Elsevier

The Lancet Oncology

Volume 12, Issue 5, May 2011, Pages 496-503
The Lancet Oncology

Review
Preventive therapy for breast cancer: a consensus statement

https://doi.org/10.1016/S1470-2045(11)70030-4Get rights and content

Summary

In March, 2010, a group of breast cancer experts met to develop a consensus statement on breast cancer prevention, with a focus on medical and therapeutic interventions. We present the conclusions in this Review. First we agreed that the term chemoprevention is inappropriate and suggested that the term preventive therapy better represents this feature of management. Two selective oestrogen-receptor modulators—tamoxifen and raloxifene—are so far the only medical options approved by the US Food and Drug Administration for preventive therapy. Of these tamoxifen has greater efficacy and can be used in premenopausal women, but raloxifene has fewer side-effects. Two newer drugs in this class, lasofoxifene and arzoxifene, also show efficacy and possibly a better overall risk-benefit profile, but need further assessment. Aromatase inhibitors might be more efficacious, and results of prevention trials are eagerly awaited. Newer agents, notably bisphosphonates and metformin, have shown promise in observational studies and need to be assessed in randomised prevention trials. Other agents, such as aspirin, other non-steroidal anti-inflammatory drugs, COX-2 inhibitors, retinoids, rexinoids, and dietary components have limited effects or are in the early phases of investigation. New contralateral tumours in women with breast cancer might be generally useful as a model for prevention, as has been seen for tamoxifen. If valid such a model would facilitate the design of simpler, cheaper, and better-focused trials for assessing new agents.

Introduction

Breast cancer is the most common cancer in women worldwide, with the annual incidence estimated to be 1·4 million cases in 2008.1 Rates are highest in North America, western Europe, and Australia, but are increasing almost everywhere, especially in developing countries. The worldwide incidence is destined to increase substantially in the next few decades.2

In March, 2010, a group of experts met in St Gallen, Switzerland, to develop a consensus statement on breast cancer prevention. In this Review we present the main findings and conclusions of this meeting. At present, strategies for prevention of breast cancer encompass lifestyle factors, such as avoidance of obesity, maintaining physical activity, and moderation of alcohol intake, as well as surgical and medical therapeutic interventions, but the discussion was limited to the last approach to maintain focus. A new umbrella term, preventive therapy, was proposed for this type of management because the term chemoprevention can evoke inappropriate associations with cancer and chemotherapy, and the terms risk reduction and risk management are too technical and non-specific, especially for the general population. Preventive therapy was felt to convey the preventive intention and the interventional character of medical treatment. It forms part of the wider strategy of preventive care that also includes non-pharmacological approaches (figure).

Section snippets

Risk assessment and response to preventive therapy

Preventive therapy for cancer is currently less well established than in other medical specialties, especially cardiovascular disease, and could benefit from lessons learned.3 Risk assessment for breast cancer clearly needs to improve so that therapy can be directed towards the women most likely to benefit. Efforts to find germline genetic variations have so far not been very helpful. They have yielded a few high-risk gene mutations that have extremely low prevalence (eg, BRCA1, BRCA2, TP53,

Multifactorial approach to prevention

When making decisions about preventive therapy for breast cancer, benefits for breast cancer and other diseases and acute and late harmful side-effects need to be taken into account. The traditional drug approval process is not suitable for preventive medicine. Reliance on one primary endpoint, as is generally required by regulatory agencies, needs to be replaced. A full assessment of preventive therapeutic interventions must, therefore, include multiple endpoints and focus on the overall

Tamoxifen

In view of the proven effectiveness of the selective oestrogen-receptor modulator (SERM) tamoxifen on recurrent and new contralateral tumours and its good toxicity profile in the treatment of hormone-receptor-positive breast cancer,13 this drug was an obvious candidate for assessment as a preventive agent. The earliest and most extensive efforts in prevention focused on this compound. Four large trials14, 15, 16, 17 were undertaken (table) and long-term follow-up data are available. An overview

Newer approaches

In addition to the antihormonal drugs, which are only effective for preventing ER-positive breast cancer, evidence is emerging that various agents that were initially developed for other diseases are effective in reducing the risk of ER-positive and ER-negative breast cancers.

Populations and research strategies

At the meeting in St Gallen, we specified some directions for future study and research. Tamoxifen and raloxifene are so far the only drugs approved by the US Food and Drug Administration for prevention of breast cancer. Despite evidence consistently showing a protective effect in high-risk women, both agents are used by only a tiny proportion of this population. Although this prescribing pattern might be partly attributable to the fear of side-effects, the lack of effective strategies to

Conclusions

Research is actively being done into preventive therapy for breast cancer, with some notable achievements so far. Two SERMs, tamoxifen and raloxifene, are licensed for use in the USA, although neither is being widely used, mainly because of a perceived concern about side-effects and poor ability to identify women at high risk. Two newer SERMs, lasofoxifene and arzoxifene, seem to have good risk-benefit profiles and trials in women at high risk of breast cancer are needed to confirm the

Search strategy and selection criteria

Topics for the Review were based on the set of questions discussed at the Sixth International Conference on Clinical Cancer Prevention in St Gallen, Switzerland, March 18–20, 2010. We searched PubMed and ClinicalTrials.gov for articles published or studies registered from 1995 to 2010, with the key phrase “breast cancer AND (chemoprevention OR prevention)”. Reference lists of reviews and key research papers were searched manually for additional references.

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