Medications for Breast Cancer Risk Reduction Can Increase Incidence of Other Cancers

Frank J. Domino, MD

Review

Nelson HD, Smith ME, Griffin JC, Fu R. Use of medications to reduce risk for primary breast cancer: A systematic review for the US Preventive Services Task Force. Ann Intern Med. 2013;158(8):604-14. http://annals.org/article.aspx?articleid=1676456.

Study Methods

The purpose of this systematic review was to evaluate the efficacy and adverse effects of medications used to reduce the risk of breast cancer.

The review analyzed English-language randomized trials on the medications’ effectiveness and adverse events, as well as observational studies on their adverse events in patient use and diagnostic accuracy studies on their risk assessment.

Results and Outcomes

Included in this review were 7 good- and fair-quality trials that evaluated the ability of tamoxifen and raloxifene to reduce the incidence of invasive breast cancer. The trials best estimated an incidence reduction of 7 to 9 invasive breast cancer cases per 1,000 women over 5 years when compared to placebo. Additional data from the Study of Tamoxifen and Raloxifene (STAR) trial showed tamoxifen reduced invasive breast cancer incidence more effectively than raloxifene by an additional 5 cases per 1,000 women.

Though neither drug reduced breast cancer-specific mortality or all-cause mortality, both reduced the incidence of vertebral and hip fractures. However, tamoxifen increased the incidence of thromboembolic events more than raloxifene, and it also raised the incidence of endometrial cancer and the development of cataracts compared to placebo and raloxifene.

Conclusion

While tamoxifen and raloxifene reduced the incidence of invasive breast cancer and fractures, they also increased the risk of deep venous thrombosis (DVT), cataracts, and uterine cancer. Nevertheless, the use of those medications for invasive breast cancer prevention should be considered in those at the greatest risk for developing the disease.

Commentary

This systematic review was undertaken at the behest of the US Preventive Services Task Force (USPSTF) to determine why the agency’s recommendation for women to take medication to prevent breast cancer has generated little participation.

The authors attempted to answer the following questions:

1. What are the benefits of tamoxifen and raloxifene when used to reduce the risk of breast cancer?
2. What are the harms of tamoxifen and raloxifene when used to reduce the risk of primary breast cancer?
3. What is the variability of outcomes in population subgroups?
4. What are the decisions regarding medication adherence and persistence?

The current USPSTF guideline¹ recommends clinicians “engage in shared, informed decision making with women who are at increased risk for breast cancer about medications to reduce their risk. For women who are at increased risk for breast cancer and at low risk for adverse medication effects, clinicians should offer to prescribe risk-reducing medication, such as tamoxifen or raloxifene.” This recommendation received a B grade, which means the agency found at least fair evidence that the medications can improve important health outcomes and provide benefits that outweigh harms.

However, this guideline also includes a recommendation “against the routine use of medications, such as tamoxifen or raloxifene, for risk reduction of primary breast cancer in women who are not at increased risk for breast cancer.” This received a D grade, meaning sufficient evidence was found to recommend against the use of the medications in low-risk women.

This immediately begs the question: What qualifies as an increased risk? While a number of methods can be used to determine a woman’s risk of developing invasive breast cancer, the most commonly accepted one is the National Cancer Institute’s Web-based Breast Cancer Risk Assessment (BCRA) Tool, which is based on the Gail model that utilizes history of breast cancer or ductal carcinoma in situ (DCIS), number of relatives with breast cancer, history of breast biopsy, and reproductive history, as well as ethnicity and race. The tool is generally used to calculate a woman's risk of developing breast cancer within the next 5 years and throughout her lifetime.

Breast cancer is not one single disease. It has a variety of subtypes clinically influenced by their receptor status and ability to become invasive. While DCIS is a non-invasive subtype of breast cancer that accounts for the vast majority of all breast cancer diagnoses, it cannot be predicted by the BCRA tool or prevented with medication. Invasive breast cancer accounts for most of the remaining cases of breast cancer, and it can originate in the ducts or lobules and be sensitive to estrogen. As tamoxifen and raloxifene block estrogen receptors, the efficacy of those medications to prevent this minority disease is the focus of the USPSTF recommendation.

This systematic review provides generalized relative risk (RR) estimates. When examined more closely, it found the use of tamoxifen results in a greater reduction in the RR of invasive breast cancer when compared to raloxifene. The review also found tamoxifen results in a lower risk of invasive breast cancer compared to placebo. In addition, there was a statistically significant reduction in risk for raloxifene versus placebo.

While this is good news, it must be balanced against the potential for harm. Across the studies comparing raloxifene to tamoxifen, there were 5 fewer incidences of invasive breast cancer in the tamoxifen group than the raloxifene group, but there were 4 more thromboembolic events among the tamoxifen patients compared to the raloxifene ones. Additionally, there were 5 more cases of endometrial cancer and 15 more cataract formations in the tamoxifen group compared to the raloxifene group. The rates of primary DVT also increased with the use of either medication.

This recommendation is deficient in a number of factors, including proper drug dose and length of treatment time, as well as the point in a woman’s lifespan to initiate the medication. Because the study was unable to determine the medications’ benefits by subgroup, it is hard to determine whether the recommendation is pertinent to patients of African American or Hispanic descent, or more applicable to those who are premenopausal compared to those who are postmenopausal.

So, what does “high risk” mean? Many experts put patients with a BCRA score of >1.66% or a history of high-risk breast lesions in the high-risk category, but do physicians or their patients consider this degree of risk “high?” Though most patients probably do not consider driving a high-risk activity, they certainly wear seatbelts on every trip. Yet, the risk of being in a serious motor vehicle accident (MVA) is far less than 1.66% on any given day. Nevertheless, most drivers accept MVAs as part of driving and believe they have some control over their MVA risk.

At a minimum, invasive breast cancer is genetically predicted; thus, it is out of a patient’s control. Would a woman want to gain some degree of control over her risk of developing the disease, even if her actual risk is very low and the medication prevented less than 1% of cases of this type of cancer over 5 years? If the medication was not known to cause any adverse events, then many women might say yes. However, the risk of thromboembolic events and uterine cancer make this balance difficult to judge.

Since understanding a patient’s risk of invasive breast cancer risk is critical, the regular use of the BCRA tool is recommended. Unfortunately, it only predicts risk and does not compare the benefit of a medication to the risk of harm.

One patient-centered approach to this recommendation is to calculate the BCRA scores of all patients while reminding them that the risk assessment tool only applies to the less common invasive breast cancer, not the far more common DCIS. Next, have an informed consent discussion with patients about the medications’ benefits in preventing estrogen-sensitive disease and risks for DVT, cataracts, and endometrial and uterine cancer. While there is no clinical data to support breast self-examination (BSE), encouraging BSE may offer patients a degree of the control, autonomy, and security they seek, especially in the postmenopausal period.

References

1. Moyer VA. Medications for Risk Reduction of Primary Breast Cancer in Women: US Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2013;159(10):698-708. http://annals.org/article.aspx?articleid=1770699.

About the Author

Frank J. Domino, MD, is Professor and Pre-Doctoral Education Director for the Department of Family Medicine and Community Health at the University of Massachusetts Medical School in Worcester, MA. Domino is Editor-in-Chief of the 5-Minute Clinical Consult series (Lippincott Williams & Wilkins). Additionally, he is Co-Author and Editor of the Epocrates LAB database, and author and editor to the MedPearls smartphone app. He presents nationally for the American Academy of Family Medicine and serves as the Family Physician Representative to the Harvard Medical School’s Continuing Education Committee.