Addressing Concerns About Breast Cancer Prevention

The paper by Vogel is an interesting personal review of the use of selective estrogen-receptor modulators (SERMs) to prevent breast cancer, raising many important issues and concerns related to this controversial topic. From the beginning, the idea of using SERMs to prevent breast cancer has been divisive, given the conflict between the opportunity to prevent a common disease and the risks of causing toxicity to large numbers of healthy women.

Experimental data reported by Craig Jordan indicated that tamoxifen could prevent mammary tumors in rodents,[1] and Cuzick and Baum demonstrated a reduction in contralateral breast cancer with adjuvant tamoxifen for treatment of operable breast cancer.[2] We then started a feasibility prevention trial at the Royal Marsden in 1986, using tamoxifen in high-risk healthy women with a strong family history of breast cancer. There was much opposition to this trial, and ICI (now AstraZeneca) would neither support the trial nor provide medication. However, early results showed acceptable accrual, toxicity, and compliance, while confirming a reduction in cholesterol and an increase in bone density in postmenopausal women.[3,4]

Four Key Studies

The Marsden trial continued to accrue women for its single-center trial, completing accrual of 2,500 participants in 1996. Meanwhile, in 1992, Bernard Fisher in Pittsburgh, Jack Cuzick in London, and Umberto Veronesi in Milan started multicenter trials. However, there was still substantial opposition to the concept of preventing breast cancer using tamoxifen in healthy women, particularly in the United States, where Dr. Fisher came under a very personal and totally unjustified attack that reached the level of Congress. Nonetheless, he successfully completed the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial in 1996, clearly showing that tamoxifen could reduce the incidence of early breast cancer in healthy women by 49% as well as reduce the risk of fractures. The main toxicities were thromboembolic and gynecologic, including a two- to threefold increase in endometrial cancer, which occurred for the most part in postmenopausal women.

A meta-analysis of the four trials trials was published in 2003, confirming these findings (Table 1 in the Vogel paper has excluded the Marsden data from the meta-analysis).[5]

Apprehensions About SERM Therapy Reconsidered

On the basis of these results, tamoxifen was approved by the US Food and Drug Administration (FDA) for risk reduction of breast cancer in healthy pre- and postmenopausal women at a Gail risk > 1.66% over 10 years. In spite of this approval, the prescription of tamoxifen by primary care physicians for breast cancer risk reduction in the United States has been low, and tamoxifen was not approved for use in healthy women in Europe. The reasons for this low usage are not clear but include concerns about toxicity, especially because of the large numbers of women needed to be treated in order to reduce a relatively small absolute number of cancers. These concerns have now been addressed in several ways.

First, the second-generation SERM raloxifene (Evista) has now been extensively evaluated in postmenopausal women and shown to be an effective agent for preventing osteoporotic fractures in the spine. It has also been shown to be equally effective as tamoxifen at reducing early breast cancer risk, but with less toxicity than tamoxifen.[6,7] Previously approved for fracture risk reduction in the US, raloxifene has now also been approved for breast cancer risk reduction in healthy postmenopausal women. Two other SERMs, arzoxifene and lasofoxifene, are being similarly assessed.

Second, we now have longer follow-up data from two tamoxifen trials: the International Breast Cancer Intervention Study (IBIS) and the continuation of the Royal Marsden feasibility trial, which now has a median follow-up of nearly 15 years and over 200 cancers.[8] The Marsden trial has shown clear evidence that most of the risk-reduction benefit occurs after the 8-year treatment period, indicating a true and prolonged prevention effect. The IBIS trial shows that the toxicity of tamoxifen occurrs for the most part during the treatment period.[9] These results indicate that the therapeutic index of benefits vs toxicity will therefore substantially improve with time and should be taken into consideration when estimating the overall benefit of SERM use for breast cancer risk reduction.

Finally, all trials clearly show that SERMs produce no reduction in estrogen receptor (ER)-negative breast cancer risk, even after a long posttreatment follow-up. Much work is therefore underway to identify women at high risk of developing ER-positive breast cancers, particularly those with commonly inherited moderate-risk breast cancer–predisposing mutations (singly or in combination). Investigators are also seeking to clarify interactions of these mutations with environmental risk factors that may increase the endocrine promotion of breast carcinogenesis, together with possible phenotypic features of some of these risk factors (such as breast density, endocrine measurements, etc). Clinical material from trials that remain blinded with long posttreatment follow-up (to maximize the magnitude of the prevention outcome) may be crucial to achieving these objectives.

Conclusions

In summary, a few years’ use of tamoxifen in premenopausal women and next-generation of SERMs in postmenopausal women might give very long-term (even lifelong) risk reduction of breast cancers with only a relatively short period of mild or no toxicity in most women. This, together with the possibility that we will be better able to identify women at significant risk of developing ER-positive breast cancer will make the whole concept of breast cancer prevention much more acceptable and much less of a controversial issue.

-Trevor J. Powles, CBE, PhD, FRCP

The main article can be found here: Preventing Breast Cancer in High-Risk Women, 2008

References:

References

1. Jordan V: Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinomata. Eur J Cancer 12:419-425, 1976.

2. Cuzick J, Baum M. Tamoxifen and contralateral breast cancer (letter). Lancet 2(8449):282, 1985.

3. Powles T, Tillyer C, Jones A, et al: Prevention of breast cancer with tamoxifen-an update on the Royal Marsden Hospital pilot programme. Eur J Cancer 26:680-684, 1990.

4. Powles T, Hardy J, Ashley S, et al: A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer. Br J Cancer 60:126-131, 1989.

5. Cuzick J, Powles T, Veronesi U, et al: Overview of the main outcomes in the breast cancer prevention trials. Lancet 361:296-300, 2003.

6. Cummings S. Eckert S, Krueger K, et al: The effect of raloxifene on risk of breast cancer in postmenopausal women. Results from the MORE randomized trial. JAMA 281:2189-2197, 1999.

7. Vogel V, Costantino J, Wickerham D, et al: Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes-The NSABP study of tamoxifen and raloxifene (STAR) P-2 trial. JAMA 295:2727-2741, 2006.

8. Powles T, Ashley S, Tidy A, et al: Twenty year follow up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J Natl Cancer Inst 99:283-290, 2007.

7. Cuzick J, Forbes J, Sestak I, et al: Long-term results of tamoxifen prophylaxis for breast cancer-96 month follow-up of the randomised IBIS-I study. J Natl Cancer Inst 99:272-282, 2007.