Clarifying risk-factor associations with quantitative breast tumor features: a pooled analysis of 24 studies

Abstract

Background

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.

Methods

Analyses of 15 731 invasive breast cancers from 24 studies evaluated associations (P for trend) between reproductive and hormonal factors, body mass index (BMI), alcohol, smoking, and family history in relation to quantitative immunohistochemical measures on tumor microarrays (estrogen receptor, progesterone receptor, HER2, KI67, TP53) and tumor grade. Analyses in a subset of 10 population-based studies estimated subtype-specific odds ratios (ORs) comparing breast cancer cases with controls. A Bayesian false-discovery probability less than 0.2 was used to identify associations with strong statistical evidence.

Results

Nulliparity and later age at menopause were associated with higher estrogen receptor positivity (P = .021 and .001 for trend, respectively), with corresponding odds ratio (OR) of 1.49 (95% CI = 1.16 to 1.90) for nulliparous vs parous and 1.07 (95% CI = 1.03 to 1.11) per 5 years. Current combined menopausal hormone therapy use was associated with lower grade (P < .001 for trend), with OR (grade 1) of 3.37 (95% CI = 2.69 to 4.21) for current vs never users. Higher BMI was associated with lower estrogen receptor positivity and higher grade in premenopausal women (P < .001 and < .001 for trend), with odds ratio (estrogen receptor positive) of 0.80 (95% CI = 0.74 to 0.87) and odds ratio (grade 1) of 0.75 (95% CI = 0.63 to 0.88) per 5 units and with higher progesterone receptor positivity and higher grade in postmenopausal women (P < .001 and < .001 for trend), with odds ratio (progesterone receptor positive) of 1.08 (95% CI = 1.03 to 1.14) and odds ratio (grade 3) of 1.10 (95% CI = 1.04 to 1.17) per 5 units.

Conclusion

This pooled analysis of 15 731 cases showed that nulliparity, age at menopause, menopausal hormone therapy, and BMI have independent, dose-response associations with estrogen receptor, progesterone receptor, 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.

Metadata

Item Type:	Article
Authors/Creators:	Adams, D. https://orcid.org/0009-0005-1953-6408 Hurson, A.N. Ahearn, T.U. https://orcid.org/0000-0003-0771-7752 Andrulis, I.L. Antoniou, A.C. Auvinen, P. Bane, A. Behrens, S. Berrington de Gonzalez, A. https://orcid.org/0000-0002-7332-8387 Białkowska, K. Bodelon, C. Bolla, M.K. Borrero, M. Brenner, H. Brock, I.W. Broeks, A. Camp, N.J. Cessna, M.H. Chanock, S.J. Chenevix-Trench, G. https://orcid.org/0000-0002-1878-2587 Copson, E. Couch, F.J. Cox, A. https://orcid.org/0000-0002-5138-1099 Cross, S.S. Devilee, P. https://orcid.org/0000-0002-8023-2009 Dunning, A.M. Easton, D.F. Eccles, D.M. Figueroa, J.D. Glendon, G. González-Neira, A. Hamann, U. Hartikainen, J.M. Hartman, M. Heemskerk-Gerritsen, B.A.M. Ho, P.J. Hodge, J.M. Holleczek, B. Hollestelle, A. Hooning, M.J. https://orcid.org/0000-0001-6763-0857 Amor, D. Andrews, L. Antill, Y. Balleine, R. Beesley, J. Bennett, I. Bogwitz, M. Bodek, S. Botes, L. Brennan, M. Brown, M. Buckley, M. Caldon, L. Campbell, I. Chakrabarti, A. Chauhan, D. Chauhan, M. Chenevix-Trench, G. Christian, A. Cohen, P. Colley, A. Crook, A. Cui, J. Courtney, E. Cummings, M. Dawson, S.-J. deFazio, A. Delatycki, M. Dickson, R. Dixon, J. Duijf, P. Edwards, S. Farshid, G. Fellows, A. Fenton, G. Field, M. Flanagan, J. Fong, P. Forrest, L. Fox, S. French, J. Friedlander, M. Gattas, M. George, P. Greening, S. Harris, M. Harraka, P. Hayward, N. Hoskins, C. Hunt, C. James, P. Jenkins, M. Kidd, A. Koehler, J. Kollias, J. Lakhani, S. Lawrence, M. Lee, J. Li, S. Lindeman, G. Lippey, J. Lipton, L. Loi, S. Mann, G. Marsh, D. McLachlan, S.A. Reed, A.M. Milne, R. Nightingale, S. O’Connell, S. O’Sullivan, S. O’Reilly, R. Ortega, D.G. Pachter, N. Pang, J.-M. Pathak, G. Patterson, B. Pearn, A. Phillips, K. Pieper, E. Ramus, S. Rickard, E. Ragunathan, A. Robinson, B. Skandarajah, A. Salisbury, E. Saunders, C. Saunus, J. Savas, P. Scott, R. Scott, C. Sexton, A. Shaw, J. Shelling, A. Srinivasa, S. Simpson, P. Southey, M. Spurdle, A. Taylor, J. Taylor, R. Thorne, H. Trainer, A. Tucker, K. Visvader, J. Walker, L. Williams, R. Winship, I. Young, M.A. Zaheed, M. Tan, B.K.-T. Tan, V.K.M. Lim, G.H. Tan, E.Y. Tan, S.-M. Iau, P.T.C. Jakubowska, A. https://orcid.org/0000-0002-5650-0501 Jones, M.E. Jones, L. Jones, B. Jung, A. Kaaks, R. Keeman, R. Lawrence, S. Li, J. https://orcid.org/0000-0001-8587-7511 Lissowska, J. Lubiński, J. Mannermaa, A. https://orcid.org/0000-0001-8250-1930 Manoochehri, M. Martens, J.W.M. Mesker, W.E. Muhammad, N. Mulligan, A.M. Obi, N. https://orcid.org/0000-0002-0903-9142 Olson, J.E. https://orcid.org/0000-0003-4944-7789 Osorio, A. Ottewell, P.D. https://orcid.org/0000-0002-4826-0771 Patel, A.V. https://orcid.org/0000-0001-8834-9896 Pita, G. Prajzendanc, K. Rashid, M.U. Ruddy, K.J. https://orcid.org/0000-0001-6298-332X Safizadeh, F. Schöttker, B. Seibold, P. https://orcid.org/0000-0001-7360-6335 Tapper, W.J. Tengström, M. Teras, L.R. https://orcid.org/0000-0003-2419-8536 Thorne, H. Timmermans, M.A.M. Tollenaar, R.A.E.M. Vachon, C.M. Wang, Q. Wesseling, J. Yadav, S. https://orcid.org/0000-0003-4630-9903 Yang, X.R. Zamora, M.P. Chang-Claude, J. Schmidt, M.K. https://orcid.org/0000-0002-2228-429X Pharoah, P.D.P. Abubakar, M. García-Closas, M. https://orcid.org/0000-0003-1033-2650
Copyright, Publisher and Additional Information:	© 2026 The Authors. Except as otherwise noted, this author-accepted version of a journal article published in JNCI: Journal of the National Cancer Institute is made available via the University of Sheffield Research Publications and Copyright Policy under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/
Keywords:	ethanol; smoking; estrogen replacement therapy; body mass index procedure; menopause; heterogeneity; breast neoplasms; genes, erbb-2tp53 geneki-67 antigen; parity; postmenopause; premenopause; protein p53estrogen receptors; receptors, progesterone; reproduction; risk factors; neoplasms; breast cancer; nulliparity; invasive breast cancer; estrogen receptor positive; progesterone receptor positive; ecological study; breast cancer risk; use techniques of reflection and clarification in communication; neoplasm grading
Dates:	Submitted: 25 February 2026 Accepted: 6 July 2026 Published (online): 24 July 2026 Published: 24 July 2026
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Date Deposited:	21 Sep 2026 15:19
Last Modified:	21 Sep 2026 15:19
Status:	Published online
Publisher:	Oxford University Press (OUP)
Refereed:	Yes
Identification Number:	10.1093/jnci/djag244
Related URLs:	PubMed URL
Sustainable Development Goals:
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:245771

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Clarifying risk-factor associations with quantitative breast tumor features: a pooled analysis of 24 studies

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