Abstract
Breast cancer is the most commonly diagnosed cancer worldwide. Earlier studies have demonstrated that breast cancer patients with particular genomic variants are more susceptible to adverse drug effects (ADEs) when they are receiving endocrine therapy. However, to establish a robust body of evidence with regard to the potential utility and predictive value of these variants, findings from these reports require replication. This study aimed to validate previously reported associations between genomic variants and medically important adverse drug effects (MIADEs) using UK Biobank (UKBB). In 2729 female participants who had received endocrine therapy in the UKBB, no statistically significant genotype-treatment interactions were observed for the outcomes examined after correction for multiple testing. Power was limited for modest interactions involving low-frequency variants and less frequent outcomes, whereas power was high to detect larger interaction effects in common-variant scenarios. Accordingly, the findings do not provide robust evidence to support previously reported pharmacogenomic associations in this dataset, and current evidence does not support the use of pharmacogenomic testing for individualised endocrine therapy selection in clinical practice.
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The genetic and phenotypic data from the UK Biobank can be accessed by applying through their website (www.ukbiobank.ac.uk/register-apply). We cannot directly grant access to the specific data fields used in this study. All other data relevant to the study are included in the article or uploaded as supplementary information.
References
Sung, H. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–49 (2021).
Burstein, H. J., Prestrud, A. A. & Griggs, J. J. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J. Clin. Oncol. 28, 3784–96 (2010).
Davies, C. et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381, 805–16 (2013).
Rydén, L., Heibert Arnlind, M., Vitols, S., Höistad, M. & Ahlgren, J. Aromatase inhibitors alone or sequentially combined with tamoxifen in postmenopausal early breast cancer compared with tamoxifen or placebo - Meta-analyses on efficacy and adverse events based on randomized clinical trials. Breast 26, 106–14 (2016).
Murphy, C. C. et al. Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review. Breast Cancer Res. Treat. 134, 459–78 (2012).
Amir, E., Seruga, B., Niraula, S., Carlsson, L. & Ocaña, A. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. JNCI J. Natl. Cancer Inst. 103, 1299–309 (2011).
Condorelli, R. & Vaz-Luis, I. Managing side effects in adjuvant endocrine therapy for breast cancer. Expert Rev. Anticancer Ther. 18(11), 1101–12 (2018).
Westbrook, K. & Stearns, V. Pharmacogenomics of breast cancer therapy: an update. Pharm. Ther. 139, 1–11 (2013).
MOKBEL, K., WEEDON, M., MOYE, V. & JACKSON, L. Pharmacogenetics of toxicities related to endocrine treatment in breast cancer: a systematic review and meta-analysis. Cancer Genom. Proteom. 21, 421–38 (2024).
Sini V, Botticelli A, Lunardi G, Gori S, Marchetti P. Pharmacogenetics and aromatase inhibitor induced side effects in breast cancer patients. Pharmacogenomics 18, 821–830 (2017).
Higgins, M. J. & Stearns, V. Pharmacogenetics of endocrine therapy for breast cancer. Annu Rev. Med. 62, 281–93 (2011).
Bycroft, C., Freeman, C. & Marchini, J. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203 (2018).
Al-Mamun MA. Effect of SULT1A1, UGT2B7, CYP3A5 and CYP2D6 polymorphisms on tamoxifen response in breast cancer patients of Bangladesh (University of Dhaka, 2017).
Argalacsova, S., Slanar, O., Bakhouche, H. & Pertuzelka, L. Impact of ABCB1 and CYP2D6 polymorphisms on tamoxifen treatment outcomes and adverse events in breast cancer patients. J. BUON 22, 1217–26 (2017).
Leyland-Jones, B., Gray, K. P. & Regan, M. M. CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1–98 trial. Breast Cancer Res. Treat. 151, 373–84 (2015).
Mazzuca, F. et al. CYP19A1 genetic polymorphisms rs4646 and osteoporosis in patients treated with aromatase inhibitor-based adjuvant therapy. Eurasia. J. Med. 48, 10–4 (2016).
Miranda, C. et al. Preliminary pharmacogenomic-based predictive models of tamoxifen response in hormone-dependent chilean breast cancer patients. Front. Pharm. 12, 661443 (2021).
Napoli, N. et al. Genetic polymorphism at Val80 (rs700518) of the CYP19A1 gene is associated with aromatase inhibitor associated bone loss in women with ER (+) breast cancer. Bone 55, 309–314 (2013).
Ntukidem, N. I. et al. Estrogen receptor genotypes, menopausal status, and the lipid effects of tamoxifen. Clin. Pharm. Ther. 83, 702–710 (2008).
Oesterreich, S., Henry, N. L. & Flockhart, D. A. Associations between genetic variants and the effect of letrozole and exemestane on bone mass and bone turnover. Breast Cancer Res. Treat. 154, 263–273 (2015).
Ohnishi, T. et al. CYP17 polymorphism and tamoxifen-induced hepatic steatosis. Hepatol. Res. 33, 178–80 (2005).
Onitilo, A. A. et al. Estrogen receptor genotype is associated with risk of venous thromboembolism during tamoxifen therapy. Breast Cancer Res. Treat. 115, 643–50 (2009).
Rodríguez-Sanz, M. et al. CYP11A1 expression in bone is associated with aromatase inhibitor-related bone loss. J. Mol. Endocrinol. 55, 69–79 (2015).
Santa-Maria, C. A., Blackford, A. & Stearns, V. Association of variants in candidate genes with lipid profiles in women with early breast cancer on adjuvant aromatase inhibitor therapy. Clin. Cancer Res. 22, 1395–1402 (2016).
Baatjes, K. et al. Cyp19a1 rs10046 pharmacogenetics in postmenopausal breast cancer patients treated with aromatase inhibitors: one-year follow-up. Curr. Pharm. Des. 26, 6007–12 (2020).
Wang, J. et al. Indications of clinical and genetic predictors for aromatase inhibitors related musculoskeletal adverse events in Chinese Han women with breast cancer. PLoS ONE 8, e68798 (2013).
Wang, J. et al. RANKL and OPG polymorphisms are associated with aromatase inhibitor-related musculoskeletal adverse events in chinese han breast cancer patients. PLoS ONE 10, e0133964 (2015).
Weng, L. et al. Genome-wide discovery of genetic variants affecting tamoxifen sensitivity and their clinical and functional validation. Ann. Oncol. 24, 1867–73 (2013).
Wickramage, I., Tennekoon, K. H., Ariyaratne, M. A. Y., Hewage, A. S. & Sundralingam, T. CYP2D6 polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study. Breast Cancer Targets Ther. 9, 111–20 (2017).
Chu, W. et al. Association between CYP3A4 genotype and risk of endometrial cancer following tamoxifen use. Carcinogenesis 28, 2139–42 (2007).
Dieudonné, A. S. et al. The rs1800716 variant in CYP2D6 is associated with an increased double endometrial thickness in postmenopausal women on tamoxifen. Ann. Oncol. J. Eur. Soc. Med. Oncol. 25, 90–5 (2014).
Garber, J. E., Halabi, S. & Berliner, N. Factor V leiden mutation and thromboembolism risk in women receiving adjuvant tamoxifen for breast cancer. J. Natl. Cancer Inst. 102, 942 (2010).
Hartmaier, R. J., Richter, A. S. & Oesterreich, S. A SNP in steroid receptor coactivator-1 disrupts a GSK3β phosphorylation site and is associated with altered tamoxifen response in bone. Mol. Endocrinol. 26, 220 (2012).
Koukouras, D. et al. Association of estrogen receptor alpha (ERα) gene polymorphisms with endometrial thickness and lipid profile in women with breast cancer treated with aromatase inhibitors. Gynecol. Endocrinol. 28, 859–62 (2012).
Kovac, M. et al. Factor V Leiden mutation and high FVIII are associated with an increased risk of VTE in women with breast cancer during adjuvant tamoxifen — Results from a prospective, single center, case control study. Eur. J. Intern Med. 26, 63–7 (2015).
Leyland-Jones, B., Gray, K. P. & Regan, M. M. ESR1 and ESR2 polymorphisms in the BIG 1-98 trial comparing adjuvant letrozole versus tamoxifen or their sequence for early breast cancer. Breast Cancer Res. Treat. 154, 543–55 (2015).
Abed, S. N. Genetic polymorphic impact of metabolizing enzyme (CYP3A4 and UGT1A4 genes) on anastrazole response in iraqi breast cancer women. Ann. Clin. Med. Case Rep. 8, 1–6 (2022).
Fox, P. et al. Dose escalation of tamoxifen in patients with low endoxifen level: Evidence for therapeutic drug monitoring - The TADE study. Clin. Cancer Res. 22, 3164–71 (2016).
Lorizio, W. et al. Clinical and biomarker predictors of side effects from tamoxifen. Breast Cancer Res. Treat. 132, 1107–18 (2012).
Jansen, L. E., Teft, W. A., Rose, R. V., Lizotte, D. J. & Kim, R. B. CYP2D6 genotype and endoxifen plasma concentration do not predict hot flash severity during tamoxifen therapy. Breast Cancer Res. Treat. 171, 701–8 (2018).
Zembutsu, H., Nakamura, S. & Nakamura, Y. Significant effect of polymorphisms in CYP2D6 on response to tamoxifen therapy for breast cancer: a prospective multicenter study. Clin. Cancer Res. 23, 2019–26 (2017).
Goetz, M. P. et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J. Clin. Oncol. 23, 9312–8 (2005).
Sestak, I. et al. Relationships between CYP2D6 phenotype, breast cancer and hot flushes in women at high risk of breast cancer receiving prophylactic tamoxifen: results from the IBIS-I trial. Br. J. Cancer 107, 230 (2012).
Duggan, C., Marriott, K., Edwards, R. & Cuzick, J. Inherited and acquired risk factors for venous thromboembolic disease among women taking tamoxifen to prevent breast cancer. J. Clin. Oncol. 21, 3588–93 (2003).
Liu, M. et al. Aromatase inhibitor-associated bone fractures: a case-cohort GWAS and functional genomics. Mol. Endocrinol. 28, 1740–51 (2014).
Liu L., Bai, Y.X. & Zhang, Q.Y. A Polymorphism at the 3’-UTR region of the aromatase gene is associated with the efficacy of the aromatase inhibitor, anastrozole, in metastatic breast carcinoma. Int. J. Mol. Sci. 14, 18973–88 (2013).
Colomer, R., Monzo, M. & Alba, E. A single-nucleotide polymorphism in the aromatase gene is associated with the efficacy of the aromatase inhibitor letrozole in advanced breast carcinoma. Clin. Cancer Res. 14, 811–6 (2008).
Knight, B. The association between the UGT2B17 gene deletion and menopause-related quality of life in postmenopausal women in the CCTG MAP.3 breast cancer chemoprevention trial (Queen’s University at Kingston, 2017).
Tamura, K., Imamura, C. K. & Tanigawara, Y. CYP2D6 genotype-guided tamoxifen dosing in hormone receptor-positive metastatic breast cancer (TARGET-1): a randomized, open-label, phase 2 study. J Clin Oncol. 38, 558–566 (2020).
Georgopoulos, N., Adonakis, G., Fotopoulos, A., Koika, V., Spinos, N., Saltamavros, A. et al. Estrogen receptor polymorphisms in tamoxifen-treated women with breast cancer. Gynecol. Endocrinol. 22, 185–9 (2006).
Bai, S. Influence of the UGT2B17 gene on the relationship between exemestane and bone mineral density in postmenopausal women (Queen's University, 2018).
Henry, N. L. et al. Lack of association between oestrogen receptor polymorphisms and change in bone mineral density with tamoxifen therapy. Br. J. Cancer 102, 294 (2010).
Okishiro, M. et al. Genetic polymorphisms of CYP2D6*10 and CYP2C19*2,*3 are not associated with prognosis, endometrial thickness, or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen. Cancer 115, 952–61 (2009).
Rangel-Méndez, J. A., Rubi-Castellanos, R., Sánchez-Cruz, J. F. & Moo-Puc, R. E. Tamoxifen side effects: pharmacogenetic and clinical approach in Mexican mestizos. Transl. Cancer Res. 8, 23 (2019).
Bojanic, K. et al. Representation of CYP3A4, CYP3A5 and UGT1A4 polymorphisms within Croatian breast cancer patients’ population. Int. J. Environ. Res. Public Health 17, 3692 (2020).
Kamdem, L. K. et al. Exemestane may be less detrimental than letrozole to bone health in women homozygous for the UGT2B17*2 gene deletion. Breast Cancer Res. Treat. 175, 297–303 (2019).
Abramson, N. et al. Effect of factor V Leiden and prothrombin G20210→A mutations on thromboembolic risk in the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial. J. Natl. Cancer Inst. 98, 904–10 (2006).
Tucker, A. N. et al. Polymorphisms in cytochrome P4503A5 (CYP3A5) may be associated with race and tumor characteristics, but not metabolism and side effects of tamoxifen in breast cancer patients. Cancer Lett. 217(1), 61–72 (2005).
Ingle, J. N., Schaid, D. J. & Weinshilboum, R. M. Genome-wide associations and functional genomic studies of musculoskeletal adverse events in women receiving aromatase inhibitors. J. Clin. Oncol. 28(31), 4674–82 (2010).
Abubakar, M. B., Lin Tan, H., Murali Krishna Bhavaraju, V. & Hua Gan, S. Impact of CYP3A4 and CYP3A5 single nucleotide polymorphisms on anastrozole-associated adverse events among Malaysian breast cancer patients. AsPac J. Mol. Biol. Biotechnol. 27, 33–42 (2019).
Irvin, W. J., Walko, C. M. & Carey, L. A. Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism: a multicenter study. J. Clin. Oncol. 29, 3232 (2011).
Umamaheswaran, G. et al. Polymorphisms of T- cell leukemia 1A gene loci are not related to the development of adjuvant letrozole-induced adverse events in breast cancer. PLoS ONE 16, e0247989 (2021).
Borrie, A. E., Rose, R. V. & Kim, R. B. Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer. Breast Cancer Res. Treat. 172, 371–9 (2018).
Damodaran, S. E. et al. Genetic polymorphisms of CYP2D6 increase the risk for recurrence of breast cancer in patients receiving tamoxifen as an adjuvant therapy. Cancer Chemother. Pharm. 70, 75–81 (2012).
Ramón Y Cajal, T. et al. Impact of CYP2D6 polymorphisms in tamoxifen adjuvant breast cancer treatment. Breast Cancer Res. Treat. 119, 33–8 (2010).
Ruddy, K. J. et al. Personalized medicine in breast cancer: Tamoxifen, endoxifen, and CYP2D6 in clinical practice. Breast Cancer Res. Treat. 141, 421–7 (2013).
Jager, N. G. L. et al. Hot flashes are not predictive for serum concentrations of tamoxifen and its metabolites. BMC Cancer 13, 612 (2013).
Bonanni, B. et al. Polymorphism in the CYP2D6 tamoxifen-metabolizing gene influences clinical effect but not hot flashes: data from the Italian tamoxifen trial [1]. J. Clin. Oncol. 24, 3708–9 (2006).
Hochberg, Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika 75, 800 (1988).
Patel, R. S. et al. Reproducible disease phenotyping at scale: example of coronary artery disease in UK Biobank. PLoS ONE 17, e0264828 (2022).
Fry, A. et al. Comparison of sociodemographic and health-related characteristics of UK Biobank participants with those of the general population. Am. J. Epidemiol. 186, 1026 (2017).
Sudlow, C., Gallacher, J., Allen, N. & Collins, R. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 12, e1001779 (2015)
Bankowski, Z. & Council for International Organizations of Medical Sciences. Reporting adverse drug reactions: definitions of terms and criteria for their use. 146 (CIOMS, 1999)
Faich, G. A., Castle, W. & Bankowski, Z. International adverse drug reaction reporting: the Cioms Project. Drug Inf. J. 24, 419–25 (1990).
Common Terminology Criteria for Adverse Events (CTCAE) | Protocol Development | CTEP [Internet]. Available from https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
European Medicines Agency. Designated medical events [Internet]. Available from https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/signal-management#designated-medical-events-section.
Important medical event terms list (MedDRA version 25.0) [Internet]. Available from https://www.ema.europa.eu/en/documents/other/meddra-important-medical-event-terms-list-version-250_en.xlsx (2022).
Ruth, K. S. et al. Events in early life are associated with female reproductive ageing: a UK Biobank study. Sci. Rep. 6, 1–9 (2016).
Pharmacogenomics Knowledge Base (PharmGKB) [Internet]. Available from https://www.pharmgkb.org/.
UK Biobank online resource centre [Internet]. Available from https://biobank.ctsu.ox.ac.uk/.
Holm, S. A simple sequentially rejective multiple test procedure. Scand. J. Stat. 65, 70 (1979).
Brookes, S. T., Whitley, E., Peters, T. J., Mulheran, P. A., Egger, M. & Davey, S. G. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives. Health Technol. Assess. 5, 1–56 (2001).
Demidenko, E. Sample size and optimal design for logistic regression with binary interaction. Stat. Med. 27, 36–46 (2008).
Riley, R. D., Hattle, M., Collins, G. S., Whittle, R. & Ensor, J. Calculating the power to examine treatment-covariate interactions when planning an individual participant data meta-analysis of randomized trials with a binary outcome. Stat. Med. 41, 4822 (2022).
Schoenfeld, D. A. & Borenstein, M. Calculating the power or sample size for the logistic and proportional hazards models. J. Stat. Comput. Simul. 75, 771–85 (2005).
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This study received support from the University of Exeter Sanctuary Scholarship. We extend our gratitude to the UK Biobank for granting access to their data for this research. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission.
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K.M., M.W., V.M. and L.J. were responsible for designing the research. K.M. generated the data, performed the analyses, interpreted the results, created the tables/figures, searched the literature and drafted the manuscript. L.J., M.W. and V.M. oversaw the study, provided expert interpretation of the data and contributed to the manuscript. K.R. contributed to data generation and the manuscript. All the authors contributed to the final paper.
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Mokbel, K., Weedon, M.N., Moye, V. et al. No evidence for genotype-treatment interactions with breast cancer endocrine therapy adverse effects in UK Biobank. npj Breast Cancer (2026). https://doi.org/10.1038/s41523-026-00923-2
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DOI: https://doi.org/10.1038/s41523-026-00923-2


