The Burdens and Uncertainties of Doing What One Should Do Free

There is a long saga of underuse of both selective estrogen receptor modulators (SERM) and aromatase inhibitors (AI) to reduce the risk of breast cancer in women who are at increased risk. (1) In the NSABP STAR trial (2), only one half of the women who were screened were eligible for the trial, and of these women only 20% enrolled. This may indicate that the women who come for risk evaluation widely overestimate their risk of developing breast cancer in the next 5 years. It is also evident that all individuals, likely including women whose risk for breast cancer is increased, discount future events. That is, a breast cancer that will occur either in 5 years or in one's lifetime is not perceived as threatening. Many women come to seek breast cancer risk assessment and risk reduction recommendations at the time of the diagnosis of breast cancer in a relative.

In this issue of the journal, Trividi and her colleagues (3) review the uptake of chemopreventive interventions by women with either atypical hyperplasia of the breast of lobular carcinoma in situ at one large, metropolitan cancer clinic. The question they address is an important one given that in studies with long-term follow-up, the relative risk for developing future breast cancer = 4 in women with atypical hyperplasia. Among women with lobular carcinoma in situ (LCIS or LIN), the annual risk of developing invasive malignancy exceeds 1%. Longitudinal cohort studies describe the absolute risk for invasive breast cancer 25 years after a biopsy showing atypical hyperplasia equal to 30% (4).

Despite these high risks for developing invasive breast cancer, the fear of the risks associated with SERMs such as tamoxifen, including uterine carcinoma and thromboembolism, is widely overestimated and greatly reduces the uptake of either SERMs or AIs for risk reduction. These side effects occur with increased frequency, however, only in postmenopausal women and not in premenopausal women. All women younger than 50 years of age actually derive net benefit from tamoxifen (i.e., reduction in breast cancer events minus side effect events, including thromboses and endometrial cancer), and women 50 years and older derive net benefit when the 5-year risk of breast cancer exceeds 3% or if they do not have a uterus (Fig. 1). This is also true for all women with either atypical hyperplasia or LCIS. In addition, in the NSABP STAR trial, no significant differences existed between the tamoxifen and raloxifene groups in patient-reported outcomes for physical health, mental health, and depression (5).

The reasons for underuse of SERMs and AIs for breast cancer risk reduction are varied and multifactorial. As Trividi and her colleagues recognize, there is a desire for many women to retain their menopausal hormone replacement therapy (which precludes use of SERMs or AIs) even though the use of postmenopausal HRT decreased by approximately 40% nationwide after the results of the Women's Health Initiative were published (6)

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. 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. It is clear that women fear breast cancer, but it appears that they fear death and not simply morbidity; if they valued avoided morbidity, the uptake of risk-reducing agents would be greater. It is also possible that women perceive that the use of SERMs of AIs to reduce risk simply trades the morbidity of breast cancer with side effects from drug therapy.

Another factor contributing to poor utilization of these agents is that primary care providers either do not know or do not understand quantitative risk assessment, nor do they understand the agents that are used to reduce risk (tamoxifen, raloxifene, AIs). In addition, the public appears to desire absolute risk reduction (100% reduction in risk, or the certainty of breast cancer prevention) with no side effects. It is quite revealing when exploring women's perception of risk that even among women with predisposing genetic mutations, such as BRCA1 or BRCA2, only half elect bilateral prophylactic mastectomy, and an unknown number, probably much less than half, elect to take chemoprevention drugs when they decline prophylactic mastectomy. Some experts have suggested that a woman's perception of her risk would be strengthened in the presence of a histologic abnormality that confirmed an increase in her risk, but the data presented by Trividi and colleagues do not substantiate this claim.

When a woman with an abnormal mammogram has a biopsy to rule out invasive breast cancer and the biopsy reveals atypia or carcinoma in situ, there is often inappropriate relief expressed by the patient's physician and a misunderstanding by the patient of the implications of carrying the benign diagnosis. It is also not known to what extent possible lack of insurance coverage for oral risk reduction medications may contribute to a woman's reluctance to initiate therapy, but there is certainly resistance by patients toward even small co-payments for medications to treat many conditions. These out-of-pocket expenses may contribute to the poor uptake of oral chemoprevention drugs. It is also likely that lack of reimbursement for provider services to counsel women about using these agents may be beyond current payment models to reimburse adequately for the extended clinic visits and practitioners' time that are required.

The authors are correct in indicating that improving communication about breast cancer risk and chemoprevention will allow clinicians to facilitate informed decision-making about risk reduction behavior and therapy. As they indicate, their study was done at a metropolitan, academic medical center and may not be generalizable to other populations. Nevertheless, a study conducted using electronic health records (EHR) in a rural teaching hospital also showed very low uptake of chemoprevention interventions by any of the physicians in a large, integrated health system serving 3.5 million people in rural, central Pennsylvania (7). Only 2% of more than 4,100 women eligible to use tamoxifen or raloxifene for breast cancer risk reduction were using either tamoxifen or raloxifene. Trividi and colleagues appropriately recognize that there are limitations in the use of the EHR to extract data, such as that looked for in this publication. The EHR rarely documents perceptions of risk and seldom includes a lengthy recounting of the discussion regarding risks and benefits when these agents are presented for use. In addition, textual data in the EHR may not be searchable in a research context. Nevertheless, these data are both useful and informative.

It is somewhat paradoxical that the authors found that younger women were less likely to initiate chemoprevention interventions given that the diagnosis of breast cancer in a woman's mother or sister is a strong initiating factor for the uptake of chemoprevention interventions. It is not clear whether misperceptions about diet and exercise and overestimation of their contribution to the risk of breast cancer may detract from the uptake of chemoprevention interventions. Social, print, and electronic media have a heavy emphasis on lifestyle factors in modifying breast cancer risk even though their contribution to risk is relatively small.

The authors report that most of the women seeking evaluation and counsel about atypical hyperplasia and LCIS were seen by a medical oncologist. This group of practitioners is probably not the ideal provider population to bring chemopreventive interventions to women who have never had a diagnosis of an invasive malignancy. Unfortunately, however, the published chemoprevention risk reduction trials in breast cancer were largely conducted in medical oncology practices, and the results (with the exception of the NSABP STAR trial) were published in journals not usually read by primary care physicians. This makes it unlikely that primary care physicians are conversant in the design and conduct of the studies or the risks and benefits of these agents. That fact withstanding, The American Society of Clinical Oncology (8), the United States Preventive Services Task Force (9), and the National Comprehensive Cancer Network Breast Cancer Risk Reduction panel (Category 1 evidence, https://www.nccn.org/professionals/physician_gls/pdf/breast_risk.pdf) have stated that in women at increased risk of breast cancer age ≥35 years, SERMs or AIs should be discussed as an option to reduce the risk of breast cancer.

Clearly, there are challenges to be addressed in the field of breast cancer risk perception and risk reduction. Education and income are known to exert large influences upon risk perception and a woman's willingness to initiate risk reduction with chemoprevention. For example, in the NSABP STAR trial, more than one fourth of the subjects enrolled in the trial reported having a postgraduate degree. An unexplored resource to promote wider acceptance of SERMs and AIs may lie in the use of social media both to identify subjects at risk, to identify them for their primary care physicians, to educate both physicians and subjects about the benefits and safety of chemoprevention agents, and to encourage the use of these agents in reducing the risk of breast cancer (9).

As Trividi and colleagues note, 15% of women between the ages of 35 and 75 years in the United States are considered at high risk for breast cancer. This makes this population of women an important public health target, particularly as we are attempting to reduce the cost of health care. Opponents of oral chemoprevention interventions would argue that the cost per year of life saved or the cost per breast cancer avoided is uneconomical, but this claim must be weighed against the fact that we currently misspend approximately $1 trillion annually in our health care system for no demonstrable benefit (10). The diversion of a small portion of these misspent funds could substantially reduce morbidity from breast cancer.

No potential conflicts of interest were disclosed.