Features

Breast Cancer Prevention and Risk: A Clinical Translation

Vivian M. Dickerson, MD

In the medical and lay news, breakthroughs in breast cancer risk and prevention seem to occur almost weekly. However, these exciting developments are usually years away from the physician’s office—if they ever arrive there at all. So what are the latest proven and practical principles that physicians can use today for early detection and risk reduction of this common and deadly disease?.

Clinicians who specialize in women’s health care need current information about breast disease and risks. Breast health is part and parcel of women’s health; the vast majority of breast cancers occur in women. In addition, ACOG is urging women’s physicians to become educated in the diagnosis and treatment of breast cancer as a means of reducing mortality.1 Notably, the ACOG 2006 survey on professional liability reveals that delay/failure in diagnosing breast cancer has become the primary allegation in gynecologic liability claims.

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RISK ASSESSMENT

Since the introduction of the Gail model of breast cancer risk assessment,2 most clinicians have become familiar with both the major and minor risk factors—few of which are modifiable. They are also aware of the risks posed by the presence of the BRCA-1 and BRCA-2 genetic mutations, and that affected women must be followed closely. For the remainder of women, a number of risk assessment models are now available—all with advantages and limitations (eg, Claus model, Tyrer-Cuzick model, BRCAPRO). The hope is to identify high-risk patients for referral to more rigorous screening, genetic counseling, and/or chemoprophylaxis or other preventive measures. In most cases, though, the value of a good assessment tool is to reassure patients and prevent unnecessary concern, testing, imaging, and office visits. Table 1 lists the major and minor risks for breast cancer—but some questions remain unanswered.

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Table 1 . Breast Cancer Risk Factors8

Does a palpable mass always confer increased risk? Patients should know that whenever they detect a new or different breast irregularity, it deserves evaluation. Any unidentified, firm, irregular, or persistent mass—regardless of whether it is painful—is considered cancerous until proved otherwise. Therefore, any such mass in a woman of reproductive age or beyond merits clinical breast examination, imaging (limited to ultrasonography in some cases), aspiration of cysts, or fine-needle/core-needle biopsy. To watch or procrastinate in the patient with a persistent mass simply because it is not identified on ultrasonography or mammography is a potential road to a delayed or missed diagnosis.

Are patients with dense breasts at greater risk of breast cancer? The patient herself is often overwhelmed, feeling that she cannot possibly distinguish between normal and abnormal. The clinician frequently has the same problem. These patients should be encouraged to perform a monthly breast self-examination (BSE) right after menses, or at the same time every month if menses are irregular or absent. They may also benefit from a twice-yearly clinical examination. Increased breast density does indeed confer an increased risk of breast cancer; when compared with women having density in less than 10% of their mammograms, women with density in 75% or more had a risk of breast cancer that is 4.7-fold greater (OR [odds ratio] 4.7;95%, CI [confidence interval] 4.8-65.9).3

What about the patient who has undergone breast augmentation? Although the breast examination can be more difficult and mammography less sensitive in these patients, there is no etiologic link between breast implants and tumors or cancer.4 In fact, although it may seem counterintuitive, at least one study has demonstrated a possible reduced risk of breast cancer in women with implants.5

Does ductal carcinoma in situ (DCIS) confer risk? Lobular carcinoma in situ (LCIS) and atypical ductal hyperplasia (ADH) both confer high risk and predict risk to both breasts. Both are included in validated risk-assessment tools. Historically, DCIS was often left untreated or misdiagnosed as benign following biopsy. With today’s earlier identification, DCIS now constitutes the largest subset of breast cancers, representing a continuum of pathology and histology from low to high grade. One study demonstrated that even low-grade DCIS, if left untreated, predicts an increased regional risk of invasive carcinoma at the same site in 30% of cases within 15 years.6

What about hormones? Today, the risks associated with hormones (particularly estrogen) are clouded. While combined estrogen-progestin use can increase breast cancer risk somewhat, estrogen alone does not—and the arguments continue. Recently, suspicion has fallen on oral contraceptives (OCs). Researchers have identified a slightly increased risk overall (OR 1.19) of premenopausal breast cancer in women who used OCs. This risk held for both parous and nulliparous women, but did not appear to be related to duration of use in the latter. To the contrary, parous women who used OCs prior to their first pregnancy were at particular risk (OR 1.44), and the risk increased with 4 years' use or longer prior to the first pregnancy (OR 1.52).7 The authors recommended that, given the relative rarity of premenopausal breast cancer, a judicious risk-benefit analysis be applied to individual patients, and that other risk factors be identified and addressed prior to prescribing.

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SCREENING

For low- to average-risk women, the American Cancer Society (ACS) recommends BSE beginning at age 20, clinical breast examinations every 1 to 3 years from ages 20 to 39, and annual clinical breast examinations/mammography after age 40.8 With the increased use of mammography, the diagnosis of breast cancer has risen significantly from 110/100,000 women per year in 1980 to 134/100,000 women per year by 2000.9 During this same period, earlier diagnosis appears to have contributed to increased identification of in situ and stage 1 cancers, with a resultant decrease in stage IV cancers and breast cancer mortality.9

High-risk patients may benefit from the addition of adjunctive screening with magnetic resonance imaging (MRI). The term adjunctive is important—MRI should not replace mammography, but rather be used with mammography for evaluation on an annual basis. Table 2 delineates the subset of high-risk women who, according to the ACS, may benefit from such screening.10,11 It is recommended that high-risk women begin MRI and mammographic screening at age 30, and continue for as long as they are in good health.

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Table 2 . Eligibility Criteria for Magnetic Resonance Imaging*10,11

The patient with dense breasts represents a common screening conundrum. Physicians may be tempted to refer these patients for more frequent or earlier mammographic testing. Mammographic screening is less sensitive in the dense breast, increasing the risk that these women will develop breast cancer between screenings.12 The role of MRI has not been definitively elucidated for this patient population. If MRI is recommended, breast density should be determined mammographically in terms of a percentage of the total breast, rather than clinically.

Women with implants represent a screening challenge as well. Currently, additional imaging is often necessary because implants make standard mammography less sensitive. Implant displacement and compression views have increased the sensitivity and specificity of mammography, but a higher rate of false-negative results persists in patients with implants. Therefore, screening mammography may not be the optimal modality for this population, and many experts recommend diagnostic mammography even in asymptomatic patients.13 Although MRIs have proved useful in detecting implant rupture, routine use for breast cancer screening is not recommended.

Is “direct-to-digital” the way to go? Many breast centers are now touting the excellence of digital or full-field digital mammography, in which the image is acquired using a digital detector rather than film. The advantages include a reduced need for call-backs and repeat imaging, better image manipulation and contrast enhancement, easier storage, and image sharing. The biggest disadvantage is cost. Research has shown that while overall diagnostic accuracy is similar for digital and film mammography, digital results are significantly better in subpopulations of patients who have very dense breasts, are under age 50, and are premenopausal or perimenopausal.14

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PREVENTION

Much has been written about lifestyle changes and primary breast cancer prevention. Modalities that appear to be effective overall include obesity prevention, aerobic exercise, and limiting or eliminating alcohol intake. Diets have been studied intensely, particularly for secondary prevention. A low-fat diet (less than 15% of total calories) has been associated with reduced breast cancer recurrence—especially for women with estrogen-receptor-negative cancers.15 A secondary-prevention study that looked at diets containing high amounts of anticarcinogenic, plant-derived foods (fruits and vegetables) demonstrated no benefit over traditional “five servings per day” diets in reducing breast cancer recurrence or increasing overall survival.16

The most important finding is that chemoprevention is effective, but appears to be significantly underused. One large trial found a 50% reduction in the relative risk of invasive and noninvasive breast cancers with tamoxifen use compared with placebo.17 This was particularly robust for estrogen-receptor−positive breast cancer and for subsequent breast cancer in women with atypical ductal hyperplasia and lobular carcinoma in situ. Another trial showed no statistically significant difference in prophylactic efficacy of tamoxifen and raloxifene, but the latter was associated with fewer thromboembolic events and hysterectomies.18 Nonetheless, the National Cancer Institute estimates that more than 2 million women could benefit from either tamoxifen or raloxifene, preventing or deferring an estimated 28,492 cancers annually. However, these patients have not received a prescription or have discontinued use due to nuisance side effects or concerns about risks.19 This alone should motivate the physician to recommend chemoprophylaxis to all qualified candidates.

There are other issues to consider when prescribing a selective estrogen receptor modulator (SERM) like raloxifene, though. The most intolerable side effect is hot flashes. Because concomitant estrogen use is not the standard of care in the United States, many clinicians are adding selective serotonin reuptake inhibitors (SSRIs). However, recent data suggest that in a genetically identified subpopulation, these substances may actually interfere with tamoxifen metabolism.20 Paroxetine and fluoxetine have the strongest effect, while citalopram and venlafaxine have a weaker effect. More studies are underway to determine whether these metabolic changes impact the efficacy of tamoxifen for either prevention or treatment. Dietary isoflavone supplements containing genistein and daidzein at low concentrations have been shown in vivo to antagonize the effect of tamoxifen. Soy—which contains naturally occurring isoflavones—is considered by some to be nature’s perfect SERM, but supporting data are lacking.

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CONCLUSION

Over the past few years, much emphasis has been placed on hereditary breast cancers and the role of vigilance and early detection. However, there are many other factors that may place a patient at risk, or make her a candidate for more aggressive screening or prevention. The goal of the womenÕs ObGyn or primary care physician is to identify these factors, discuss options with patients, and create individualized risk-benefit profiles. Many new and exciting technologies are on the horizon in breast cancer diagnosis and treatment, but for the health care provider, prevention and screening are at the forefront of practice, patient safety, and satisfaction.

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Vivian M. Dickerson, MD, is Clinical Professor of Obstetrics and Gynecology, University of California, Irvine; Director of WomenÕs Health Care and Programs, Hoag Memorial Hospital, Newport Beach, CA; and Editor-in-Chief, The Female Patient.

References

1. Committee on Gynecologic Practice, ACOG. ACOG Committee Opinion. Number 334, May 2006 (replaces No. 186, September 1997): Role of the obstetrician-gynecologist in the screening and diagnosis of breast masses. Obstet Gynecol. 2006;107(5):1213-1214.
2. Gail MH, Brinton LA, Byar DP et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989; 81(24):1879-1886.
3. Boyd NF, Guo H, Martin LJ, et. al. Mammographic density and the risk and detection of breast cancer. N Engl J Med. 2007;356(3):227-236.
4. McLaughlin JK, Nyren O, Blot WJ, et. al. Cancer risk among women with cosmetic breast implants: a population-based cohort study in Sweden. J Natl Cancer Inst. 1998;90(2):156-162.
5. Deapen DM, Bernstein L, Brody GS. Are breast implants anticarcinogenic? A 14-year follow-up of the Los Angeles study. Plast Reconstr Surg. 1997;99(5):1346-1353.
6. Sanders ME, Schuyler PA, Dupont WE, Page DL. The natural history of low-grade ductal carcinoma in situ of the breast in women treated by biopsy only revealed over 30 years of long-term follow-up. Cancer. 2005;103(12):2481-2484.
7. Kahlenborn C, Modugno F, Potter DM, Severs WB. Oral contraceptive use as a risk factor for premenopausal breast cancer: a meta-analysis. Mayo Clin Proc. 2006;81(10):1290-1302.
8. American Cancer Society. Detailed guide: breast cancer. Can breast cancer be found early? www.cancer.org/docroot/CRI/content/CRI_2_4_3X_Can_breast_cancer_be_found_early_5.asp?sitearea=. Accessed September 19, 2007.
9. Ries LAG, Eisner MP, Kosary CL, et al, eds. SEER Cancer Statistics Review, 1975-2002, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2002/, based on November 2004 SEER data submission, posted to the SEER web site 2005. Accessed September 19, 2007.
10. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57(2):75-89.
11. Lehman CD, Gatsonis C, Kuhl CK, et al. MRI evaluation of the contralateral breast in women with recently diagnosed breast cancer. N Engl J Med. 2007;356(13):1295-1303.
12. McCormack VA, dos Santos Silva I. Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidelmiol Biomarkers Prev. 2006;15(6): 1159-1169.
13. Handel N, Silverstein MJ. Breast cancer diagno-sis and prognosis in augmented women. Plast Reconstr Surg. 2006;118(3):587-593.
14. Pisano ED, Gatsonis C, Hendrick E, et al. Diagnostic performance of digital versus film mammography for breast cancer screening. N Engl J Med. 2005;353(17):1773-1783.
15. Chlebowski RT, Blackburn GL, Thomson CA, et al. Dietary fat reduction and breast cancer outcome: interim efficacy results from the WomenÕs Intervention Nutrition Study (WINS). J Natl Cancer Inst. 2006;98(24):1767-1776.
16. Pierce JP, Natarajan L, Caan BJ, et al. Influence of a diet very high in vegetables, fruit and fiber and low in fat on prognosis following treatment for breast cancer: the WomenÕs Healthy Eating and Living (WHEL) randomized trial. JAMA. 2007; 298(3):289-298.
17. Fisher B, Costantino 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.
18. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006; 295(23):2727-2741.
19. Breast Cancer Risk Assessment Tool. National Cancer Institute web site. www.cancer.gov/bcrisktool. Accessed September 19, 2007.
20. Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005;97(1):30-39.

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