Carryover effects of aromatase inhibitors in prevention
Authors: Saranya Chumsri, E Aubrey Thompson
Journal: The Lancet (2019)

Breast cancer is the most common cancer diagnosed among women worldwide. WHO has estimated that more than 2·1 million women are diagnosed with breast cancer each year, and that it causes around 627 000 deaths annually.1WHOBreast cancer.https://www.who.int/cancer/prevention/diagnosis-screening/breast-cancer/en/Date: 2019Date accessed: December 10, 2019Google Scholar Breast cancer is a devastating disease that affects not only a patient's physical but also their psychosocial wellbeing. Thus, prevention might yield the most cost-effective strategy to control this disease long term. Two major classes of endocrine therapies have been shown to be effective in preventing breast cancer in high-risk women: selective oestrogen receptor modulators (SERMs) and aromatase inhibitors. Carryover effect is the term used to describe long-lasting benefit of endocrine therapies after stopping the initial treatment. This term was first used to describe the persistent benefit of adjuvant tamoxifen beyond 5 years after completion of treatment. In the adjuvant setting, the Early Breast Cancer Trialists' Collaborative Group (EBCTCG)2Early Breast Cancer Trialists' Collaborative GroupEffects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.Lancet. 2005; 365: 1687-1717Summary Full Text Full Text PDF PubMed Scopus (6411) Google Scholar showed that 5 years of adjuvant tamoxifen resulted in a 41% reduction in the risk of breast cancer recurrence and 34% reduction in breast cancer mortality at 15 years compared with placebo. The risk reduction benefit appeared to be constant over the 15-year period, with absolute differences of 11·4% at 5 years, 13·6% at 10 years, and 11·8% at 15 years when comparing tamoxifen with control. For adjuvant aromatase inhibitors, the EBCTCG3Early Breast Cancer Trialists' Collaborative GroupAromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials.Lancet. 2015; 386: 1341-1352Summary Full Text Full Text PDF PubMed Scopus (832) Google Scholar reported an additional 20% reduction in risk of recurrence and 15% reduction in risk of death from breast cancer at 10 years when 5 years of aromatase inhibitors were compared with 5 years of tamoxifen. Similarly, absolute benefit remains constant over the 10-year period, with 3·1% reduction in the risk of recurrence at 5 years and 3·6% at 10 years.3Early Breast Cancer Trialists' Collaborative GroupAromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials.Lancet. 2015; 386: 1341-1352Summary Full Text Full Text PDF PubMed Scopus (832) Google Scholar In the prevention setting, initial clinical trials have focused on SERMs, particularly tamoxifen and raloxifene. For tamoxifen, the same degree of risk reduction was observed in years 0–10 and after 10 years, with 28% reduction in the risk of developing breast cancer during the first 0–10 years and 31% reduction after 10 years.4Cuzick 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. 2015; 16: 67-75Summary Full Text Full Text PDF PubMed Scopus (280) Google Scholar In The Lancet, Jack Cuzick and colleagues5Cuzick J Sestak I Forbes JF et al.Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial.Lancet. 2019; (published online Dec 12.)https://doi.org/10.1016/S0140-6736(19)32955-1Summary Full Text Full Text PDF PubMed Scopus (73) Google Scholar report the results of long-term follow-up from the International Breast Cancer Intervention Study II (IBIS-II). The IBIS-II trial is a randomised controlled phase 3 trial that evaluated the benefit of anastrozole compared with placebo to reduce the risk of breast cancer development in high-risk women. This trial enrolled 3864 postmenopausal women (median age 59·4 years, IQR 55·0–63·4) with increased risk of breast cancer. Patients were randomly assigned in a double-blind way to receive either anastrozole (n=1920) or placebo (n=1944) for 5 years. With the median follow-up of 131 months (IQR 105–156), this updated analysis showed an overall 49% reduction in the risk of breast cancer development with anastrozole (hazard ratio [HR] 0·51, 95% CI 0·39–0·66, p<0·0001). When the risk reduction benefit of anastrozole in the first 5 years was compared with benefit after 5 years, there was no statistically significant difference between the two timepoints (p=0·087). However, the relative risk reduction for breast cancer appeared to be greater in the initial 5 years, with 61% reduction (HR 0·39, 95% CI 0·27–0·58, p<0·0001) compared with 37% reduction (HR 0·64, 95% CI 0·45–0·91, p=0·014) after 5 years. Nevertheless, the risk reduction remained statistically significant after 5 years and the degree of benefit was still greater than with tamoxifen. To date, only two large phase 3 trials6Goss PE Ingle JN Ales-Martinez JE et al.Exemestane for breast-cancer prevention in postmenopausal women.N Engl J Med. 2011; 364: 2381-2391Crossref PubMed Scopus (761) Google Scholar, 7Cuzick J Sestak I Forbes JF et al.Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial.Lancet. 2014; 383: 1041-1048Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar have evaluated aromatase inhibitors in the prevention setting. The MAP.3 trial6Goss PE Ingle JN Ales-Martinez JE et al.Exemestane for breast-cancer prevention in postmenopausal women.N Engl J Med. 2011; 364: 2381-2391Crossref PubMed Scopus (761) Google Scholar evaluated exemestane versus placebo in postmenopausal women with risk factors for breast cancer. This study also showed comparable risk reduction benefit of 65% at the median follow-up of 35 months. However, the MAP.3 trial was unblinded after the initial report, making it impossible to evaluate long-term effects of exemestane after stopping treatment. In the prevention setting, as here in Cuzick and colleagues' study, the biggest concern is often related to the risk–benefit ratio of the specific therapy. Because the treatment will be given to healthy individuals without a diagnosis of breast cancer, the risk–benefit ratio should be favourable to justify the use of that particular drug in the prevention setting. Thus, it is reassuring that the protective benefit of aromatase inhibitors appears to persist over time even after stopping therapy. Moreover, there was no significant difference in breast cancer-specific mortality among patients who received anastrozole (two deaths in the anastrozole group vs three deaths in the placebo group). This finding contrasts with the previous IBIS-I trial,4Cuzick 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. 2015; 16: 67-75Summary Full Text Full Text PDF PubMed Scopus (280) Google Scholar which evaluated tamoxifen in the prevention setting. In the IBIS-I update with the longer median follow-up of 16 years, fewer cases of breast cancer occurred in the tamoxifen group (7% vs 10%, HR 0·71, 95% CI 0·60–0·83, p<0·0001).4Cuzick 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. 2015; 16: 67-75Summary Full Text Full Text PDF PubMed Scopus (280) Google Scholar Overall, breast cancer-specific mortality did not differ between the groups in that trial; however, it was noted that there were numerically a few more deaths from breast cancer in the tamoxifen group than in the placebo group after 10 years of follow-up,8Chlebowski RT IBIS-I tamoxifen update: maturity brings questions.Lancet Oncol. 2015; 16: 7-9Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar but this was not statistically significant.4Cuzick 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. 2015; 16: 67-75Summary Full Text Full Text PDF PubMed Scopus (280) Google Scholar It is also encouraging that in IBIS-II5Cuzick J Sestak I Forbes JF et al.Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial.Lancet. 2019; (published online Dec 12.)https://doi.org/10.1016/S0140-6736(19)32955-1Summary Full Text Full Text PDF PubMed Scopus (73) Google Scholar side-effects related to anastrozole, which were observed during the active treatment, appeared to resolve after discontinuation of anastrozole. Additionally, there was no new safety concern reported with the longer follow-up after stopping anastrozole. Cardiovascular deaths also did not differ between groups (13 deaths in the anastrozole group vs nine deaths in the placebo group). However, less serious side-effects that can affect patients' qualify of life and adherence, such as arthralgia, hot flushes, and vaginal dryness, were not formally collected in this trial after completion of active therapy. In the IBIS-II trial, only 74·6% of patients adhered and completed 5 years of anastrozole. Therefore, future studies are needed to evaluate novel drugs with fewer side-effects and better risk–benefit ratio. Several ongoing clinical trials are assessing a variety of lifestyle interventions and diet (NCT00148057, NCT02295059, NCT02068092) and novel drugs, such as a topical form of tamoxifen (NCT02993159) and cancer vaccines (NCT03793829). Cuzick and colleagues5Cuzick J Sestak I Forbes JF et al.Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial.Lancet. 2019; (published online Dec 12.)https://doi.org/10.1016/S0140-6736(19)32955-1Summary Full Text Full Text PDF PubMed Scopus (73) Google Scholar provide the first, to our knowledge, evidence of the carryover effect of aromatase inhibitors in the prevention setting and show long-lasting benefit of aromatase inhibitors even after stopping therapy. With longer follow-up, it is also reassuring that there are no new safety concerns. Taking these data together, this article provides more compelling information for clinicians and patients to consider aromatase inhibitors for breast cancer prevention. We declare no competing interests.