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Comparative Study
. 2021 Sep;10(18):6456-6467.
doi: 10.1002/cam4.4158. Epub 2021 Aug 31.

Relationship of established risk factors with breast cancer subtypes

Anne Marie McCarthy  1 , Tara Friebel-Klingner  1 , Sarah Ehsan  1 , Wei He  2 , Michaela Welch  3 , Jinbo Chen  1 , Despina Kontos  1 , Susan M Domchek  1 , Emily F Conant  1 , Alan Semine  4 , Kevin Hughes  2   5 , Aditya Bardia  2   5 , Constance Lehman  2   5 , Katrina Armstrong  2   5
Affiliations
Comparative Study

Relationship of established risk factors with breast cancer subtypes

Anne Marie McCarthy et al. Cancer Med. 2021 Sep.

Abstract

Background: Breast cancer is a heterogeneous disease, divided into subtypes based on the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Subtypes have different biology and prognosis, with accumulating evidence of different risk factors. The purpose of this study was to compare breast cancer risk factors across tumor subtypes in a large, diverse mammography population.

Methods: Women aged 40-84 without a history of breast cancer with a screening mammogram at three United States health systems from 2006 to 2015 were included. Risk factor questionnaires were completed at mammogram visit, supplemented by electronic health records. Invasive tumor subtype was defined by immunohistochemistry as ER/PR+HER2-, ER/PR+HER2+, ER, and PR-HER2+, or triple-negative breast cancer (TNBC). Cox proportional hazards models were run for each subtype. Associations of race, reproductive history, prior breast problems, family history, breast density, and body mass index (BMI) were assessed. The association of tumor subtypes with screen detection and interval cancer was assessed using logistic regression among invasive cases.

Results: The study population included 198,278 women with a median of 6.5 years of follow-up (IQR 4.2-9.0 years). There were 4002 invasive cancers, including 3077 (77%) ER/PR+HER2-, 300 (8%) TNBC, 342 (9%) ER/PR+HER2+, and 126 (3%) ER/PR-HER2+ subtype. In multivariate models, Black women had 2.7 times higher risk of TNBC than white women (HR = 2.67, 95% CI 1.99-3.58). Breast density was associated with increased risk of all subtypes. BMI was more strongly associated with ER/PR+HER2- and HER2+ subtypes among postmenopausal women than premenopausal women. Breast density was more strongly associated with ER/PR+HER2- and TNBC among premenopausal than postmenopausal women. TNBC was more likely to be interval cancer than other subtypes.

Conclusions: These results have implications for risk assessment and understanding of the etiology of breast cancer subtypes. More research is needed to determine what factors explain the higher risk of TNBC for Black women.

Keywords: breast cancer; cancer epidemiology; etiology; risk factors; tumor subtypes.

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Conflict of interest statement

The authors have the following corporate relationships to disclose: Emily Conant: Dr. Conant has grants and is on the advisory board for iCAD, Inc. and for Hologic, Inc. Kevin Hughes: Dr. Hughes receives honoraria from Hologic (Surgical implant for radiation planning with breast conservation and wire‐free breast biopsy) and Myriad Genetics, Dr. Hughes has financial interests in CRA Health (Formerly Hughes RiskApps) which recently was sold to Volpara. CRA Health develops risk assessment models/software with a particular focus on breast cancer and colorectal cancer. Dr. Hughes is a founder of the company. Dr. Hughes is the Co‐Creator of Ask2Me.Org which is freely available for clinical use and is licensed for commercial use by the Dana Farber Cancer Institute and the MGH. Dr. Hughes's interests in CRA Health and Ask2Me. Org were reviewed and are managed by Massachusetts General Hospital and Partners Health Care in accordance with their conflict of interest policies. Aditya Bardia: Dr. Bardia is a consultant or on the advisory board for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Taiho, Sanofi, Daiichi Pharma/Astra Zeneca, Puma, Biotheranostics Inc., Phillips, Eli Lilly, Foundation Medicine. Dr. Bardia is contracted to do research with or has grants (to institution) with Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics, Daiichi Pharma/Astra Zeneca. The remaining authors have no conflicts to disclose.

Figures

FIGURE 1
FIGURE 1
Exclusion criteria by site. Figure shows exclusion criteria for mammography patients across three sites, Massachusetts General Hospital (MGH), Newton‐Wellesley Hospital (NWH), and the University of Pennsylvania Health System (Penn). For all sites, participants with prior breast cancer, prior breast implant, age outside of the 40–84 range, cancer diagnosis within 6 months of screening, BRCA1/2 mutation, patients with <6 months of study time, and deceased patients with missing date of death were excluded. This resulted in a total of 79,671 for MGH, 52,331 patients for NWH, and 66,276 patients for Penn
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References

    1. Howlader N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106(5). 10.1093/jnci/dju055. - DOI - PMC - PubMed
    1. Haque R, Ahmed SA, Inzhakova G, et al. Impact of breast cancer subtypes and treatment on survival: an analysis spanning two decades. Cancer Epidemiol Biomarkers Prev. 2012;21(10):1848‐1855. - PMC - PubMed
    1. Parise CA, Caggiano V. Breast Cancer Survival Defined by the ER/PR/HER2 Subtypes and a Surrogate Classification according to Tumor Grade and Immunohistochemical Biomarkers. J Cancer Epidemiol. 2014;2014:469251. - PMC - PubMed
    1. Barnard ME, Boeke CE, Tamimi RM. Established breast cancer risk factors and risk of intrinsic tumor subtypes. Biochim Biophys Acta. 2015;1856(1):73‐85. - PubMed
    1. Centers for Disease Control and Prevention . National Health and Nutrition Examination Survey: 2011–2012 Data Documentation, Codebook, and Frequencies. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2013. Updated 2015. Accessed June 22, 2021. https://wwwn.cdc.gov/nchs/nhanes/search/datapage.aspx?Component=Examinat...

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