Authors
Daniel Adams, Amber N Hurson, Thomas U Ahearn, Irene L Andrulis, Antonis C Antoniou, Päivi Auvinen, Anita Bane, Sabine Behrens, Amy Berrington de Gonzalez, Katarzyna Białkowska, Clara Bodelon, Manjeet K Bolla, Maria Borrero, Hermann Brenner, Ian W Brock, Annegien Broeks, Nicola J Camp, Melissa H Cessna, Stephen J Chanock, Georgia Chenevix-Trench, Ellen Copson, Fergus J Couch, Angela Cox, Simon S Cross, Peter Devilee, Alison M Dunning, Douglas F Easton, Diana M Eccles, Jonine D Figueroa, Gord Glendon, Anna González-Neira, Ute Hamann, Jaana M Hartikainen, Mikael Hartman, Bernadette A M Heemskerk-Gerritsen, Peh Joo Ho, James M Hodge, Bernd Holleczek, Antoinette Hollestelle, Maartje J Hooning, kConFab Investigators , SGBCC Investigators , Anna Jakubowska, Michael E Jones, Louise Jones, Brandt Jones, Audrey Jung, Rudolf Kaaks, Renske Keeman, Scott Lawrence, Jingmei Li, Jolanta Lissowska, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, John W M Martens, Wilma E Mesker, Noor Muhammad, Anna Marie Mulligan, Nadia Obi, Janet E Olson, Ana Osorio, Penelope D Ottewell, Alpa V Patel, Guillermo Pita, Karolina Prajzendanc, Muhammad U Rashid, Kathryn J Ruddy, Fatemeh Safizadeh, Ben Schöttker, Petra Seibold, William J Tapper, Maria Tengström, Lauren R Teras, Heather Thorne, Mieke A M Timmermans, Rob A E M Tollenaar, Celine M Vachon, Qin Wang, Jelle Wesseling, Siddhartha Yadav, Xiaohong R Yang, M Pilar Zamora, Jenny Chang-Claude, Marjanka K Schmidt, Paul D P Pharoah, Mustapha Abubakar, Montserrat García-Closas
Published in
Journal of the National Cancer Institute. Jul 24, 2026. Epub Jul 24, 2026.
Abstract
Breast cancer is etiologically heterogeneous, but which risk factors differ in their associations across tumor subtypes remains unclear. We conducted a large, pooled analysis to evaluate independent, dose-response associations between breast cancer risk factors and quantitative tumor features.
Analyses of 15,731 invasive breast cancers from 24 studies evaluated associations (p-trend) between reproductive and hormonal factors, body mass index (BMI), alcohol, smoking, and family history in relation to quantitative immunohistochemistry measures on tissue microarrays (ER, PR, HER2, KI67, TP53) and tumor grade. Analyses in a subset of 10 population-based studies estimated subtype-specific odds ratios (ORs) comparing cases to controls. A Bayesian False Discovery Probability (BFDP) <0.2 was used to identify associations with strong statistical evidence.
Nulliparity and later age at menopause were associated with higher ER-positivity (p-trend=0.021 and 0.001, respectively), with corresponding OR[ER+] (95% CI) = 1.49 (1.16-1.90) for nulliparous vs. parous and 1.07 (1.03-1.11) per 5 years. Current combined menopausal hormone therapy (MHT) use was associated with lower grade (p-trend<0.001), with OR [grade1] = 3.37 (2.69-4.21) for current vs. never users. Higher BMI was associated with lower ER-positivity and higher grade in premenopausal women (p-trend<0.001 and <0.001), with OR[ER+] = 0.80 (0.74-0.87) and OR[grade1] = 0.75 (0.63-0.88) per 5 units, and with higher PR-positivity and higher grade in postmenopausal women (p-trend<0.001 and <0.001), with OR[PR+] = 1.08 (1.03-1.14) and OR[grade 3] = 1.10 (1.04-1.17) per 5 units.
This pooled analysis of 15,731 cases showed that nulliparity, age at menopause, MHT, and BMI have independent, dose-response associations with ER, PR, and grade, clarifying patterns of etiologic heterogeneity. Associations with HER2, KI67 and TP53, or other risk factors did not meet our threshold for strong evidence.
PMID:
42498670
Bibliographic data and abstract were imported from PubMed on 25 Jul 2026.
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