Guideline Gap: Are We Failing High-Risk Women in Breast Cancer Prevention?

By Felicia L. Pasadyn, MA

Peer Reviewed 

Research demonstrates that less than 10% of physicians currently follow the United States Preventive Services Task Force (USPSTF) “B” recommendations for breast cancer prevention in nonpregnant adults, which recommend tamoxifen, raloxifene, or anastrozole for women with a 5-year breast cancer risk of 3% or greater.¹ Does this shockingly low adherence to a national health recommendation necessitate a USPSTF guideline change or reveal a massive problem?

A USPSTF Grade “B” recommendation means that a preventive intervention is recommended based on at least fair evidence that the service improves health outcomes and that the benefits outweigh the harms.² USPSTF Grade “B” recommendations range from offering statins for primary prevention of cardiovascular disease in adults aged 40-75, to screening for chlamydia and gonorrhea in sexually active women under 25, to administering PHQ-9 and AUDIT questionnaires for depression and alcohol misuse in adults. A key non-pharmacologic USPSTF Grade “B” recommendation for breast cancer prevention is mammography every two years for women aged 40-74. Research shows that about 80% of physicians consistently implement this USPSTF recommendation, with some doctors recommending yearly mammograms for women in certain age groups or risk categories.^3,4,5 When clinicians enforce these important interventions, they can prevent disease and mortality and improve quality of life. Are most American physicians dropping the ball on the other breast cancer prevention recommendation?

To assess a woman’s five-year risk of breast cancer, clinicians often use the Breast Cancer Risk Assessment Tool (BCRAT), also known as the Gail Model, the most widely used model in clinical practice. The Gail Model incorporates eight items, including reproductive history, age, race, and family history of breast cancer in first-degree relatives. It takes only about five minutes to complete and provides a reliable estimate of 5-year and lifetime breast cancer risk, helping guide conversations about chemoprevention.

Several studies have demonstrated a significant reduction in the incidence of invasive breast cancer when women with a five-year breast cancer risk of ?3% are prescribed tamoxifen, raloxifene, or anastrozole; thus, the USPSTF recommends the use of these medications as chemoprevention. Tamoxifen and raloxifene are selective estrogen receptor modulators (SERMs) that reduce breast cancer risk through their actions on estrogen receptors (ERs). In breast tissue, tamoxifen and raloxifene act primarily as estrogen antagonists, as they bind to ERs, preventing estrogen from binding and activating the receptors. This inhibition reduces the growth and proliferation of ER-positive breast cancer cells. Additionally, both tamoxifen and raloxifene have been shown to inhibit the proliferation of ER-negative breast cancer cells through non-ER-mediated mechanisms, such as the inhibition of glutamine uptake, which leads to oxidative stress and apoptosis.⁶ Anastrozole, a third-generation aromatase inhibitor, exerts its effects by selectively inhibiting aromatase, the enzyme responsible for the conversion of androgens to estrogens in peripheral tissues. This inhibition leads to a significant reduction in circulating estrogen levels, thereby hampering the growth of hormone receptor-positive breast cancers in postmenopausal women.

The 2013 NSABP P-1 trial demonstrated that tamoxifen reduces the risk of invasive breast cancer by 49% in women at increased risk (relative risk 0.51; 95% CI 0.39-0.66) across various age categories.⁷ Raloxifene was evaluated in the 2019 STAR trial and showed a 38% reduction in breast cancer risk compared to placebo, with a relative risk of 0.62 (95% CI 0.54-0.71).⁸ The 1999 MORE trial also supported these findings, indicating a 76% reduction in invasive breast cancer risk (RR 0.24; 95% CI 0.13-0.44).⁹ For anastrozole, the 2020 IBIS-II trial reported a 53% reduction in breast cancer incidence among postmenopausal women at high risk, with a hazard ratio of 0.47 (95% CI 0.32-0.68); this trial also demonstrated a sustained reduction in breast cancer risk beyond the initial five years of follow-up.¹⁰ These data collectively reinforce the significant risk reduction conferred by taking tamoxifen, raloxifene, or anastrozole to prevent breast cancer in high-risk populations.

Multiple studies, however, have indicated poor adherence to breast cancer chemoprevention guidelines. A study by Pinsky and colleagues reported the low use of raloxifene and tamoxifen, with only 6.6% of eligible women using raloxifene and 0.85% using tamoxifen.¹ These rates reflect patient adherence and uptake, not prescribing behavior alone, and suggest that barriers exist both at the level of physician prescribing and patient acceptance. The rarity of chemoprophylaxis use implies that there are barriers to guideline enforcement.

These drugs are not without risks. The USPSTF updated their systematic review in 2019, corroborating that all three medications were associated with a lower incidence of invasive breast cancer compared to placebo, although recognizing each medication also had distinct adverse effect profiles. Tamoxifen and raloxifene were associated with increased risks of thromboembolic events, with tamoxifen also increasing the risk of endometrial cancer and cataracts; anastrozole was associated with musculoskeletal symptoms and a higher incidence of fractures.⁸

The side effect profile is one reason for such low physician adherence to the USPSTF guidelines. Applying accurate breast cancer risk models in clinical practice can be difficult, and there is a lack of easily accessible and user-friendly prediction tools for estimating risk/benefit profiles of the medications per patient.¹¹ Furthermore, many physicians are not adequately trained in risk- assessment models and chemoprevention options, which precludes them from prescribing these medications with confidence.¹² In addition, the need for continued adherence to the medication regimen for five years and the fear of potential side effects contribute to early discontinuation among patients.¹² Thus, beyond side effects, barriers such as uncertain risk assessment and medication adherence also hinder the uptake of these preventive measures.

On one hand, addressing these barriers through robust breast cancer risk modeling, risk-benefit analysis discussions, and better education could potentially improve adherence to these guidelines. On the other hand, maybe the USPSTF guidelines on this subject matter should not always be enforced without question. The American Society of Clinical Oncology emphasizes the importance of shared decision-making in this context.¹³ Moving forward, the decision to use these medications should be individualized. For women with a high risk of breast cancer and low risk of adverse effects, the benefits of chemoprevention may outweigh the risks. Conversely, for women with significant risk factors for adverse effects, the shared decision-making may result in a decision to refrain from chemoprevention.

The risks and benefits of following the USPSTF B recommendations for breast cancer prevention should be carefully weighed on an individual basis but not ignored. Especially given the side effect profile of the three suggested preventive medications, the decision should involve a thorough discussion between the patient and provider, considering the patient’s risk factors, comorbidities, and preferences.

Felicia L. Pasadyn, MA, is a Class of 2027 medical student at NYU Grossman School of Medicine

Reviewed Michael Tanner, MD, Executive Editor, Clinical Correlations

Image courtesy of Wikimedia Commons, source: https://commons.wikimedia.org/w/index.php?search=mammography&title=Special%3AMediaSearch&type=image

References  

1. Pinsky PF, Miller E, Heckman-Stoddard B, Minasian L. Use of raloxifene and tamoxifen by breast cancer risk level in a Medicare-eligible cohort. Am J Obstet Gynecol. 2018;218(6):606.e1–606.e9. https://pubmed.ncbi.nlm.nih.gov/29630889/
2. Harris RP, Helfand M, Woolf SH, et al. Current methods of the U.S. Preventive Services Task Force: A review of the process. Am J Prev Med. 2020;58(3):316–331.
3. Berkowitz Z, Zhang X, Richards TB, et al. Multilevel small area estimation for county-level prevalence of mammography use in the United States using 2018 data. J Womens Health (Larchmt). 2023;32(2):216–223. https://pubmed.ncbi.nlm.nih.gov/36301186/
4. Lee J, Gordon PB, Whitman GJ. “Do unto others as you would have them do unto you”: Breast imagers’ perspectives regarding screening mammography for others and for themselves–do they practice what they preach? AJR Am J Roentgenol. 2015;204(6):1336-1344.
5. Smith RA, Andrews KS, Brooks D, et al. Cancer screening in the United States, 2019: A review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin. 2019;69(3):184-210.
6. Todorova VK, Kaufmann Y, Luo S, Klimberg VS. Tamoxifen and raloxifene suppress the proliferation of estrogen receptor-negative cells through inhibition of glutamine uptake. Cancer Chemother Pharmacol. 2011;67(2):285-291.
7. Pagani O, Gelber S, Colleoni M, Price KN, Simoncini E. Impact of SERM adherence on treatment effect: International Breast Cancer Study Group Trials 13-93 and 14-93. Breast Cancer Res Treat. 2013;142(2):455-459.
8. Nelson HD, Fu R, Zakher B, Pappas M, McDonagh M. 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. 2019;322(9):868-886. https://pubmed.ncbi.nlm.nih.gov/31479143/
9. Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. 1999;281(23):2189-2197.
10. Cuzick J, Sestak I, Forbes JF, et al; IBIS-II Investigators. Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial. 2020;395(10218):117-122.
11. Noonan S, Pasa A, Fontana V, et al. A survey among breast cancer specialists on the low uptake of therapeutic prevention with tamoxifen or raloxifene. Cancer Prev Res (Phila). 2018;11(1):38-43.
12. Bambhroliya A, Chavez-MacGregor M, Brewster AM. Barriers to the use of breast cancer risk reduction therapies. J Natl Compr Canc Netw. 2015;13(7):927-935. https://pubmed.ncbi.nlm.nih.gov/26150584/
13. Visvanathan K, Fabian CJ, Bantug E, et al. Use of endocrine therapy for breast cancer risk reduction: ASCO clinical practice guideline update. J Clin Oncol. 2019;37(33):3152-3165.

Share: Twitter | Facebook | Email