Breast Cancer in Younger Women Assessment and Risk Management

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Breast cancer is a growing concern among premenopausal women. With an emphasis on this patient population, this article discusses the known risk factors for breast cancer; models for quantitative risk assessment; and strategies for modifying breast cancer risk, including screening mammography, prophylactic mastectomy, and primary pharmacologic prevention.

Breast cancer is an important public health problem. In 1999, approximately 190,000 US women will be diagnosed with this disease. Although 65% to 70% of breast cancers occur in women age 50 and older, thousands of younger women are found to have breast malignancies each year. Nevertheless, the chance that any individual woman will develop breast cancer before age 50 is small: Only 1 in 2525 women develop breast cancer by age 30, and only 1 in 217 develop it by age 40.¹

Although the absolute numbers are small, the incidence of breast cancer rises steeply through the premenopausal years. After menopause, the rate of increase declines, but it persists to some degree throughout the life span.² In a sense, then, breast cancer can be viewed as two separate diseases--one affecting premenopausal women and another affecting older women.

EPIDEMIOLOGY
Age is the most important risk factor for breast cancer, but geographic location also plays a role. For example, Asian women, as compared with their North American or Western European counterparts, have a very low risk of developing the disease.³ However, migration studies have shown that the lifetime risk of breast cancer among Asian women who move to North America increases to a level that is between that found in Asia and that found in North America. And first-generation Asian-American women have a lifetime risk of breast cancer that is identical to that of native North American Caucasian women.

The incidence of preinvasive breast cancer (i.e., ductal carcinoma in situ) has risen recently; this change has been attributed, at least in part, to a dramatic increase in mammographic screening that began during the mid-1980s.⁴ This age-adjusted increase has been observed in both Caucasian and African-American women but is less dramatic in women age 35 to 39. At the same time, the incidence of invasive breast cancer has fallen, accompanied by a smaller drop in mortality. The reasons for these decreases are not known but may involve both wider use of screening mammography and improvements in adjuvant hormone therapy and chemotherapy.

RISK FACTORS
Women have a significant degree of anxiety about their risk of developing breast cancer.⁵ Studies of women's estimates of their annual risk show overestimations ranging from 20- to 60-fold.⁶ Furthermore, some women who are known to be at increased risk for breast cancer experience emotional stress as severe as that in women who actually have invasive breast cancer.⁷ These data suggest that physicians must make a greater effort to educate their patients about breast cancer risk factors and incidence, and to provide counseling to women who are at increased risk.⁸

Table 1 lists factors that have been shown to increase a woman's risk of developing breast cancer. These factors are presented in terms of relative risk--that is, the ratio of the lifetime incidence in women with that particular risk factor as compared with the lifetime incidence in controls. As examples, early menarche, late menopause, and older age at the first live birth (or nulliparity) all increase breast cancer risk. It is important to note that since World War II, the proportion of women who are nulliparous has risen steadily and progressively.⁹ This may translate into an increased incidence of breast cancer as these women reach their postmenopausal years.

1.3

16%

0.05

1.5

6%

0.03

1.9

21%

0.16

1.5

15%

0.07

2.0

4%

0.04

4.0

1%

0.03

1.7

8%

0.05

5.0

4%

0.14

1.2

18%

0.03

1.7

12%

0.08

1.5

18%

0.08

A history of benign breast disease (especially a case in which a biopsy has been performed) also increases the risk of breast cancer. Proliferative changes increase the risk even more, and atypical lobular or ductal hyperplasia is associated with the most significant rise in risk.

A family history of invasive breast cancer in a first-degree relative (i.e., mother, sister, or daughter) represents a major risk factor, especially if two or more first-degree relatives are affected. Obesity is associated with an increased risk--an important consideration given the rising prevalence of obesity in the United States. Recent studies have shown that moderate to heavy alcohol use can also elevate breast cancer risk substantially through a dose-response effect.¹⁰ The use of hormone replacement therapy may slightly increase risk among current users, but this rate appears to return to baseline within 5 years of cessation of use.¹¹ Exercise may decrease the risk of breast cancer, especially when it is initiated early in life, is vigorous, and is performed 3 to 4 times weekly.

Although the mechanisms whereby these factors mediate the risk of breast cancer are not fully understood, alterations in levels of circulating estrogens and progestins--or in local tissue metabolism of these hormones--may play a role. Indeed, circulating levels of estrone and estradiol are higher in nulliparous women than in parous women, whereas concentrations of sex hormone-binding globulin are lower.¹² Regardless, only half of current breast cancer cases can be explained by known risk factors; that is, the population-attributable risk is only about 50%.¹³ Thus, a large number of women with no identifiable risk factors will develop breast cancer. More research is desperately needed to account for these cases.

Dietary fat intake--at least during the 10 or 15 years before the diagnosis of breast cancer--does not appear to influence the risk of invasive breast cancer.¹⁴ However, it is possible that fat or other substances consumed between menarche and the age at first live birth may influence the lifetime risk of breast cancer. At this time, no pertinent data are available.

QUANTITATIVE ASSESSMENT
Epidemiologic models have been developed to help clinicians predict a patient's risk of developing breast cancer. The model published by Gail and colleagues uses five risk factors (age at menarche, current age, number of breast biopsies, age at first live birth, and number of first-degree relatives with breast cancer) to project the 10-, 20-, and 30-year probabilities of developing breast cancer.¹⁵ The National Cancer Institute has translated this model into a Windows-compatible program that will determine both
5-year and lifetime likelihood for any given patient. This Breast Cancer Risk Assessment Tool can be obtained by contacting the Office of Cancer Communications, National Cancer Institute, Building 31, Room 10A02, 31 Center Drive MSC 2580, Bethesda, MD 20892-2580, or by logging on to http://cancertrials.nci.nih.gov. Providing this information to women who are concerned about their risk of developing breast cancer can reduce anxiety, motivate participation in screening programs, and identify those at very high risk who may desire proactive prevention.⁸

The Gail model may not be the ideal instrument to assess risk in women whose family history suggests the presence of a predisposing genetic mutation. Mutations of the BRCA1, BRCA2, ataxia-telangiectasia, p53, and other genes have been associated with a marked increase in lifetime breast cancer risk.¹⁶ Women with multiple affected first-degree relatives, relatives who are affected at younger ages, or relatives with ovarian cancer, bilateral breast cancer, and/or male breast cancer are suitable candidates for referral to a medical geneticist or genetic counselor for education, advice, and predictive genetic testing.

RISK MANAGEMENTMammography
Great debate surrounds the use of screening mammography in women age 40 to 49. Furthermore, no data are available to indicate whether screening mammography is beneficial in women younger than 40 who are at increased risk of breast cancer. The potential benefits of mammographic screening include decreased mortality, increased application of conservative surgery, and reassurance from negative findings. However, mammographic screening has a number of risks--particularly in younger women. These include physical discomfort from breast compression, unnecessary additional testing due to false-positive findings in denser breast tissue, potential overtreatment of diagnosed lesions that are not life-threatening, inappropriate reassurance derived from false-negative findings, and psychological sequelae from undergoing a screening procedure with an uncertain outcome.

A number of arguments can be advanced in favor of screening mammography in younger women who are at increased risk for breast cancer. Provided that both sensitivity and specificity are high, this diagnostic procedure may have an enhanced yield in this patient population. Until a prospective screening study is performed in young women at high risk, though, no definitive recommendations for mammography can be made. Malpractice litigation by younger women whose breast cancers were missed by their physicians is increasing, but this is not sufficient justification for widespread population-based screening in this group. Conversely, younger women who present with breast complaints must be evaluated carefully and their concerns weighed seriously. Women with single, dominant breast masses must undergo diagnostic evaluation that should include three-view mammography and ultrasonography. The availability of magnetic resonance imaging (MRI) for the breast may facilitate diagnosis in younger women with dense breasts; for now, however, the use of MRI remains investigational.

Prophylactic Mastectomy
There are few indications for preventive bilateral mastectomy in women who are under close surveillance, because most incident breast cancers will be detected early, when they are treatable and/
or curable. However, some women with predisposing genetic mutations or premalignant lesions (e.g., lobular carcinoma in situ, atypical ductal or lobular hyperplasia) may elect to undergo prophylactic mastectomy. In addition, women who have scarring related to multiple breast biopsies may opt for the surgery because screening mammography is less reliable in this population. Some women report significant psychological relief following prophylactic mastectomy, although prospective evaluations in this regard are currently lacking. Retrospective reviews indicate that prophylactic mastectomy is effective in eliminating about 90% of subsequent invasive breast cancers.¹⁷ Therefore, in a few limited instances, prophylactic mastectomy may be an appropriate management strategy (Table 2).

Primary Drug Prevention

Women who are at high risk for developing breast cancer may now consider pharmacologic prophylaxis. Results from the Breast Cancer Prevention Trial indicate that the use of tamoxifen, a first-generation selective estrogen receptor modulator (SERM), can reduce the incidence of breast cancer in high-risk women by 50%.

¹⁸

This benefit applies to both younger and older patients, women with multiple affected first-degree relatives, and women with breast biopsies showing premalignant atypical hyperplasia and lobular carcinoma in situ (Figure). Also, because tamoxifen has an estrogenic effect on bone, it may reduce fracture incidence.

On the downside, tamoxifen use has been associated with increased incidence of invasive endometrial cancer, thromboembolic cardiovascular events (e.g., stroke, transient ischemic attack, deep vein thrombosis, pulmonary embolus), and symptomatic side effects (e.g., vasomotor instability, vaginal dryness) in postmenopausal women. Except for vasomotor instability and vaginal dryness, however, the serious adverse effects associated with tamoxifen are not substantially increased in premenopausal women. The US Food and Drug Administration has approved the use of tamoxifen as prophylaxis against breast cancer in women at high risk. Therefore, younger women who are shown through quantitative risk assessment or genetic testing to be at high risk may be appropriate candidates for this intervention (Table 3).

This intervention should be considered in women with:

Other potential candidates for tamoxifen prophylaxis are women with:

Caution should be exercised when tamoxifen use is considered in women with:

Physicians need to fully inform these candidates of the potential risks and benefits of tamoxifen therapy. It is essential to ensure that patients do not become pregnant while taking tamoxifen because of its known mutagenic, genotoxic, and teratogenic effects. Younger women with a known genetic predisposition for the development of breast cancer must be aware that the pathogenic mechanisms of the responsible genes are still unclear, and that the preventive effects of a SERM may be mutation-specific. Finally, the long-term toxicity of these agents has not been fully explored in younger women--especially in those who carry genetic mutations.

Given these caveats, younger patients who are at high risk of breast cancer can be offered tamoxifen as primary prevention. The report from the Breast Cancer Prevention Trial states that whereas additional studies are needed, it would be inappropriate to withhold tamoxifen from high-risk women who may benefit from its use in breast cancer prevention.¹⁸

Tamoxifen represents the prototype of the SERMs. Newer second- and third-generation SERMs (e.g., raloxifene) have been developed and are being evaluated. Until data specific to younger women at high risk are available for these newer agents, however, it is inappropriate to use them for the primary prevention of breast cancer.

CONCLUSION
Several important strategies are available for the quantitative evaluation of breast cancer risk. These tools can lead to improved patient education and the development of specific management protocols based on the modalities outlined here. Women with concerns about their risk of developing breast cancer may be reassured by an objective assessment of their actual quantified risk. Women whose calculated objective risk is high can be offered close clinical surveillance and participation in conventional or investigational diagnostic imaging procedures. The use of tamoxifen for primary prevention of breast cancer may be offered to selected premenopausal women who are at very high risk for the disease. In addition, physicians who provide care to women are encouraged to closely follow the fast-breaking findings in this field so that they can inform their patients about new preventive options and direct them to the interventions that are most appropriate to their risk status.

References:

REFERENCES

1. Ries LAG, Kosary CL, Hankey BF, et al, eds. SEER Cancer Statistics Review. 1973-1996. Bethesda, MD: National Cancer Institute; 1999.

2. Spicer DV, Krecker EA, Pike MC. The endocrine prevention of breast cancer. Cancer Invest. 1995;13:494-504.

3. Howe GM, ed. Global Geocancerology. New York, NY: Churchill-Livingstone; 1986.

4. Ernster VL, Barclay J, Kerlikowske K, et al. Incidence of and treatment for ductal carcinoma in situ of the breast. JAMA. 1996;275:913-918.

5. Lerman C, Rimer BK, Engstrom PF. Cancer risk notification: psychological and ethical implications. J Clin Oncol. 1991;9: 1275-1282.

6. Black WC, Nease RF Jr, Tosteson ANA. Perceptions of breast cancer risk and screening effectiveness in women younger than 50 years of age. J Natl Cancer Inst. 1995;87:720-731.

7. Lerman C, Schwartz M. Adherence and psychological adjustment among women at high risk for breast cancer. Breast Cancer Res Treat. 1993;28:145-155.

8. Vogel VG. Counseling the high-risk woman. In: Stoll BA, ed. Reducing Breast Cancer Risk in Women. Boston, MA: Kluwer Academic Publishers; 1995:69-80.

9. Madigan MP, Ziegler RG, Benichou J, et al. Proportion of breast cancer cases in the United States explained by well-established risk factors. J Natl Cancer Inst. 1995;87: 1681-1685.

10. Longnecker MP, Newcombe PA, Mittendorf R, et al. Risk of breast cancer in relation to lifetime alcohol consumption. J Natl Cancer Inst. 1995:87:923-929.

11. Colditz GA, Hankison SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med. 1995;332: 1589-1593.

12. Bernstein L, Pike MC, Ross RK, et al. Estrogen and sex hormone-binding globulin levels in nulliparous and parous women. J Natl Cancer Inst. 1985;74:741-745.

13. Harris JR, Lippman ME, Veronesi U, Willett W. Breast cancer. N Engl J Med. 1992;327:319-328.

14. Hunter DJ, Spiegelman D, Adami O, et al. Cohort studies of fat intake and the risk of breast cancer--a pooled analysis. N Engl J Med. 1996;334:356-361.

15. 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;81:1879-1886.

16. Brody LC, Biesecker BB. Breast cancer susceptibility genes. BRCA1 and BRCA2. Medicine. 1998;77:208-226.

17. Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med. 1999; 340:77-84.

18. 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;90:1371-1388.

Victor G. Vogel, MD, MHS, is Director of the Comprehensive Breast Program, University of Pittsburgh Cancer Institute/Magee-Womens Hospital, and Professor of Medicine and Epidemiology, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Originally published in The Female Patient -- August, 1999

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