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September/October 2013
Chemoprevention Reduces Breast Cancer RiskBy Burcu Ozdemir, MD, and Lisa C. Hutchison, PharmD, MPH Strong scientific evidence exists that many breast cancers could be prevented. For women assessed as having a high risk of developing the disease, chemoprevention offers an underutilized option. Breast cancer is the most common type of cancer in women after nonmelanoma skin cancers, causing significant morbidity and mortality all over the world. In fact, it is estimated that roughly 40,000 women will die from this disease in 2013.1 The average woman in the United States has about a 12% to 13% risk of developing breast cancer in her lifetime. This year 230,000 women will be diagnosed with invasive breast cancer, and about 55,000 will be diagnosed with ductal carcinoma in situ (DCIS). The most significant risks factors for breast cancer are age and family history.1 Although screening for early detection is practiced routinely, providers rarely offer chemoprevention for breast cancer. There is reluctance among clinicians to discuss and implement chemoprevention or prescribe drugs for breast cancer prevention. The US Preventive Services Task Force recommends that high-risk women between the ages of 40 and 70 be assessed for their likelihood of developing the disease and should be offered chemoprevention if they are at low risk of thromboembolic disease and endometrial cancer.2 However, it is important to note that the task force suggests that women aged 60 and older are at high risk of developing complications from chemoprevention, so physicians should use precautions and tailor treatment to each patient’s case. Assessing Risk The risk assessment tool consists of seven questions (see sidebar on page ••) and can be found as an interactive tool at www.cancer.gov/bcrisktool. Computation of the risk is complicated; however, the easily accessible Web tool will calculate the risk based on the answers to a few questions. A five-year risk of developing breast cancer greater than 1.66% is considered sufficient to start a discussion for prevention, as the risk at this level exceeds the risk of life-threatening side effects from chemopreventive medication. Additional risks for breast cancer, such as high estrogen levels, a past history of chest irradiation, dense breasts on mammograms, postmenopausal combination hormone replacement use, and gene mutations such as those on BRCA1 and BRCA2,1 which are not included in the assessment tool, may be considered in patient discussions to determine the advisability of chemoprevention. Two main categories of preventive medications are available—selective estrogen receptor modulators (SERMs) and aromatase inhibitors—once it has been determined that a woman has a high risk of developing breast cancer. Currently two medications are approved by the FDA for the primary prevention of breast cancer: tamoxifen and raloxifene. The duration of therapy recommended for primary breast cancer prevention is five years for both medications. However, raloxifene could possibly be used for a longer period of time because of less serious side effects. Lasofoxifene is another recently developed SERM proven to reduce breast cancer risk. However, it does not have FDA indication for primary breast cancer prevention and currently is not available in the United States. Exemestane is an aromatase inhibitor also proven to reduce breast cancer risk. The American Society of Clinical Oncology recommends it as one of the options for primary breast cancer prevention in high-risk women. SERMs Tamoxifen The landmark NSABP included 13,388 women who did not have breast cancer but were at high risk of developing the disease. They were randomized to receive either a placebo or 20 mg of tamoxifen daily for five years. The study was double blinded and accepted women from the ages of 35 to 75. At the end of the five-year study, the tamoxifen group reduced their breast cancer risk by 49%. The chance of developing estrogen-receptor–positive (ER+) cancer was reduced by 69%, but there was no reduction in estrogen-receptor–negative (ER-) cancers. Considering that 70% of all breast cancers are ER+, this was an impressive result. Tamoxifen also reduced the risk of noninvasive cancer by 50%. However, life-threatening side effects of tamoxifen included an increased risk of endometrial cancer and increased thromboembolic events. Both risks were significant mainly for women over the age of 50 but not for those aged 35 to 50. Women in the tamoxifen group were 2.53 times more likely to develop endometrial cancer. For randomly selected women, this risk ranged from 1.3 to 4.9 times higher. But just as women are different, their risks of developing cancer differ. For example, women without a uterus will not experience an increased risk of endometrial cancer, and older women will have a much higher risk than younger women. In the NSABP, thromboembolic events occurred in 22 patients taking placebo and 35 patients taking tamoxifen, representing a 1.6 times increased risk. Compared with the placebo group, pulmonary embolus was observed three times more often in the tamoxifen group. Other common side effects noted in the study were hot flashes, night sweats, cold sweats, vaginal discharge, and increased incidence of cataracts. Another possible benefit of tamoxifen was a decreased incidence of fractures in the treatment group, but this did not reach statistical significance in this study.4 The FDA has approved tamoxifen for breast cancer risk reduction in women aged 35 and older (pre- and postmenopausal) with a defined five-year breast cancer risk of greater than or equal to 1.66%. Women with a high risk of serious adverse events should not use tamoxifen, nor should those who have a personal or strong family history of thromboembolic events or patients with risk factors for thrombosis, such as immobilization, fractures, or recent pelvic, orthopedic, or brain surgery. Patients with a history of endometrial cancer are also excluded as candidates for tamoxifen chemoprevention. The ideal patient for tamoxifen use is a woman with a five-year breast cancer risk above or equal to 1.66%, who does not have a uterus and has a low risk of thromboembolic events. The recommended dose is 20 mg daily for five years. Raloxifene In this study nearly 20,000 women were randomized to receive either tamoxifen or raloxifene for five years. There was no significant difference for invasive breast cancer between the two arms of the study. Raloxifene was not as effective as tamoxifen when it came to decreasing the incidence of DCIS and lobular carcinoma in situ. However, women in the raloxifene group were significantly less likely to experience thromboembolic events, cataracts, and hysterectomies for benign disease compared with women taking tamoxifen. Also, raloxifene did not increase endometrial cancer risk. When subjects in the STAR trial were followed for a median of 81 months, raloxifene attained approximately 76% of tamoxifen’s effectiveness for prevention.5 Currently raloxifene is approved by the FDA for the primary prevention of breast cancer in high-risk postmenopausal women. It is also FDA approved for the treatment of osteopenia and osteoporosis. The recommended dose is 60 mg daily for five years. Lasofoxifene The main life-threatening side effect was the increased incidence of thromboembolic events. This side effect was more prominent with a lower lasofoxifene dose and less prominent with a higher dose (paradox effect).6 There was no increase in endometrial cancer in the treatment group. Lasofoxifene is available only in Europe for treating osteoporosis. The recommended dose is 0.5 mg daily for five years. Aromatase Inhibitors Exemestane There were no differences between the placebo and exemestane groups regarding fractures, cardiovascular events, other cancers, or treatment-related deaths. In general, exemestane was well tolerated with no life-threatening complications. Arthritic pain and hot flashes were the main side effects. Additionally, there was no difference in new diagnoses of osteoporosis and new fractures between exemestane and the placebo group.7 The American Society of Clinical Oncology updated its guidelines to include exemestane on the list of pharmacologic interventions for women with an increased breast cancer risk. An ideal patient for exemestane is a high-risk postmenopausal woman who has a uterus, does not have osteoporosis, and may or may not have risk factors for thromboembolic events. The recommended dose is 25 mg daily for five years. Barriers to Offering Chemoprevention A small Canadian study published in 2006 investigated women’s attitudes toward chemoprevention. Researchers in this study found that many women with a high risk of developing breast cancer (62% to 67%) were very interested in chemoprevention. The top four criteria that increased a woman’s chance of accepting chemoprevention were believing in its effectiveness, being proactive about her health care, believing the side effects were tolerable, and overcoming the fear of ingesting pills.8 With the promising prospects for a significant reduction in the incidence of breast cancer, why is there such a discrepancy between the evidence and the practice of chemoprevention? Several reasons have been proposed to explain the lack of chemoprevention utilization: • There’s a lack of easily measurable and modifiable markers to determine increased risk. Unlike measuring lipids for heart disease risk, there is no available serum marker for increased breast cancer risk. High risk must be calculated, which is time consuming and has not been well accepted. Until recently, it was not common to have electronic records or access to the Internet in the clinical setting. The current increase in the use of electronic medical records allows greater accessibility to risk calculators, making risk assessment easier. The Breast Cancer Risk Assessment Tool can be built into a patient’s history or completed online. • The term “chemoprevention” may suggest that the agents to be used are much more toxic and potentially harmful than they actually are. It may be helpful to refer to it as primary breast cancer prevention. • There’s a lack of education about and promotion of the therapy among primary care physicians. Since tamoxifen is generic and raloxifene is soon to be generic, there is no promotion from drug companies to educate primary care physicians about using chemoprevention. Primary breast cancer prevention should be a part of the curriculum for primary care specialties such as gynecology, internal medicine, and family practice. Additionally, developing high-risk breast cancer clinics could help educate future primary care physicians. • Breast cancer organizations fail to promote breast cancer chemoprevention. Although many well-known and well-financed breast cancer organizations exist, their main focus has been on early diagnosis rather than prevention. This has led many patients and physicians alike to believe prevention is impossible or unavailable. Although various insurance companies’ medication coverage encompasses specific formularies, there appear to be no significant problems for patients who opt for breast cancer chemoprevention. Tamoxifen is generic and relatively inexpensive, and experience shows no difficulty in securing insurance coverage. Raloxifene is currently expensive, but with its patent due to expire in March 2014, it will likely become available in generic form. Some insurance companies cover the cost of raloxifene, but most require a high copay. Exemestane is generic and, to date, hasn’t presented problems with respect to insurance coverage. Final Thoughts A pervasive lack of interest in chemoprevention creates a major obstacle to future research on breast cancer prevention. Some of the resources focused on early breast cancer detection should be converted to education and improved implementation of breast cancer prevention. — Burcu Ozdemir, MD, is an assistant professor of geriatrics and a clinical attending physician at the University of Arkansas for Medical Sciences. She also works at the Thomas and Lyon Center of Longevity. — Lisa C. Hutchison, PharmD, MPH, is a professor in the college of pharmacy at the University of Arkansas for Medical Sciences and a clinical pharmacist in the Donald W. Reynolds Institute on Aging. In addition to having published many articles and book chapters, she is the coeditor of Fundamentals of Geriatrics Pharmacotherapy: An Evidence-Based Approach.
Breast Cancer Risk Assessment Tool 2. What is her age? What was her age at the time of her first menstrual period? 4. What was her age at the time of her first live birth of a child? 5. How many of her first-degree relatives (mother, sisters, daughters) have breast cancer? 6. Has she ever had a breast biopsy? a. How many breast biopsies has she had? b. Has she had at least one breast biopsy with atypical hyperplasia? 7. What is her race/ethnicity? a. What is her subrace/ethnicity?
References 2. US Preventive Services Task Force. Chemoprevention of breast cancer: recommendations and rationale. Ann Intern Med. 2002;137(1):56-58. 3. Breast cancer risk assessment tool. National Cancer Institute website. http://www.cancer.gov/bcrisktool. 4. Fisher B, Constantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90(18):1371-1388. 5. Vogel VG, Costantino JP, Wickerham DL, et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: preventing breast cancer. Cancer Prev Res (Phila). 2010;3(6):696-706. 6. Cummings SR, Ensrud K, Delmas PD, et al. Lasofoxifene in postmenopausal women with osteoporosis. N Engl J Med. 2010;362(8):686-696. 7. Goss PE, Ingle JN, Ales-Martinez JE, et al. Exemestane for breast cancer prevention in postmenopausal women. N Engl J Med. 2011;364(25):2381-2391. 8. Heisey R, Pimlott N, Clemons M, Cummings S, Drummond N. Women’s views on chemoprevention of breast cancer: qualitative study. Can Fam Physician. 2006;52:624-625. |
