Dr. Cuzick offers the manuscript below to put the results of the Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial in focus for MedicalResearch.com.
The Prevention of Breast Cancer
The first human evidence that drug treatment might reduce the incidence of breast cancer was reported in 19851, where it was found that use of tamoxifen in a trial of women with breast cancer to reduce recurrence of existing tumours also had a major impact on new tumours in the opposite breast, reducing them from 10 to 3. That observation has subsequently been confirmed in several other adjuvant trials and an overview of all such trials indicates that after an average of about 8 years of follow up, 5 years of tamoxifen reduced new contralateral tumours by 39%, with similar effects in years 0-5 and 5-10 in women with oestrogen receptor positive or unknown primary tumours2. These observations and positive results from animal studies3, led to the evaluation of 5 years of tamoxifen in women without breast cancer, but at high risk in 4 large trials. A recent overview4 indicates a 33% reduction in all breast cancer after a 10 years follow up, with a larger reduction in years 0-5 (48%), when treatment was given, and a continuing (22%) effect in years 5-10. Reductions were seen for oestrogen receptor positive invasive cancer (44%) and DCIS (28%), but no effect was seen for both oestrogen receptor negative invasive cancer, where in fact a non-significant 13% (P=0.4) increase was observed. Somewhat larger effects were seen for these other selective estrogen receptor modulators (SERMs) – raloxifene, lasofoxifene and arzoxifene – in trials of osteoporotic women, where the primary endpoint was fracture reduction4. A subsequent head-to-head trial of raloxifene vs tamoxifen, showed tamoxifen to be about 20% more effective, but raloxifene had fewer side effects5. Lasofoxifene not only showed benefits for breast cancer reduction but also reduced fracture rates and heart disease6, and this multi-dimensional set of benefits makes it an attractive candidate for prevention.
More recently the aromatase inhibitors have been shown to be more effective than tamoxifen in the treatment of postmenopausal women with ER positive breast cancer, and again the first evidence that it might be more effective for prevention came from its effect on contralateral tumours in the ATAC trial7. That observation has now been widely replicated8, and the combined evidence suggested that about 45% of the cancers not prevented by tamoxifen are prevented by an aromatase inhibitors. Thus, given that tamoxifen produces a 40% reduction in the trials of tamoxifen vs nothing, a 65% – 70% reduction would be projected for the aromatase inhibitors (AIs).
Two large studies have now been conducted to evaluate the roles of aromatase inhibitors in prevention in high risk women without breast cancer. The MAP.3 study9 evaluated exemestane in 4560 women and reported after a 35 month median follow up; the IBIS-2 study looked at anastrozole in 3846 women and report after 60 months median follow up. Both studies found a 53% in all breast cancer (including DCIS) and larger reductions were seen for invasive ER positive disease.
The side effect profiles of tamoxifen and the aromatase inhibitors are somewhat different. The major side effects of tamoxifen are endometrial cancer and thromboembolism, although both are rare. For aromatase inhibitors increased fracture rates due to, lower oestrogen levels, was seen with the ATAC trial10, but IBIS-2 showed that this could be managed by performing a bone density scan (DXA) initially, giving a bisphosphonate to osteoporotic women and repeat testing with bisphosphonate use as needed for those who are osteopenic. As a result fracture rates were only slightly and non-significantly raised (from 7.6% to 8.5%). A similar lack of fracture increase was seen in the MAP.3 trial9. Musculoskeletal aches and pains and vasomotor symptoms (hot flushes) were the commonest side effects, but the rates in the placebo arm were 90% (58% vs 64%) and 85% (49% vs 57%), resp. of those in the active treatment arm, indicating that many of these side effects are being wrongly attributed to the treatment in uncontrolled situations.
Tamoxifen and raloxifene are approved by the FDA for prevention in the USA, and recently NICE approval was granted in the UK. Given the better efficacy and tolerability of aromatase inhibitors it seems likely that NICE will also approve them soon as well. However, a major challenge remains in achieving greater usage in high risk women, where benefits clearly outweigh risks. One attractive option is to integrate a preventive consultation into the breast screening programme. This seems an ideal time to assess breast cancer risk and a single centre study in Manchester11 found that the offer of discussing risk and preventive actions at this time were positively received by 95% of the women approached. Such an activity requires the availability of a trained research nurse or doctor to provide this information, but would only be needed for the first screening appointment.
A comprehensive risk assessment requires 3 elements:
- Aquestionnaire based identification of known risk factors, such as those used in the Tyrer-Cuzick model12;
- Measurement of breast density from the mammogram;
- and where acceptable, measurement of the genetic risk profile. This would be based on the large number of SNPs identified (76 validated SNPs currently reported), which individually have a small impact on risk but when combined into a risk score are likely to provide useful additional, but not definitive, risk assessment information13.
Initial indications are that these 3 components are largely independent and each provides a similar amount of information for the population in general.
With an accurate method to assess risk now available, the stage is set to discuss a range of preventive actions which at one end would include bilateral mastectomy for the very few women at extremely high risk (typically > 70% lifetime risk), to preventive therapy with aromatase inhibitors, tamoxifen or raloxifene for high risk women (25-70% risk), and lifestyle changes, including more physical activity and weight control for those at average or slightly increased lifetime risk (10-25%), as well as for high risk individuals. Weight control has proved a difficult goal for the general population, and simple programmes to increase physical activity are likely to be the most attractive in terms of acceptability. While increased physical activity has been shown to be associated with reduced breast cancer rates in several observational studies14,15 , the level of exercise required may be difficult to achieve in the general population, and other confounding factors may also impact these findings. Randomised trials are needed to fully evaluate the achievable benefits of exercise in breast cancer prevention16,17.
Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial
Prof Jack Cuzick PhD,Ivana Sestak PhD,Prof John F Forbes MD,Prof Mitch Dowsett PhD,Jill Knox MSc,Simon Cawthorn MD,Prof Christobel Saunders MD,Nicola Roche MD,Prof Robert E Mansel MD,Gunter von Minckwitz MD,Bernardo Bonanni MD,Tiina Palva MD,Prof Anthony Howell MD,on behalf of the IBIS-II investigators
The Lancet – 22 March 2014 ( Vol. 383, Issue 9922, Pages 1041-1048 )
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- EBCTCG. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687-717.
- Jordan C. Tamoxifen for the prevention of breast cancer. De Vita 1990;Cancer Prevention:p. 1–12.
- Cuzick 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;381:1827-34.
- Vogel VG, Costantino JP, Wickerham DL, et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer. Cancer Prev Res (Phila) 2010;3:696-706.
- LaCroix AZ, Powles T, Osborne CK, et al. Breast cancer incidence in the randomized PEARL trial of lasofoxifene in postmenopausal osteoporotic women. J Natl Cancer Inst 2010;102:1706-15.
- Baum M, Budzar AU, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002;359:2131-9.
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- Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008;9:45-53.
- Evans DG, Warwick J, Astley SM, et al. Assessing individual breast cancer risk within the U.K. National Health Service Breast Screening Program: a new paradigm for cancer prevention. Cancer Prev Res (Phila) 2012;5:943-51.
- Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors. Stat Med 2004;23:1111-30.
- Brentnall AR, Evans DG, Cuzick J. Distribution of breast cancer risk from SNPs and classical risk factors in women of routine screening age in the UK. Br J Cancer 2014;110:827-8.
- Howard RA, Leitzmann MF, Linet MS, Freedman DM. Physical activity and breast cancer risk among pre- and postmenopausal women in the U.S. Radiologic Technologists cohort. Cancer Causes Control 2009;20:323-33.
- Chlebowski RT. Nutrition and physical activity influence on breast cancer incidence and outcome. Breast 2013;22 Suppl 2:S30-7.
- Winzer BM, Whiteman DC, Reeves MM, Paratz JD. Physical activity and cancer prevention: a systematic review of clinical trials. Cancer Causes Control 2011;22:811-26.
- Rock CL, Byers TE, Colditz GA, et al. Reducing breast cancer recurrence with weight loss, a vanguard trial: the Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) Trial. Contemp Clin Trials 2013;34:282-95.