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. 2025 Jul 1;8(7):e2519236.
doi: 10.1001/jamanetworkopen.2025.19236.

Exogenous Hormones, Tumor Intrinsic Subtypes, and Breast Cancer

Charlotte Le Cornet  1 , Audrey Y Jung  1 , Sabine Behrens  1 , Pooja Middha  1   2 , Thérèse Truong  3 , Helena Jernström  4 , Manjeet K Bolla  5 , Qin Wang  5 , Melissa C Southey  6   7   8 , Laura E Beane Freeman  9 , Stella Koutros  9 , Jennifer Stone  10   11 , Gad Rennert  12 , Katerina Shulman  13 , Kristan J Aronson  14 , Rachel A Murphy  15   16 , Pascal Guénel  3 , Alpa V Patel  17 , Clara Bodelon  17 , Lauren R Teras  17 , Shamim Shahi  17 , James V Lacey  18   19 , Laure Dossus  20 , Rudolf Kaaks  1 , Bernd Holleczek  21 , Hermann Brenner  22   23 , Hiltrud Brauch  24   25   26 , Reiner Hoppe  24   27 , Kamila Czene  28 , Per Frans Leonard Hall  28   29 , Arto Mannermaa  30   31   32 , Anna H Wu  33 , Nadia Obi  34   35 , Kyriaki Michailidou  5   36 , Mihalis I Panayiotidis  37   38 , Catriona McLean  39 , Christopher A Haiman  40 , Annelie Augustinsson  4 , Wei Zheng  41 , Xiao-Ou Shu  41 , Charles M Perou  42 , Melissa A Troester  43 , Sarah Van Alsten  43 , A Heather Eliassen  44   45   46 , Mustapha Abubakar  9 , Peter Kraft  9 , Thomas U Ahearn  9 , D Gareth Evans  47   48 , Alicja Wolk  49 , Roger L Milne  6   8   11 , Douglas F Easton  5   50 , Paul D P Pharoah  51 , Marjanka K Schmidt  52   53   54 , Montserrat García-Closas  55 , Celine M Vachon  56 , Renée T Fortner  1   57 , Jenny Chang-Claude  1   58
Affiliations

Exogenous Hormones, Tumor Intrinsic Subtypes, and Breast Cancer

Charlotte Le Cornet et al. JAMA Netw Open. .

Abstract

Importance: Etiologic heterogeneity in breast carcinogenesis needs to be well characterized for targeted prevention. Associations between menopausal hormonal therapy (MHT) and oral contraceptive (OC) use and breast cancer intrinsic-like subtypes are not well understood.

Objective: To examine whether exogenous hormone use is differentially associated with breast cancer subtypes and to evaluate heterogeneity by intrinsic-like subtypes.

Design, setting, and participants: This study pooled data from 31 nested and population-based case-control studies involved in the Breast Cancer Association Consortium. The study population included individuals with breast cancer and control participants from 13 case-control studies nested in prospective cohorts (recruited between 1982 and 2011) and 18 population-based case-control studies (recruited between 1990 and 2013). Data analysis was performed in June 2024.

Exposure: MHT use (estrogen-progestin therapy [EPT] or estrogen-only therapy [ET]) in postmenopausal women and OC use in premenopausal women (never, past use, or current use).

Main outcomes and measures: Breast cancer intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-ERBB2 [formerly HER2 or HER2/neu]-like, ERBB2 enriched-like, or triple-negative) were determined by immunohistochemistry of tumor sections. Polytomous logistic regression was performed to estimate the association between exogenous hormones and risk of breast cancer by intrinsic-like subtypes. Analyses by subtypes were stratified by body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]; healthy weight, 18.5-<25; overweight, 25-<30; or obesity, ≥30).

Results: This study included 42 269 individuals with breast cancer (11 901 [28.2%] premenopausal and 30 368 [71.8%] postmenopausal; 23 353 [55.2%] had a known intrinsic-like subtype) and 71 072 control participants. The mean (SD) age of all participants was 57.9 (10.9) years. In postmenopausal women, associations between current MHT use (EPT or ET) and breast cancer differed by subtype. Current EPT users with healthy weight were more likely to be diagnosed with luminal A-like (odds ratio [OR], 2.51 [95% CI, 2.26-2.80]) or luminal B-ERBB2-like (OR, 1.95 [95% CI, 1.61-2.37]) subtypes. These associations were attenuated but remained for individuals with overweight (OR, 1.40 [95% CI, 1.02-1.92]) or obesity (OR, 1.68 [95% CI, 1.01-2.78]). EPT use increased the odds of being diagnosed with luminal B-like tumors solely in women with healthy weight (OR, 1.47 [95% CI, 1.17-1.86]). Current ET use was positively associated with luminal A-like disease in women with healthy weight only (OR, 1.16 [95% CI, 1.01-1.32]), showing inverse associations with higher BMI (obesity: OR, 0.65 [95% CI, 0.50-0.85]). In premenopausal women, recent OC use was associated with luminal B-ERBB2-like (OR, 1.50 [95% CI, 1.09-2.08]), ERBB2 enriched-like (OR, 2.33 [95% CI, 1.55-3.51]), and triple-negative (OR, 1.75 [95% CI, 1.33-2.29]; P < .04 for heterogeneity) tumors.

Conclusions and relevance: In this study, clear differences were observed in associations between current EPT use and luminal-like breast cancer subtypes and other subtypes. EPT users with healthy weight were more likely to be diagnosed with luminal-like breast cancer compared with nonusers. Subtype heterogeneity was less apparent in associations of OC and ET use. Future studies on contemporary formulations, patterns of use, and routes of administration of exogenous hormone usage are warranted.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Jung reported being employed by Thermo Fisher Scientific during the conduct of the study. Dr Jernström reported receiving grants from the Fru Berta Kamprad Foundation and from Cancerfonden during the conduct of the study. Dr Murphy reported receiving consulting fees from Pharmavite outside the submitted work. Dr Shu reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Perou reported receiving grants from the National Cancer Institute (NCI) Breast Specialized Program of Research Excellence during the conduct of the study. In addition, Dr Perou reported holding stock in and receiving royalties for US Patent No. 12,995,459 from Bioclassifier LLC outside the submitted work. Dr Eliassen reported receiving grants from the NIH during the conduct of the study. Dr Ahearn reported being employed by the NCI during the conduct of the study. Dr Milne reported receiving grants from the National Health and Medical Research Council of Australia during the conduct of the study. Dr Easton reported receiving grants (paid to University of Cambridge) from Cancer Research UK, the European Union, Genome Canada, and the Canadian Institutes of Health Research during the conduct of the study. Dr Pharoah reported receiving grants from Cancer Research UK during the conduct of the study. Dr Schmidt reported receiving grants from the European Union (Breast Cancer Stratification Project [B-CAST]) during the conduct of the study. Dr Vachon reported receiving grants from the NCI during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Case-Control Analyses of Associations Between Estrogen-Progestin Therapy (EPT) Use and Intrinsic-Like Subtypes According to Body Mass Index (BMI)
A to E, Intrinsic-like subtypes are categorized as follows: luminal A–like (hormone receptor [HR]–positive, ERBB2 [formerly HER2 or HER2/neu]-negative, grades 1 and 2) (A), luminal B–like (HR-positive, ERBB2-negative, grade 3) (B), luminal B–ERBB2-like (HR-positive, ERBB2-positive, any grade) (C), ERBB2 enriched–like (HR-negative, ERBB2-positive, any grade) (D), and triple-negative (HR-negative, ERBB2-negative, any grade) (E). Three polytomous logistic regression models were fit (EPT use, duration of EPT use, and time since last EPT use) in association with intrinsic-like subtypes. The multivariable model was adjusted for reference age (age at diagnosis for individuals with breast cancer and age at interview for control participants), study, estrogen therapy use, and oral contraceptive use. Heterogeneity in EPT use associations between intrinsic-like subtypes was evaluated by comparing models that assume common associations across subtypes to those allowing different associations by subtype. BMI was calculated as weight in kilograms divided by height in meters squared and categorized as follows: healthy weight (18.5-<25 [dark blue markers]), overweight (25-<30 [orange markers]), or obesity (≥30 [light blue markers]). P < .05 was considered significant. Intrinsic-like subtype heterogeneity is denoted with open circles. Odds ratios (ORs) are presented with 95% CIs (error bars). ORs and 95% CIs could not be estimated for the association between current EPT use for less than 5 years with risk of ERBB2-enriched–like cancer due to the small number of women with obesity.
Figure 2.
Figure 2.. Case-Control Analyses of Associations Between Estrogen Therapy (ET) Use and Intrinsic-Like Subtypes According to Body Mass Index (BMI)
A to E, Intrinsic-like subtypes are categorized as follows: luminal A–like (hormone receptor [HR]–positive, ERBB2 [formerly HER2 or HER2/neu]-negative, grades 1 and 2) (A), luminal B–like (HR-positive, ERBB2-negative, grade 3) (B), luminal B–ERBB2-like (HR-positive, ERBB2-positive, any grade) (C), ERBB2 enriched–like (HR-negative, ERBB2-positive, any grade) (D), and triple-negative (HR-negative, ERBB2-negative, any grade) (E). Three polytomous logistic regression models were fit (ET use, duration of ET use, and time since last ET use) in association with intrinsic-like subtypes. The multivariable model was adjusted for reference age (age at diagnosis for individuals with breast cancer and age at interview for control participants), study, estrogen-progestin therapy use, and oral contraceptive use. Heterogeneity in ET use associations between intrinsic-like subtypes was evaluated by comparing models that assume common associations across subtypes to those allowing different associations by subtype. BMI was calculated as weight in kilograms divided by height in meters squared and categorized as follows: healthy weight (18.5-<25 [dark blue markers]), overweight (25-<30 [orange markers]), or obesity (≥30 [light blue markers]). P < .05 was considered significant. Intrinsic-like subtype heterogeneity is denoted with open circles. Odds ratios (ORs) are presented with 95% CIs (error bars). Undefined estimate due to small number found in women with obesity for the association between current ET use for less than 5 years with risk of ERBB2-enriched–like cancer.
Figure 3.
Figure 3.. Case-Control Analyses of Associations Between Oral Contraceptive (OC) Use and Intrinsic-Like Subtypes
A to E, Intrinsic-like subtypes are categorized as follows: luminal A–like (hormone receptor [HR]–positive, ERBB2 [formerly HER2 or HER2/neu]-negative, grades 1 and 2) (A), luminal B–like (HR-positive, ERBB2-negative, grade 3) (B), luminal B–ERBB2-like (HR-positive, ERBB2-positive, any grade) (C), ERBB2 enriched–like (HR-negative, ERBB2-positive, any grade) (D), and triple-negative (HR-negative, ERBB2-negative, any grade) (E). Three polytomous logistic regression models were fit: OC use, duration of OC use, and time since last OC use in association with intrinsic-like subtypes. The multivariable model was adjusted for reference age (age at diagnosis for individuals with breast cancer and age at interview for control participants), study, and body mass index. Heterogeneity in estrogen therapy use associations between intrinsic-like subtypes was evaluated by comparing models that assume common associations across subtypes to those allowing different associations by subtype. P < .05 was considered significant. Intrinsic-like subtype heterogeneity is denoted with open circles. Odds ratios (ORs) are presented with 95% CIs (error bars).
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