. Caan. Hormonal risk factors and breast cancer prognosis and survival by PAM50 molecular subtype. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-29. doi:10.1158/1538-7445.AM2013-LB-29