Abstract PS7-02: The relationship of established breast cancer risk factors with breast cancer subtypes
Authors: McCarthy Anne Marie , Friebel Tara , He Wei , Welch Michaela , Ehsan Sarah , Hughes Kevin , Semine Alan , Chen Jinbo , Kontos Despina , Domchek Susan , Conant Emily , Bardia Aditya , Lehman Constance , Armstrong Katrina 
Published: February 2021

Background: Molecular characterization of breast tumors has revealed four subtypes which differ in expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Breast cancer subtypes have different prognosis and unique risk factors. Breast cancer risk assessment models mainly reflect risk of ER/PR+ HER2- tumors, the most common subtype, and may not reflect risk of other subtypes. The study objective was to compare associations of established breast cancer risk factors across invasive breast cancer subtypes.

Methods: The study population included women aged 40-84 years who had a screening mammogram at Massachusetts General Hospital, Newton Wellesley Hospital, or the University of Pennsylvania from 2006-2015. Patients completed a risk factor questionnaire and additional risk factors were ascertained from clinical records. Women with prior breast cancer, breast implants, or BRCA1/2 mutations were excluded. Women diagnosed with breast cancer within 6 months were excluded to remove those with cancer at the time of risk assessment. Tumor characteristics were obtained from linkage with hospital and state cancer registries. For invasive tumors, subtype was defined based on immunohistochemistry as ER and/or PR+ HER2-, ER and/or PR+HER2+, ER and PR- HER2+, or ER and PR and HER2- (triple negative breast cancer, TNBC). Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for breast cancer using time from mammogram to cancer diagnosis or censoring. Separate Cox models were fit for each subtype, and patients who developed DCIS or another subtype, died, or were alive and cancer free on December 31, 2017 were censored. Age, biopsy history, atypical hyperplasia, age at menarche, age at first live birth, family history, race, BMI, and breast density at the time of screening were included in the models.

Results: The study population (N=197,836) had a mean age of 54 years and 74% of patients were white, 15% were Black, and 11% were other races. During a mean follow-up of 6.3 years, 4,510 (2.3%) women developed breast cancer. Of these cancers, 1068 (24%) were DCIS. Of the invasive cancers, 2675 (77%) were ER/PR+HER2-, 290 (8%) were ER/PR+HER2+, 108 (3%) were ER/PR-HER2+, 264 (8%) were TNBC and 105 (3%) had missing subtype. For ER/PR+HER2- cancers, all risk factors were consistent with the literature and statistically significant. Breast density was associated with increased risk of all four subtypes compared to women with less dense breasts. Atypical hyperplasia was strongly associated with HER2+ cancers (HR=2.97 CI 1.63-5.40 p&lt;0.01), less strongly associated with ER/PR+HER2- cancers, and not significantly associated with TNBC. Black women had higher risk of TNBC than white women (HR=2.61 CI 1.91-3.57 p&lt;0.01).

Conclusion Our results highlight both similarities and heterogeneity in risk factors across breast cancer subtypes. Prior diagnosis of atypical hyperplasia was more strongly associated with HER2+ compared to HER2- tumors. While it is well known that Black women have higher risk of TNBC, it is striking that the more than two-and-a-half-fold increased risk persisted even with comprehensive adjustment for breast cancer risk factors in a screened population. These results suggest that additional factors, such as genetics, biomarkers, and environmental exposures should be included in risk assessment to better capture risk of less common breast cancer subtypes such as TNBC.

Risk factors for breast cancer subtypes among 197,836 women undergoing screening mammography*ER/PR+ HER2- N=2674ER/PR+ HER2+ N=290ER/PR-HER2+ N=108ER/PR/HER2- N=264HR,95% CIpHR,95% CIpHR,95% CIpHR,95% CIpBlack vs. white unadjusted0.67,0.58-0.77&lt;0.010.73,0.48-1.090.120.91,0.49-1.680.772.61,1.96-3.46&lt;0.01Black vs. white multivariate*0.72,0.63-0.83&lt;0.010.75,0.49-1.150.191.23,0.65-2.330.532.61,1.91-3.57&lt;0.01Atypical Hyperplasia*1.38,1.02-1.870.042.77,1.42-5.42&lt;0.013.89,1.03-14.70.040.43,0.06-3.140.401 FDR** vs. none1.46,1.32-1.63&lt;0.011.16,0.82-1.650.391.93,1.18-3.160.011.11,0.75-1.630.602 FDR** vs. none2.12,1.67-2.71&lt;0.011.17,0.44-3.150.751.90,0.47-7.760.372.81,1.44-5.49&lt;0.01BMI ≥25 vs. &lt;25 kg/m2*1.37,1.25-1.50&lt;0.011.35,1.04-1.750.031.07,0.71-1.640.741.29,0.97-1.730.08Dense vs. non-dense breasts1.55,1.42-1.69&lt;0.011.75,1.34-2.29&lt;0.011.97,1.25-3.10&lt;0.011.65,1.26-2.17&lt;0.01*Adjusted for all factors in the table and additionally age, biopsy, age at menarche, age at first live birth**FDR= first degree relative with breast cancer

Citation Format: Anne Marie McCarthy, Tara Friebel, Wei He, Michaela Welch, Sarah Ehsan, Kevin Hughes, Alan Semine, Jinbo Chen, Despina Kontos, Susan Domchek, Emily Conant, Aditya Bardia, Constance Lehman, Katrina Armstrong. The relationship of established breast cancer risk factors with breast cancer subtypes [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-02.