Other agents have emerged, although initially developed for other diseases, which might be useful for the prevention of breast cancer in high-risk women. New generations of chemopreventive agents that do not modulate the endocrine pathways have been studied recently.
Metformin is a safe drug widely used by millions of people for the treatment of non-insulin-dependent diabetes. It works by targeting the enzyme AMP-activated protein kinase, which induces muscles to take up glucose from the blood. The rationale for the use of metformin in breast cancer prevention comes from obesity being an independent risk factor for breast cancer in postmenopausal women. Many studies have shown that long-term use of metformin may have a beneficial effect on breast cancer risk. Small biomarker studies in women with breast cancer in a placebo-controlled setting are ongoing and these results may lead to larger chemoprevention trials with metformin.
Bisphosphonates were originally developed for the treatment of osteoporosis and are commonly used in the breast cancer setting in controlling bone loss induced by AIs and chemotherapy. In addition, adjuvant breast cancer trials evaluating the oral bisphosphonate clodronate suggested a reduction in cancer recurrence, but the findings were mixed.38 Several studies have now shown that bisphosphonates reduce breast cancer in postmenopausal women by around 30%.38,39 These findings require a cautious interpretation since bisphosphonates are given to women with a low bone mineral density and these women are at a decreased risk of breast cancer. However, these agents are well tolerated, and primary prevention trials are needed to fully investigate the risk–benefit ratio of these agents for breast cancer prevention. It is not clear if they are suitable for premenopausal women.
Nonsteroidal anti-inflammatory drugs
Long-term follow-up of randomized trials using aspirin in the prevention of vascular disease showed that daily use reduced the incidence of colorectal cancer and several other cancers. Evidence from case–control and cohort studies indicates a reduction of breast cancer risk by about 10% for aspirin and possibly a little more for ibuprofen.40,41 Similar results have been found with other nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors.42 Although an effect of NSAIDs on breast cancer risk reduction is too small to make a conclusive decision regarding its sole use in the prevention of breast cancer, these drugs may be part of a broad intervention approach, specifically since a beneficial effect is seen on colorectal cancers and cardiovascular disease.43
The IBIS-III trial will integrate several chemopreventive agents in one trial. This trial will directly address the issue of late recurrence in postmenopausal breast cancer survivors and will include integrated biological studies to explore mechanisms of drug action and to identify which patients are at greatest risk of late recurrence. Specifically, this trial will attempt to determine which cancers are most susceptible to control with metformin and/or an AI and/or a bisphosphonate in a 2×2×2 factorial trial. Of particular interest will be any possible positive synergism between these agents.
The prevention of ER-positive breast cancer with SERMs is well established, and they are the only option for premenopausal women to date. However, despite their efficacy, these drugs have not been well accepted as preventive agents by high-risk women or clinicians, mostly because of adverse events. For postmenopausal women, the AIs have been established for the treatment of breast cancer and recent publications also favor those drugs over SERMs in the preventive setting. Both the MAP3 and IBIS-II trials have reported a significant reduction for invasive breast cancer in postmenopausal women in the preventive setting.
Biomarkers are important for the identification of women at high risk, and breast density is currently the most attractive measure. Breast density is a well-established risk factor for breast cancer and it has been shown that change in breast density might predict drug effectiveness and therefore be a useful surrogate marker.44 Similarly, a recent publication has reported that mammographic density during the use of adjuvant endocrine treatment was a significant predictor for recurrence in women with ER-positive breast cancer.45
The prevention of incidence or recurrence of ER-negative disease remains a huge challenge, and other agents have to be developed for the prevention of these tumors. Recent research interests have been in so-called non-endocrine-based pathways, such as epidermal growth factor 1 or human epidermal growth factor. NSAIDs,46 COX-2 inhibitors,47,48 retinoids, rexinoids, and statins49,50 may also protect against both receptor positive and receptor negative tumors, but results only from observational studies or adjuvant studies are available at the moment, and there are still inconsistencies. A new agent, deguelin, which prevents mammary tumorigenesis, has shown important advances in the prevention of ER-negative breast cancer.51