Is Prevention Better Than Cure?
The antihormonal therapy of breast cancer has probably reached its zenith, but the application of SERMs for the chemoprevention of breast cancer is providing a new dimension for the consideration of public health. Despite progress in the treatment of breast cancer, prevention remains a viable strategy. In the 1970’s laboratory studies showed that tamoxifen prevented carcinogen induced rat mammary cancer, probably via an ER mediated mechanism47). Gradually, this work was translated to clinical trial and the results demonstrated that tamoxifen would be a useful agent to test as a chemo-preventative22). The NSABP-1 trial subsequently showed that in high risk women, tamoxifen significantly decreased the risk of breast cancer by 50% in pre and postmenopausal volunteers. Tamoxifen is approved in the United States for risk reduction of breast cancer in high risk pre-menopausal and postmenopausal women. Despite the fact that chemoprevention is a pioneering application for tamoxifen, there are justifiable concerns about toxic side effects. The side effects (primarily venous thrombosis and endometrial cancer, though the incidence is small) have limited the use of tamoxifen by primary care practitioners. Nevertheless, it must be stressed that the side effects are limited to postmenopausal women.
There are no significant increases in endometrial cancer and thrombosis in postmenopausal women.
Tamoxifen remains the chemo-preventative agent of choice in this risk group48, 49). To address the issue of side effects (e.g. endometrial cancer) with tamoxifen, a noval SERM strategy was devised. If SERMs can prevent bone loss and prevent recurrent cancer at the same time50, 51), why not develop a SERM to prevent osteoporosis and prevent breast cancer at the same time? This evidenced based hypothesis52) has now been evaluated with the application of raloxifene to prevent osteoporosis. Breast cancer and endometrial cancer are reduced when raloxifene is used to treat osteoporosis53, 54). It is now possible to state that thou-
sands of women treated with raloxifene to prevent osteoporosis will have significant reductions in their breast cancer incidence49, 55, 56). Based on the successful evaluation of raloxifene as an osteoporosis drug, raloxifene was then targeted to postmenopausal women at high risk for breast cancer.
The studies of tamoxifen and raloxifene (STAR) trial was designed to compare and contrast tamoxifen and raloxifene for the reduction in the incidence of breast cancer in high risk women and to improve the side effect profiles57). The results of the trial demonstrated that the SERMs are equivalent in the prevention of invasive breast cancer, but it appears that tamoxifen is slightly better in preventing noninvasive breast cancer. Nevertheless, the results do not reach statistical significance. The side effect profile of raloxifene is better than tamoxifen. Raloxifene treated women have a reduced incidence of endometrial cancer, hysterectomies, cataracts and cataract surgery.
Overall, raloxifene can be stated to be an effective agent to reduce breast cancer risk in postmenopausal women.
It is important to emphasize that no other classes of hormonal therapy have been evaluated successfully for prevention other than SERMs.
Aromatase inhibitors are slightly superior to SERMs for patients with breast cancer. Unfortunately, aromatase inhibitors cannot be used in premenopausal women. Therefore, the future consideration for the aromatase inhibitors is the balance of side effects between SERMs and aromatase inhibitors. The side effect profile of osteoporosis, fractures, and musculoskeletal pain in high risk patients will be addressed by an international clinical trial by the International Breast Intervention Study (IBIS II). Anastrazole is being evaluated for prevention in high risk post menopausal women.
The study involves 6,000 women who will be randomized to receive anastrazole or placebo. Another group of 4,000 women with locally excised DCIS will be randomized to receive anastrazole or tamoxifen. After 5 years of treatment, rates of breast cancer and side effect profiles will be examined between the groups58). The important trial (P4) to compare and contrast raloxifene with the aromatase inhibitor letrozole is being conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP). These data will not be available until 2014.
When treating patients with ER positive breast cancer, there are many new choices available for patients. Recurrent cancer which is SERM resistant and side effects such as venous thrombosis and endometrial cancer prompted investigation into aromatase inhibitors. Currently, clinical trials indicate that aromatase inhibitors should be used for initial hormonal therapy. One must keep in mind that although aromatase inhibitors are superior for prevention of recurrence, some patients still get recurrent breast cancer and the absolute difference between aromatase inhibitors and tamoxifen is a small percentage when comparing individual studies. Furthermore, the BIG trial is the only trial that stratified patients into node negative and node positive patients in terms of disease free survival rates. Letrozole was significantly more beneficial with node positive patients, and there was no difference between node negative patients. If fractures, bone pain and other side effects are intolerable, tamoxifen is still a viable option for prevention of recurrence, especially in node negative patients with no uterus and without a history of clotting. In node positive patients, aromatase inhibitors are probably the best initial treatment option. Treatment for recurrent cancer should be tailored for individual patients based on disease characteristics and tolerance of side effects such as osteopenia and musculoskeletal pain, cardiac risk, risk of venous thrombosis, and risk of uterine cancer. For the future, prevention of breast cancer remains the most ideal situation and a significant number of patients will continue to benefit from the use of tamoxifen or raloxifene, with an additional benefit of maintaining bone density. The era of multifunctional medicines has arrived.
Supported by 5T32CA10365-03 (RRP) and by the Department of Defense Breast Program under award number BC050277 Center of Excellence (Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense) (VCJ), SPORE in Breast Cancer CA 89018 (VCJ), R01 GM067156 (VCJ), FCCC Core Grant NIH P30 CA006927 (VCJ), the Avon Foundation and the Weg Fund of Fox Chase Cancer Center (VCJ).
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Roshani R. Patel, Catherine G. N. Sharma, and V. Craig Jordan
Fox Chase Cancer Center, Philadelphia
Reprint requests to V. Craig Jordan OBE, PhD, DSc, Vice President and Research Director for Medical Science, Alfred G. Knudson Chair of Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497
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