Prognostic relation of body mass index on extended aromatase inhibition treatment in postmenopausal patients with estrogen receptor positive breast cancer: A retrospective analysis of the SOLE trial. - 2025
Prognostic relation of body mass index on extended aromatase inhibition treatment in postmenopausal patients with estrogen receptor positive breast cancer: A retrospective analysis of the SOLE trial.
Body mass index; Breast cancer; Extended endocrine therapy; Obesity; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Letrozole; Receptors, Estrogen; Aged; Female; Humans; Middle Aged; Disease-Free Survival; Letrozole/administration & dosage; Postmenopause; Prognosis; Retrospective Studies; Antineoplastic Agents, Hormonal/therapeutic use; Aromatase Inhibitors/therapeutic use; Aromatase Inhibitors/administration & dosage; Body Mass Index; Breast Neoplasms/drug therapy; Breast Neoplasms/pathology; Breast Neoplasms/metabolism; Breast Neoplasms/mortality; Obesity/complications; Receptors, Estrogen/metabolism; Breast Neoplasms; Oncology; Cancer Research
Abstract :
[en] [en] BACKGROUND: Obesity is associated with a greater risk of developing distant recurrences in patients with estrogen receptor-positive (ER+) breast cancer. This association is however poorly investigated in patients treated with extended endocrine treatment (ET). We therefore evaluated the prognostic role of BMI in the SOLE trial, where postmenopausal patients, after having completed 4-6 years of adjuvant ET, were treated with 5 additional years of continuous or intermittent letrozole.
PATIENTS & METHODS: We considered the 3606 patients with ER+ /HER2- lymph node-positive BC with available BMI from the SOLE trial (NCT00553410). Distant-recurrence free interval (DRFI) was the main endpoint, and breast cancer-free interval (BCFI), disease-free survival (DFS) and overall survival (OS) secondary endpoints. Adjusted risk ratios (RR) for distant metastases were estimated with crude cumulative incidence models.
RESULTS: 38.6 % of the patients were underweight or normal weight, 36.5 % overweight and 24.9 % obese. BMI was associated with age, tumor size, number of positive lymph nodes, menopausal status and type of prior ET. In the adjusted analyses, the prognostic value of BMI was dependent on prior ET and extended ET arm (second-order interaction p-value<0.001 for DRFI, BCFI and DFS, but not for OS). For instance, in patients treated with both a selective estrogen receptor modulator and an aromatase inhibitor in the first five years, obesity, as compared to normal-weight, was associated with better (RRDRFI=0.61, 95 %CI: 0.42-0.90) and worse (RRDRFI=2.31, 95 %CI: 1.41-3.78) outcomes in the adjusted models, in patients treated with continuous and intermittent letrozole in the extended ET, respectively.
CONCLUSION: We observed that the prognostic relation of BMI changes according to the type of adjuvant ET and mode of administration of extended AI. This warrants further investigation.
Disciplines :
Oncology
Author, co-author :
Biganzoli, Giacomo; Unit of Medical Statistics, Biometry and Epidemiology, Department of Biomedical and Clinical Sciences (DIBIC) "L. Sacco" & DSRC, LITA Vialba campus, University of Milan, Milan, Italy
Isnaldi, Edoardo; KU Leuven, Department of Oncology, Laboratory for Translational Breast Cancer Research, Leuven, Belgium
Richard, François ; KU Leuven, Department of Oncology, Laboratory for Translational Breast Cancer Research, Leuven, Belgium
Marano, Giuseppe ; Unit of Medical Statistics, Biometry and Epidemiology, Department of Biomedical and Clinical Sciences (DIBIC) "L. Sacco" & DSRC, LITA Vialba campus, University of Milan, Milan, Italy
Boracchi, Patrizia ; Unit of Medical Statistics, Biometry and Epidemiology, Department of Biomedical and Clinical Sciences (DIBIC) "L. Sacco" & DSRC, LITA Vialba campus, University of Milan, Milan, Italy
Maetens, Marion; KU Leuven, Department of Oncology, Laboratory for Translational Breast Cancer Research, Leuven, Belgium
Floris, Giuseppe ; KU Leuven, Translational Cell and Tissue Research Unit, Department of Imaging and Pathology, Leuven, Belgium, University Hospitals Leuven, Department of Pathology, Leuven, Belgium
Neven, Patrick; Gynecologic Oncology and Multidisciplinary Breast Center, University Hospitals UZ-Leuven, KU Leuven, Leuven, Belgium
Jerusalem, Guy ; Université de Liège - ULiège > Département des sciences cliniques > Oncologie
Munzone, Elisabetta ; Division of Medical Senology, IEO European Institute of Oncology IRCCS, Milan, Italy
Hitre, Erika; Department of Medical Oncology and Clinical Pharmacology "B", National Institute of Oncology, Budapest, Hungary
Gombos, Andrea ; Medical Oncology Department, Institut Jules Bordet and Université Libre de Bruxelles (ULB), Brussels, Belgium
Thompson, Alastair; Division of Surgical Oncology, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, USA
Aebi, Stefan ; Division of Medical Oncology, Cancer Center, Lucerne Cantonal, Hospital, Lucerne, Switzerland, Faculty of Medicine, University of Bern, Bern, Switzerland
Dell'Orto, Patrizia ; IBCSG Central Pathology Office, Milan, Italy
Viale, Giuseppe ; IBCSG Central Pathology Office, Milan, Italy, Department of Pathology and Laboratory Medicine, IEO European Institute of Oncology IRCCS, Milan, Italy
Regan, Meredith M; IBCSG Statistical Center, Division of Biostatistics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
Colleoni, Marco ; Division of Medical Senology, IEO European Institute of Oncology IRCCS, Milan, Italy
Biganzoli, Elia; Unit of Medical Statistics, Biometry and Epidemiology, Department of Biomedical and Clinical Sciences (DIBIC) "L. Sacco" & DSRC, LITA Vialba campus, University of Milan, Milan, Italy, KU Leuven, Department of Oncology, Laboratory for Translational Breast Cancer Research, Leuven, Belgium
Desmedt, Christine ; KU Leuven, Department of Oncology, Laboratory for Translational Breast Cancer Research, Leuven, Belgium. Electronic address: christine.desmedt@kuleuven.be
Prognostic relation of body mass index on extended aromatase inhibition treatment in postmenopausal patients with estrogen receptor positive breast cancer: A retrospective analysis of the SOLE trial.
ERC - European Research Council Fondation contre le Cancer Novartis SAKK - Schweizerische Arbeitsgruppe für klinische Krebsforschung
Funding text :
The SOLE trial, including prospective tissue collection, was funded by Novartis, the manufacturer of letrozole, and by the IBCSG, a division of the ETOP IBCSG Partners Foundation . Additional support for the IBCSG from Frontier Science and Technology Research Foundation (FSTRF), Swiss Group for Clinical Cancer Research (SAKK), Cancer Research Switzerland, Oncosuisse, Cancer League Switzerland , and the Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK). The present retrospective study was funded by the Luxembourg Cancer Foundation (grant FC/2018/07 ), the Belgian Cancer Foundation ( FAF- C/2018/1302 ) and the Consolidator Grant approved by the European Research Council (ERC, FAT-BC 101003153 ).
Ward, Z.J., Bleich, S.N., Cradock, A.L., Barrett, J.L., Giles, C.M., Flax, C., et al. Projected U.S. state-level prevalence of adult obesity and severe obesity. N Engl J Med 381:25 (2019 Dec 19), 2440–2450.
Mcpherson K., Brown M., Brown Associates M. Foresight Tackling Obesities: Future Choices-Modelling Future Trends in Obesity and the Impact on Health 2 nd Edition. [cited 2022 Aug 1]; Available from: 〈www.foresight.gov.uk〉.
Renehan, A.G., Zwahlen, M., Egger, M., Adiposity and cancer risk: New mechanistic insights from epidemiology [Internet], Nature Reviews Cancer, Vol. 15, 2015, Nature Publishing Group, 484–498 〈https://pubmed.ncbi.nlm.nih.gov/26205341/〉 [cited 2020 Dec 2].
Jiralerspong, S., Goodwin, P.J., Obesity and breast cancer prognosis: Evidence, challenges, and opportunities [Internet]. J Clin Oncol Am Soc Clin Oncol, Dec 10, 2016, 4203–4216 Available from: 〈http://www.ncbi.nlm.nih.gov/pubmed/27903149〉.
Lohmann, A.E., Soldera, S.V., Pimentel, I., Ribnikar, D., Ennis, M., Amir, E., et al. Association of obesity with breast cancer outcome in relation to cancer subtypes: a meta-analysis. JNCI: J Natl Cancer Inst [Internet], 2021 Feb 23 〈https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab023/6147022〉 [cited 2021 Mar 10]; Available from:.
Harborg, S., Cronin-Fenton, D., Jensen, M.B.R., Ahern, T.P., Ewertz, M., Borgquist, S., Obesity and risk of recurrence in patients with breast cancer treated with aromatase inhibitors. JAMA Netw Open, 6(10), 2023.
Breast Cancer Trialists, E., Group, C., Reductions in recurrence in women with early breast cancer entering clinical trials between 1990 and 2009: a pooled analysis of 155 746 women in 151 trials. Lancet [Internet] 404:10461 (2024 Oct 12), 1407–1418 〈https://www.thelancet.com/action/showFullText?pii=S0140673624017458〉 [cited 2025 Mar 28].
Pan, H., Gray, R., Braybrooke, J., Davies, C., Taylor, C., McGale, P., et al. 20-Year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med 377 (2017 Nov 9), 1836–1846.
Hongchao, Pan, Richard, Gray, Rosie, Bradley, JanniHellen, Gelband, Marianne, Ewertz, SwainSandra, M., et al. Overweight, obesity and prognosis in 206,904 women in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) database. Abstr GS2-09 [Internet], 2024 cited 2025 Mar 28]. Available from: 〈https://sabcs.multilearning.com/sabcs/2024/breast-cancer-symposium/4150562/hongchao.pan.gs2-09.overweight.obesity.and.prognosis.in.206.904.women.in.the.html〉.
Ewertz, M., Jensen, M.B., Gunnarsdóttir, K.Á., Højris, I., Jakobsen, E.H., Nielsen, D., et al. Effect of obesity on prognosis after early-stage breast cancer. J Clin Oncol 29:1 (2011 Jan 1), 25–31.
Nechuta, S., Chen, W.Y., Cai, H., Poole, E.M., Kwan, M.L., Flatt, S.W., et al. A pooled analysis of post-diagnosis lifestyle factors in association with late estrogen-receptor-positive breast cancer prognosis. Int J Cancer [Internet] 138:9 (2016 May 1), 2088–2097 〈https://pubmed.ncbi.nlm.nih.gov/26606746/〉 [cited 2022 Jul 4].
Blok, E.J., Kroep, J.R., Kranenbarg, E.M.K., Duijm-De Carpentier, M., Putter, H., van den Bosch, J., et al. Optimal duration of extended adjuvant endocrine therapy for early breast cancer; results of the IDEAL Trial (BOOG 2006-05). JNCI: J Natl Cancer Inst [Internet] 110:1 (2018 Jan 1), 40–48 〈https://academic.oup.com/jnci/article/110/1/40/4093022〉 [cited 2022 Sep 27].
Gnant M. Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer. 2021.
Jerusalem, G., Farah, S., Courtois, A., Chirgwin, J., Aebi, S., Karlsson, P., et al. Continuous versus intermittent extended adjuvant letrozole for breast cancer: final results of randomized phase III SOLE (Study of Letrozole Extension) and SOLE Estrogen Substudy. Ann Oncol [Internet] 32:10 (2021 Oct 1), 1256–1266 〈https://pubmed.ncbi.nlm.nih.gov/34384882/〉 [cited 2024 Jul 31].
Colleoni, M., Luo, W., Karlsson, P., Chirgwin, J., Aebi, S., Jerusalem, G., et al. Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 19:1 (2018 Jan), 127–138.
A healthy lifestyle - WHO recommendations [Internet]. [cited 2022 Aug 1]. Available from: 〈https://www.who.int/europe/news-room/fact-sheets/item/a-healthy-lifestyle-who-recommendations〉.
Ewertz, M., Jensen, M.B., Gunnarsdottir, K.A., Hojris, I., Jakobsen, E.H., Nielsen, D., et al. Effect of obesity on prognosis after early-stage breast cancer. J Clin Oncol [Internet] 29:1 (2010), 25–31 Available from: 〈http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids= 21115856〉.
Putter, H., Fiocco, M., Gekus, R.B., Tutorial in biostatistics. Compet risk multi-State Models Stat Med 26:11 (2007 May 20), 2389–2430.
Ambrogi, F., Biganzoli, E., Boracchi, P., Model-based estimation of measures of association for time-to-event outcomes. BMC Med Res Method [Internet] 14:1 (2014 Aug 9), 1–14 〈https://bmcmedresmethodol.biomedcentral.com/articles/10.1186/1471-2288-14-97〉 [cited 2023 Mar 28];.
R Core Team [Internet], R: A language and environment for statistical computing. 2020, R Foundation for Statistical Computing, Vienna, Austria.
Halekoh, U., Højsgaard, S., Yan, J., The R package geepack for generalized estimating equations [Internet]. JSS J Stat Softw, 15, 2006 Available from: 〈http://www.jstatsoft.org/〉.
Bretz F., Westfall P., Hothorn T. 2008. Simultaneous Inference in General Parametric Models. [cited 2023 Mar 28]; Available from: http://www.stat.uni-muenchen.de.
Coradini, D., Daidone, M.G., Boracchi, P., Biganzoli, E., Oriana, S., Bresciani, G., et al. Time-dependent relevance of steroid receptors in breast cancer. J Clin Oncol [Internet] 18:14 (2000 Jul 21), 2702–2709 〈http://www.ncbi.nlm.nih.gov/pubmed/10894869〉 cited 2023 Mar 28].
Biglia, N., Peano, E., Sgandurra, P., Moggio, G., Pecchio, S., Maggiorotto, F., et al. Body mass index (BMI) and breast cancer: impact on tumor histopatologic features, cancer subtypes and recurrence rate in pre and postmenopausal women. Gynecol Endocrinol, 29(3), 2013.
Blair, C.K., Wiggins, C.L., Nibbe, A.M., Storlie, C.B., Prossnitz, E.R., Royce, M., et al. Obesity and survival among a cohort of breast cancer patients is partially mediated by tumor characteristics. NPJ Breast Cancer [Internet], 5(1), 2019 Dec 1 〈https://pubmed.ncbi.nlm.nih.gov/31602394/〉 (Available from:).
Santa-Maria, C.A., Yan, J., Xie, X.J., Euhus, D.M., Aggressive estrogen-receptor-positive breast cancer arising in patients with elevated body mass index. Int J Clin Oncol [Internet] 20:2 (2015 Apr 1), 317–323 Available from: 〈https://pubmed.ncbi.nlm.nih.gov/24913910/〉.
Lubián López, D.M., Butrón Hinojo, C.A., Castillo Lara, M., Sánchez-Prieto, M., Sánchez-Borrego, R., Mendoza Ladrón de Guevara, N., et al. Relationship of breast volume, obesity and central obesity with different prognostic factors of breast cancer. Sci Rep [Internet], 11(1), 2021 Dec 1 Available from: 〈https://pubmed.ncbi.nlm.nih.gov/33479372/〉.
Luís, C., Dias, J., Firmino-Machado, J., Fernandes, R., Pereira, D., Baylina, P., et al. A retrospective study in tumour characteristics and clinical outcomes of overweight and obese women with breast cancer. Breast Cancer Res Treat [Internet] 198:1 (2023 Feb 1), 89–101 Available from: 〈https://pubmed.ncbi.nlm.nih.gov/36576677/〉.
Dowsett, M., Howell, A., Breast cancer: aromatase inhibitors take on tamoxifen. Nat Med [Internet] 8:12 (2002 Dec 1), 1341–1344 Available from: 〈https://pubmed.ncbi.nlm.nih.gov/12457166/〉.
Wakeling, A.E., Valcaccia, B., Antioestrogenic and antitumour activities of a series of non-steroidal antioestrogens. J Endocrinol [Internet] 99:3 (1983), 455–464 Available from: 〈https://pubmed.ncbi.nlm.nih.gov/6644236/〉.
Powles, T.J., Hickish, T., Kanis, J.A., Tidy, A., Ashley, S., Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol [Internet] 14:1 (1996), 78–84 Available from: 〈https://pubmed.ncbi.nlm.nih.gov/8558225/〉.
Harper-Wynne, C.L., Sacks, N.P.M., Shenton, K., MacNeill, F.A., Sauven, P., Laidlaw, I.J., et al. Comparison of the systemic and intratumoral effects of tamoxifen and the aromatase inhibitor vorozole in postmenopausal patients with primary breast cancer. J Clin Oncol [Internet] 20:4 (2002 Feb 15), 1026–1035 Available from: 〈https://pubmed.ncbi.nlm.nih.gov/11844826/〉.
Endocrine status of premenopausal node-positive breast cancer patients following adjuvant chemotherapy and long-term tamoxifen - PubMed [Internet]. [cited 2024 Jul 31]. Available from: 〈https://pubmed.ncbi.nlm.nih.gov/3123050/〉.
Dixon, J.M., Renshaw, L., Young, O., Murray, J., Macaskill, E.J., McHugh, M., et al. Letrozole suppresses plasma estradiol and estrone sulphate more completely than anastrozole in postmenopausal women with breast cancer. J Clin Oncol [Internet] 26:10 (2008 Apr), 1671–1676 Available from: 〈http://ascopubs.org/doi/10.1200/JCO.2007.13.9279〉.
Pfeiler, G., Königsberg, R., Singer, C.F., Seifert, M., Dubsky, P.C., Samonigg, H., et al. Impact of body mass index (BMI) on endocrine therapy in premenopausal breast cancer patients: An analysis of the ABCSG-12 trial. J Clin Oncol [Internet], 28(15_), 2010 May 20 512–512. Available from: 〈http://ascopubs.org/doi/10.1200/jco.2010.28.15_suppl.512〉.
Majed, B., Dozol, A., Ribassin-Majed, L., Senouci, K., Asselain, B., Increased risk of contralateral breast cancers among overweight and obese women: a time-dependent association. Breast Cancer Res Treat [Internet] 126:3 (2011 Apr), 729–738 Available from: 〈https://pubmed.ncbi.nlm.nih.gov/20872242/〉.
Chan, D.S.M., Vieira, A.R., Aune, D., Bandera, E. v, Greenwood, D.C., McTiernan, A., et al. Body mass index and survival in women with breast cancer—systematic literature review and meta-analysis of 82 follow-up studies [Internet]. Annals of Oncology, 25, 2014, Elsevier Ltd, 1901–1914 Available from: 〈http://www.dietandcancerreport.org/index.php〉.
Pfeiler, G., Hlauschek, D., Mayer, E.L., Deutschmann, C., Kacerovsky-Strobl, S., Martin, M., et al. Impact of BMI in patients with early hormone receptor-positive breast cancer receiving endocrine therapy with or without palbociclib in the PALLAS Trial. J Clin Oncol [Internet] 41:33 (2023 Nov 20), 5118–5130 Available from: 〈https://pubmed.ncbi.nlm.nih.gov/37556775/〉.
Johnston, S.R.D., Toi, M., O'Shaughnessy, J., Rastogi, P., Campone, M., Neven, P., et al. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol [Internet] 24:1 (2023 Jan 1), 77–90 Available from: 〈https://pubmed.ncbi.nlm.nih.gov/36493792/〉.
Slamon, D.J., Fasching, P.A., Hurvitz, S., Chia, S., Crown, J., Martín, M., et al. Rationale and trial design of NATALEE: a Phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+ /HER2− early breast cancer. Ther Adv Med Oncol, 2023, 15.
