26th September 2019. Dr Chee L Khoo
We put patients at high risk of cardiovascular events on statins as primary prevention. We sometimes put patients with high risk of cerebrovascular disease on aspirin to prevent strokes. What about patients who are at high risk of breast cancer? Now, these are not patients who already had breast cancer. We are talking about patients who have not had cancer but are at higher than average risk of developing breast cancer. Can we put them on something to prevent or reduce the disease? Is there evidence to support these medications to reduce the risk of breast cancer?
Breast cancer is the most common cancer diagnosed in Australian women and will account for approximately 29 per cent of all new cancers in Australian women in 2019. In 2019, it is estimated that 19,371 women and 164 men will be diagnosed with breast cancer (1). The risk of being diagnosed with breast cancer increases with age. Approximately 79 per cent of new cases of breast cancer are in women over the age of 50. The average age of first diagnosis of breast cancer in women is 61. Approximately 5-10 per cent of breast cancers are due to a strong family history or genetic mutation, such as BRCA1 or BRCA2.
The US Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific preventive care services for patients without obvious related signs or symptoms. It recently recommended that clinicians consider offering risk reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women who are at increased risk for breast cancer and at low risk for adverse medication effects (B recommendation) (2). This recommendation applies to asymptomatic women >35 years old including women with previous benign breast lesions on biopsy (such as atypical ductal or lobular hyperplasia and lobular carcinoma in situ). This recommendation does not apply to women who have a current or previous diagnosis of breast cancer or ductal carcinoma in situ (DCIS).
In the US, numerous risk assessment tools have been used to estimate a woman’s risk of developing breast cancer over the subsequent 5 years. There is no single cut-off for defining increased risk for all women. Women at greater risk, such as those with at least a 3% risk for breast cancer in the next 5 years, are likely to derive more benefit than harm from risk-reducing medications (3) and should be offered these medications if their risk of harms is low.
Some examples of combinations of multiple risk factors in women at increased risk include:
- >65years with1 first-degree relative with breast cancer
- >45 years with more than 1 first-degree relative with breast cancer or 1 first-degree relative who developed breast cancer before age 50years
- >40years with a first-degree relative with bilateral breast cancer
- presence of atypical ductal or lobular hyperplasia or lobular carcinoma in situ on a prior biopsy
Women with documented BRCA1 and 2 and women with a history of chest radiation therapy (such as for treatment of childhood or adolescent Hodgkin or non-Hodgkin lymphoma) are at especially high risk for breast cancer.
Drugs to reduce the risk of breast cancer
We have evidence that tamoxifen reduced the incidence of invasive breast cancer by 7 events per 1000 women over 5 years. We also have evidence that raloxifene reduced incidence by 9 events per 1000 women over 5 years (4,5). The Study of Tamoxifen and Raloxifene (STAR) trial, which compared tamoxifen with raloxifene, found that tamoxifen reduced breast cancer risk more than raloxifene after long-term follow-up (4). Aromatase inhibitors were found to reduce the incidence of invasive breast cancer by 16 events per 1000 women over 5 years.
Tamoxifen, raloxifene, and aromatase inhibitors all reduce primary breast cancer risk in postmenopausal women. Use of raloxifene and aromatase inhibitors is indicated only in postmenopausal women; only tamoxifen is indicated for risk-reduction of primary breast cancer in premenopausal women.
These absolute benefits are likely even higher for women with a predicted breast cancer risk of 3%or greater.
What about the harms?
There is no free lunch. The use of tamoxifen and raloxifene is associated with increased risk for venous thrombo-embolism and vasomotor symptoms. Tamoxifen also increases the risk for endometrial cancer and cataracts. These risks are increased in older women although women who have had a hysterectomy are not at risk for endometrial cancer. Harms of aromatase inhibitors include vasomotor symptoms, gastrointestinal symptoms, and musculoskeletal pain.
So, who needs what?
The USPSTF does not endorse any particular risk prediction tool. However, the NCI Breast Cancer Risk Assessment Tool (6) and the Breast Cancer Surveillance Consortium Risk Calculator (7) are based on models tested in US populations and are publicly available for clinicians and patients to use as part of the process of shared, informed decision-making about taking risk-reducing medications for breast cancer.
In Australia, we have the Familial Risk Assessment – Breast and Ovarian Cancer (FRA-BOC) on-line tool (8). It is designed for use by health professionals such as general practitioners and nurses. It assists health professionals to reassure the majority of women who are at population risk, based on their family history. It also identifies women who should be referred to a family cancer clinic for further assessment and advice.
- US Preventive Services Task Force. Medication Use to Reduce Risk of Breast Cancer US Preventive Services Task Force Recommendation Statement. JAMA. 2019;322(9):857-867. doi:10.1001/jama.2019.11885
- Freedman AN, Yu B, Gail MH, et al. Benefit/risk assessment for breast cancer chemoprevention with raloxifene or tamoxifen for women age 50 years or older. J Clin Oncol. 2011; 29(17):2327-2333.doi:10.1200/JCO.2010.33.0258
- Nelson HD, Fu R, Zakher B, et al. Medication Use for the Risk Reduction of Primary Breast Cancer in Women: A Systematic Review for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2019.
- Nelson HD, Fu R, Zakher B, et al. Medication use for the risk reduction of primary breast cancer in women: updated evidence report and systematic review for the US Preventive Services Task Force [published September 3, 2019]. JAMA. doi:10.1001/jama.2019.5780
- National Cancer Institute (NCI). The Breast Cancer Risk Assessment Tool. NCI website. https://bcrisktool.cancer.gov/. 2017.
- Breast Cancer Surveillance Consortium (BCSC). Breast Cancer Surveillance Consortium Risk Calculator. BCSC website. https://tools.bcsc-scc. org/bc5yearrisk/calculator.htm. 2015.