IBIS-I tamoxifen update: maturity brings questions
Authors: Rowan T Chlebowski
Journal: The Lancet Oncology (2014)

The International Breast cancer Intervention Study (IBIS-I) is a randomised, placebo-controlled chemoprevention clinical trial of the effects of tamoxifen in a population of women at high risk of developing breast cancer. Jack Cuzick and colleagues' report in The Lancet Oncology1Cuzick J Sestak I Cawthorn S et al.Tamoxifen for prevention of breast cancer: extended long-term follow up of the IBIS-I breast cancer prevention trial.Lancet Oncol. 2014; (published online Dec 11.)http://dx.doi.org/10.1016/S1470-2045(14)71171-4Google Scholar is an important update of the IBIS-I trial. The achievement of such long-term follow-up (median 16 years), especially with more than 74% of participants remaining masked to randomisation, is commendable. An ongoing reduction in the incidence of oestrogen receptor-positive breast cancer through 16 years' cumulative median follow-up after 5 years of tamoxifen use results in a very favourable number needed to treat of only 22 (95% CI 19–26) women receiving tamoxifen for 5 years to prevent one case of breast cancer in the next 20 years. The findings have clinical implications because many women could be spared the psychological and physical problems associated with a breast cancer diagnosis and related treatment.2Trentham-Dietz A Sprague BL Klein R et al.Health-related quality of life before and after a breast cancer diagnosis.Breast Cancer Res Treat. 2008; 109: 379-387Crossref PubMed Scopus (53) Google Scholar The results build on those from eight other selective oestrogen receptor modulator chemoprevention trials that showed a reduction in breast cancer risk through 10 years' follow-up.3Cuzick J Sestak I Bonanni B et al.Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data.Lancet. 2013; 381: 1827-1834Summary Full Text Full Text PDF PubMed Scopus (351) Google Scholar However, the slightly higher number of deaths from breast cancer in the tamoxifen group than in the placebo group, which persisted beyond 10 years' follow-up in IBIS-I, raises a series of questions. In Cuzick and colleagues' IBIS-I update, 99 fewer breast cancers occurred in the tamoxifen group than in the placebo group (251 [7%] in 3579 vs 350 [10%] in 3575 respectively; hazard ratio [HR] 0·71 [95% CI 0·60–0·83], p<0·0001), but surprisingly, there were five more deaths from breast cancer in the tamoxifen group than in the placebo group (31 vs 26; odds ratio 1·19 [95% CI 0·68–2·10], p=0·8). After 10 years' follow-up, the discordance between the effect of tamoxifen on breast cancer incidence and deaths from breast cancer was more pronounced (18 deaths in the tamoxifen group vs nine with placebo; odds ratio 2·00 [95% CI 0·85–5·06], p=0·08]), although it is important to note that this was not significantly different. To resolve such differences is not easy, since the authors state that the survival results could not be attributed to differing menopausal hormone therapy use or oestrogen receptor-negative disease.1Cuzick J Sestak I Cawthorn S et al.Tamoxifen for prevention of breast cancer: extended long-term follow up of the IBIS-I breast cancer prevention trial.Lancet Oncol. 2014; (published online Dec 11.)http://dx.doi.org/10.1016/S1470-2045(14)71171-4Google Scholar The IBIS-I trial was undertaken when determination of HER2 status was not possible. Since endocrine therapy is less effective in oestrogen receptor-positive, HER2-positive advanced breast cancer4Chlebowski RT Strategies to overcome endocrine therapy resistance in hormone receptor-positive advanced breast cancer.Clin Invest. 2014; 4: 19-33Crossref Google Scholar than in oestrogen receptor-positive, HER2-negative disease, could a differential distribution of HER2-positive cases, under the influence of tamoxifen therapy, have affected the breast cancer survival findings? This important issue needs to be addressed. The IBIS-I findings contrast with those from tamoxifen use in the adjuvant setting where, in women with early-stage oestrogen receptor-positive disease, at 15 years of follow-up after 5 years of tamoxifen use, congruence was recorded between tamoxifen's effect on breast cancer recurrence (relative risk [RR] 0·53 [SE 0·03]) and on deaths from the disease (RR 0·71 [SE 0·05]).5Early Breast Cancer Trialists' Collaborative Group (EBCTCG)Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomized trials.Lancet. 2011; 378: 771-784Summary Full Text Full Text PDF PubMed Scopus (1944) Google Scholar Even in a trial that enrolled and randomly assigned 7154 women, the findings about deaths from breast cancer could represent the effect of chance alone in the small sample of 57 deaths that occurred. In this regard, although the authors1Cuzick J Sestak I Cawthorn S et al.Tamoxifen for prevention of breast cancer: extended long-term follow up of the IBIS-I breast cancer prevention trial.Lancet Oncol. 2014; (published online Dec 11.)http://dx.doi.org/10.1016/S1470-2045(14)71171-4Google Scholar cite previous power calculations to indicate that more survival events are needed before definitive assessment, additional events would be unlikely to appreciably change the results since the trend is in the opposite direction and survival curves that cross are unlikely to become positive. Although the magnitude and even the existence of breast cancer overdiagnosis by screening remains controversial,6Bleyer A Welch HG Effect of three decades of screening mammography on breast-cancer incidence.N Engl J Med. 2012; 367: 1998-2005Crossref PubMed Scopus (1005) Google Scholar, 7Helvie MA Chang JT Hendrick RE Banerjee M Reduction in late-stage breast cancer incidence in the mammography era: implications for overdiagnosis of invasive cancer.Cancer. 2014; 120: 2649-2656Crossref PubMed Scopus (92) Google Scholar could tamoxifen treatment in IBIS-I have been selectively preventing breast cancers with extremely favourable prognoses? Additional follow-up of the other selective oestrogen receptor modulator prevention trials might address this issue. In IBIS-I, tamoxifen was less effective in reducing breast cancer risk in women who used menopausal hormone therapy than in those who did not use hormone therapy.1Cuzick J Sestak I Cawthorn S et al.Tamoxifen for prevention of breast cancer: extended long-term follow up of the IBIS-I breast cancer prevention trial.Lancet Oncol. 2014; (published online Dec 11.)http://dx.doi.org/10.1016/S1470-2045(14)71171-4Google Scholar Menopausal hormone therapy8Manson JE Chlebowski RT Stefanick ML et al.Menopausal hormone therapy and health outcomes during the intervention and extended post-stopping phases of the Women's Health Initiative randomized trials.JAMA. 2013; 310: 1353-1368Crossref PubMed Scopus (1012) Google Scholar and tamoxifen3Cuzick J Sestak I Bonanni B et al.Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data.Lancet. 2013; 381: 1827-1834Summary Full Text Full Text PDF PubMed Scopus (351) Google Scholar, 5Early Breast Cancer Trialists' Collaborative Group (EBCTCG)Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomized trials.Lancet. 2011; 378: 771-784Summary Full Text Full Text PDF PubMed Scopus (1944) Google Scholar can both affect breast cancer and other chronic diseases, and their combined effect on most of these illness is unknown. In the Women's Health Initiative randomised trials, oestrogen plus progestin, in the form of conjugated equine oestrogen, increases breast cancer incidence and deaths from breast cancer, whereas oestrogen alone reduces breast cancer incidence and deaths.9Chlebowski RT Anderson GL Menopausal hormone therapy and cancer: changing clinical observations of target site specificity.Steroids. 2014; 90: 53-59Crossref PubMed Scopus (29) Google Scholar Additionally, these hormone therapy regimens also have effects on other cancers.9Chlebowski RT Anderson GL Menopausal hormone therapy and cancer: changing clinical observations of target site specificity.Steroids. 2014; 90: 53-59Crossref PubMed Scopus (29) Google Scholar Future IBIS-I subgroup analyses should separate the effects of these two hormone therapy regimens. Overall survival is a reasonable endpoint for advanced breast cancer and adjuvant trials. In prevention trials that incorporate analyses after long-term follow-up, an increasingly larger proportion of deaths from other causes occur, years or decades after interventions are stopped. In the current IBIS-I report, only 57 (15%) of 389 total deaths were related to breast cancer. Alternative endpoints should be considered for future chemoprevention trials, especially for those that enrol older participants similar to those entered in IBIS-I. At present, despite positive findings in terms of their effect on breast cancer incidence, the use of selective oestrogen receptor modulators for breast cancer chemoprevention in clinical practice is very infrequent.10Waters EA McNeel TS Stevens WM Freedman AN Use of tamoxifen and raloxifene for breast cancer chemoprevention in 2010.Breast Cancer Res Treat. 2012; 134: 875-880Crossref PubMed Scopus (123) Google Scholar The discordance between tamoxifen's effects on breast cancer incidence and outcome noted in the IBIS-I update could merely represent the effects of chance alone, or alternatively might indicate that tamoxifen mainly decreases the incidence of cancers with a very favourable prognosis, increases cancers with unfavourable outcomes, or both. How these alternative ideas are viewed will determine the effect of the IBIS-I update on breast cancer chemoprevention practice in the clinic. I have received consulting fees or honoraria from Novartis, Amgen, and Genomic Health; fees for participation in review activities for Pfizer and Novo Nordisk; payment for lectures from Novartis; and payment for educational activities from Educational Concepts Group. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trialThese results show that tamoxifen offers a very long period of protection after treatment cessation, and thus substantially improves the benefit-to-harm ratio of the drug for breast cancer prevention. Full-Text PDF Open Access