Despite strong evidence that it is efficacious, chemoprevention has been underused in eligible women. Reasons offered not to adopt and initiate strategies to reduce the risk of breast cancer include the fear of adverse effects, medication costs, lack of reasonably accurate and feasible methods for assessing an individual's personal risk, and lack of established risk thresholds that maximize benefit and minimize harms. The article by Macdonald and colleagues remind us that the problem of lack of uptake of risk-reducing medications for breast cancer remains a worldwide clinical challenge despite endorsements from national and international organizations that recommend the use of risk-reducing medications for breast cancer with level I evidence. Several strategies are suggested to improve uptake and utilization of safe and effective chemoprevention medications with high therapeutic indices.
See related article by Macdonald et al., p. 131
Multiple studies have shown that several hormonally targeted agents reduce tumor incidence in women who are at increased risk for breast cancer. In addition, we have several strategies to identify women at increased risk: quantitative risk models (1, 2), increased mammographic density, circulating estrogen levels, and the presence of high-risk benign breast disease, such as atypical hyperplasia and lobular carcinoma in situ (3). Some investigators have suggested that absolute risk data should be used in place of models to describe breast cancer risk in this population (4). Guidelines for high-risk women could be updated, for example, to include women with atypical hyperplasia, and MRI screening could be considered an option for them, to be performed in addition to mammography.
The selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, and the aromatase inhibitor, anastrozole, have been studied prospectively in multiple randomized controlled trials that examined benefits, life-threatening side effects, and quality-of-life outcomes. Estimates of the population benefit of using SERMs for breast cancer risk reduction have been published (5–7), and we have estimates of the cost per year of life saved. Yet, despite the fact that the number of women needed to treat to prevent a case of breast cancer is acceptable with both SERMs and aromatase inhibitors, no drug has been able to tip the clinical utility scale to broad usage within the high-risk population for breast cancer risk reduction.
Despite strong evidence that it is efficacious, chemoprevention has been underused in eligible women (8). Reasons offered not to adopt and initiate strategies to reduce the risk of breast cancer include the fear of adverse effects, medication costs, lack of reasonably accurate and feasible methods for assessing an individual's personal risk, and lack of established risk thresholds that maximize benefit and minimize harms.
The article by Macdonald and colleagues remind us that the problem of lack of uptake of risk-reducing medications for breast cancer remains a worldwide clinical challenge despite endorsements from national and international organizations that recommend the use of risk-reducing medications for breast cancer with level I evidence. Tamoxifen became government-subsidized for primary breast cancer prevention in Australia in 2016, while national guidelines in Australia have recommended that physicians consider tamoxifen for women with a lifetime risk of breast cancer at least 1.5 times the population risk (≥16%) since 2010.
The NCI estimated almost a decade ago that 2.4 million women with specific age and risk characteristics would benefit from using tamoxifen for reducing risk of breast cancer (9). Nevertheless, some observers have said that when a healthy woman takes an oral medication every day, it serves as a reminder of future risk, and for some women, pill taking may indicate a state of unwellness (10). Many have criticized the published breast cancer risk reduction trials for not showing a mortality reduction, often not recognizing that none of the trials was designed to show such a reduction, and often minimizing the enormous value of avoiding the morbidity associated with a diagnosis of breast cancer. Women fear breast cancer, but it appears that they fear death and not simply morbidity. If they valued avoiding morbidity from breast cancer, the uptake of risk-reducing agents would be greater. It is also possible that women perceive that the use of SERMs or aromatase inhibitors to reduce risk simply trades the morbidity of breast cancer with side effects from drug therapy. These unfounded concerns overlook the data from the STAR trial comparing tamoxifen and raloxifene, where there were no significant differences between the two treatment groups in patient-reported outcomes for physical health, mental health, and depression (11–13). The tamoxifen group reported better sexual functioning.
This Australian study is not the first to identify underuse of these medications. A 2002–2004 survey of 350 primary care physicians in the United States, who were members of the American Medical Association, found that only 27% had prescribed tamoxifen for breast cancer risk reduction in the previous year (14). An important predictor of a physician providing a tamoxifen prescription for chemoprevention was the perception that the drug's benefit in preventing breast cancer outweighed the drug's risks: physicians who were unsure of this balance were much less likely to recommend or prescribe tamoxifen. Other surveys also showed that a minority of primary care physicians were prescribing tamoxifen or raloxifene for breast cancer prevention (15). A study in California found that the most frequent barriers to counseling reported by clinicians were “not enough time” (40%) and “insufficiently informed about risk reduction options” (19%). Concerns about serious side effects, including endometrial cancer, also were important barriers, and a perceived weak or unfavorable risk–benefit ratio for an individual patient made taking a SERM for chemoprevention unacceptable.
Absolute Benefit of Risk Reduction
Tamoxifen will prevent 20 invasive and 20 noninvasive breast cancers in each 1,000 women at a 5-year risk of 4% versus causing 2.25 endometrial cancers (in women with an intact uterus at study entry) and 3.3 thromboembolic events in the same group of women over 7 years (16). Similarly, raloxifene will prevent 15 invasive and 16 noninvasive breast cancers over 7 years in 1,000 women at an elevated 5-year risk (4%) versus causing about 2.5 thromboembolic events and no endometrial cancers in the same group over 7 years. For these major effects, tamoxifen causes 40 beneficial versus about five adverse effects (benefit/risk ratio of ∼7:1) and raloxifene causes 31 beneficial versus 2.5 adverse effects (benefit/risk ratio of ∼13:1) over 7 years. These ratios indicate a rather extraordinary net gain for women at a 4% 5-year risk of breast cancer and would improve substantially for women at a 4% or higher risk, who number hundreds of thousands in the United States, Europe, and Australia. SERMs are not the only agents that reduce the risk of breast cancer. The IBIS-II trial demonstrated the efficacy and safety of the aromatase inhibitor, anastrozole, for reduction of breast cancer risk in postmenopausal women who are at high risk of the disease (17).
This Australian study addresses important aspects of global underuse of risk-reducing agents. The study is unique in assessing the views of both women and their clinicians regarding use of risk-reducing medications. The authors point out that clinicians' knowledge and resources are key domains that could be targeted to enhance uptake of chemoprevention medications. The lack of knowledge about the risks and benefits identified in this study occurred despite international recommendations for the use of risk-reducing medications by high-risk women. Importantly, the study found that family practitioners identified barriers and facilitators for use of risk-reducing medications, including a perceived difficulty in selecting suitable patients, the need for better tools to identify suitable patients, and inadequate confidence in their ability to perform quantitative breast cancer risk assessments. Given that half of all women older than 60 years of age can be regarded as being at increased risk on the basis of age alone (5), the Australian authors appropriately recognized that restructuring interventions and providing additional training could change the behavior of both patients and their clinicians.
A significant strength of this study is its use of the Theoretical Domains Framework as the conceptual basis for the questionnaire. Survey questions were developed by experts in sociology, qualitative research, breast surgery, and primary care, and the survey was piloted in face-to-face interviews. These features contribute to the study's generalizability as well.
It is instructive that just half of the women, one-third of the family physicians, and only 3% of breast surgeons were not aware of chemoprevention suggesting that lack of knowledge alone may not explain the widespread underuse of pharmacologic agents to reduce the risk of breast cancer. The study is useful because in that it identified both facilitators and barriers for both patients and clinicians regarding the uptake of risk-reducing medications. Fear of side effects remains an important barrier among both patients and their clinicians. It is reassuring that despite a lack of awareness and confidence in the use of risk-reducing medications, 75% of family practitioners in the Australian study viewed initial discussions of these medications as part of their role. While they did not feel that writing initial prescriptions was part of their role, the study indicated that they agreed with providing ongoing prescription renewals.
Several additional reasons have been put forth to explain why patients may not be willing to adopt a SERM for breast cancer risk reduction (3). Patients (and perhaps their physicians) are confused by the concept of probabilistic risk. Hormone replacement therapy is still widely used by postmenopausal women, but it is contraindicated with concurrent SERM therapy. Patients erroneously perceive the risks of SERM therapy to be greater than its benefits, and they perceive the risks of therapy-related side effects to be greater than their risk of breast cancer. This problem is confounded by the fact that they (and perhaps their physicians) are confused by the concept of probabilistic risk. Finally, they fear endometrial cancer out of proportion to its true tamoxifen-related risk and do not understand that there is no increased risk of uterine malignancy associated with raloxifene.
The authors are correct in stating that they have identified a significant knowledge resource for both women and clinicians in Australia with this study. They conclude correctly that the application of a behavioral change model using both an individual- and a system-based approach with education, training, and incentives, along with environmental restructuring, could increase the uptake of risk-reducing medications for breast cancer.
There is a need for better preventive medicine courses in medical schools, and for social-based incentives, such as decreased insurance rates and tax benefits for patients who initiate risk-reducing medications for breast cancer. Information presented at the time of screening mammography can, perhaps, improve uptake of these medications. One possible use of negative incentives would be to target providers with litigation for failure to use risk-reducing medications. The need for the use of social media as an information source also needs to be explored further. The development of a serologic marker to be used as positive feedback incentives for the use of risk-reducing medications would be welcomed, although none is in sight.
No disclosures were reported.