Medicines to prevent breast cancer in women at above-average risk of developing breast cancer

What is the issue?

Breast cancer is the most frequent type of cancer and the second cause of death by cancer in women. Therefore, any strategy which can reduce its burden is eagerly awaited. Cancer prevention agents (CPAs) are medicines that might fulfil this need. Currently, two main types of CPAs are available to combat breast cancer: selective estrogen receptor modulators (SERMs, such as tamoxifen and raloxifene) and aromatase inhibitors (such as exemestane and anastrozole). Women without personal history of breast cancer, but with above-average risk of developing this disease (that is, with a lifetime risk greater than 17%) represent the usual target population for CPAs.

Review question

This Cochrane Review aimed to summarize the evidence on the efficacy and toxicity of CPAs for the prevention of primary breast cancer.

Key messages

CPAs can reduce the incidence of breast cancer although at the cost of some toxicity. Aromatase inhibitors may be more effective than SERMs in reducing the risk of developing breast cancer. Aromatase inhibitors are not associated with the increased severe toxicity (i.e. cancer of the lining of the womb (endometrial cancer)) and thromboembolic events (blood clots)) that characterize the use of tamoxifen (although the lack of long-term data on aromatase inhibitors in unaffected women do not allow us to draw definitive conclusions). Additional data are needed to fully address the issues of breast cancer prevention by risk-reducing medicines, with emphasis on collecting information on side effects.

What was studied in the review?

The review authors found six studies enrolling 50,927 women to receive one CPA or placebo (a pretend treatment, e.g. a sugar pill). Three studies involving 23,013 women compared tamoxifen and placebo, two studies involving 8424 women compared aromatase inhibitors (exemestane or anastrozole) and placebo, and one study involving 19,490 women that compared tamoxifen and raloxifene.

What are the main results of the review?

Based on the three studies that compared tamoxifen to placebo, tamoxifen probably reduced the risk of developing breast cancer by 32% compared to placebo. However, tamoxifen was associated with a 28% increased risk of severe side effects compared to placebo based on two studies involving 20,361 women. In particular, women taking tamoxifen experienced higher incidence of endometrial cancer and thromboembolism than women having no medicine.

For women who received either an aromatase inhibitor (exemestane or anastrozole) or placebo, aromatase inhibitors reduced the risk of breast cancer by 53% compared to placebo. Data from two studies involving 8352 women indicated that aromatase inhibitors increased the risk of severe side effects by 18% compared to placebo. These differences were sustained especially by endocrine (hormonal; e.g. hot flashes), gastrointestinal (e.g. diarrhea), and musculoskeletal (e.g. joint pain) side effects, whereas there were no differences in either endometrial cancer or thromboembolism rates.

For women who received either tamoxifen or raloxifene, raloxifene probably performed worse than tamoxifen in terms of breast cancer incidence reduction, but its use was associated with a 13% reduction of toxicity rates especially endometrial cancer and thromboembolism.

A specialized method named a 'network meta-analysis' allowed us to compare medications never directly compared to each other in a study. Based on this network meta-analysis, aromatase inhibitors may have led to a 23% additional risk reduction of developing breast cancer compared to tamoxifen. However, the reliability of the evidence was low meaning that further research is likely to have an impact on our confidence in this result. This analysis could not be performed on toxicity data.

How up-to-date is this review?

The review authors searched for studies that had been published up to 17 August 2018.

Authors' conclusions: 

For women with an above-average risk of developing breast cancer, CPAs can reduce the incidence of this disease. AIs appear to be more effective than SERMs (tamoxifen) in reducing the risk of developing breast cancer. AIs are not associated with an increased risk of endometrial cancer and thromboembolic events. However, long-term data on toxicities from tamoxifen are available while the follow-up toxicity data on unaffected women taking AIs is relatively short. Additional data from direct comparisons are needed to fully address the issues of breast cancer prevention by risk-reducing medications, with special regards to acceptability (i.e. the benefit/harm ratio).

Read the full abstract...
Background: 

Breast cancer is the most frequently occurring malignancy and the second cause of death for cancer in women. Cancer prevention agents (CPAs) are a promising approach to reduce the burden of breast cancer. Currently, two main types of CPAs are available: selective estrogen receptor modulators (SERMs, such as tamoxifen and raloxifene) and aromatase inhibitors (AIs, such as exemestane and anastrozole).

Objectives: 

To assess the efficacy and acceptability of single CPAs for the prevention of primary breast cancer, in unaffected women, at an above-average risk of developing breast cancer.

Using a network meta-analysis, to rank single CPAs, based on their efficacy and acceptability (an endpoint that is defined as the inverse of CPA-related toxicity).

Search strategy: 

We searched the Cochrane Breast Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov on 17 August 2018. We handsearched reference lists to identify additional relevant studies.

Selection criteria: 

We included randomized controlled trials (RCTs) that enrolled women without a personal history of breast cancer but with an above-average risk of developing a tumor. Women had to be treated with a CPA and followed up to record the occurrence of breast cancer and adverse events.

Data collection and analysis: 

Two review authors independently extracted data and conducted risk of bias assessments of the included studies, and assessed the certainty of the evidence using GRADE. Outcome data included incidence of breast carcinoma (both invasive and in situ carcinoma) and adverse events (both overall and severe toxicity). We performed a conventional meta-analysis (for direct comparisons of a single CPA with placebo or a different CPA) and network meta-analysis (for indirect comparisons).

Main results: 

We included six studies enrolling 50,927 women randomized to receive one CPA (SERMs: tamoxifen or raloxifene, or AIs: exemestane or anastrozole) or placebo. Three studies compared tamoxifen and placebo, two studies compared AIs (exemestane or anastrozole) versus placebo, and one study compared tamoxifen versus raloxifene. The risk of bias was low for all RCTs.

For the tamoxifen versus placebo comparison, tamoxifen likely resulted in a lower risk of developing breast cancer compared to placebo (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.62 to 0.76; 3 studies, 22,832 women; moderate-certainty evidence). In terms of adverse events, tamoxifen likely increased the risk of severe toxicity compared to placebo (RR 1.28, 95% CI 1.12 to 1.47; 2 studies, 20,361 women; moderate-certainty evidence). In particular, women randomized to receive tamoxifen experienced a higher incidence of both endometrial carcinoma (RR 2.26, 95% CI 1.52 to 3.38; high-certainty evidence) and thromboembolism (RR 2.10, 95% CI 1.14 to 3.89; high-certainty evidence) compared to women who received placebo.

For the AIs versus placebo comparison, AIs (exemestane or anastrozole) reduced the risk of breast cancer by 53% (RR 0.47, 95% CI 0.35 to 0.63; 2 studies, 8424 women; high-certainty evidence). In terms of adverse events, AIs increased the risk of severe toxicity by 18% (RR 1.18, 95% CI 1.09 to 1.28; 2 studies, 8352 women; high-certainty evidence). These differences were sustained especially by endocrine (e.g. hot flashes), gastrointestinal (e.g. diarrhea), and musculoskeletal (e.g. arthralgia) adverse events, while there were no differences in endometrial cancer or thromboembolism rates between AIs and placebo.

For the tamoxifen versus raloxifene comparison, raloxifene probably performed worse than tamoxifen in terms of breast cancer incidence reduction (RR 1.25, 95% CI 1.09 to 1.43; 1 study, 19,490 women; moderate-certainty evidence), but its use was associated with lower toxicity rates (RR 0.87, 95% CI 0.80 to 0.95; 1 study, 19,490 women; moderate-certainty evidence), particularly relating to incidence of endometrial cancer and thromboembolism.

An indirect comparison of treatment effects allowed us to compare the SERMs and AIs in this review. In terms of efficacy, AIs (exemestane or anastrozole) may have reduced breast cancer incidence slightly compared to tamoxifen (RR 0.67, 95% CI 0.46 to 0.98; 5 RCTs, 31,256 women); however, the certainty of evidence was low. A lack of model convergence did not allow us to analyze toxicity data.

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