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• Offer screening magnetic resonance imaging (MRI) to patients with a known BRCA 1 or 2 mutation, a strong family history of breast cancer, or a lifetime risk of breast cancer >20% to 25%. B
• For early-stage breast cancer, lumpectomy and sentinel node mapping with excision is the preferred method for staging. A
• Monitor patients receiving tamoxifen for signs and symptoms of venous thromboembolism, cataracts, and uterine malignancy, and patients on aromatase inhibitors for the development of osteoporosis. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Late last year, the US Preventive Services Task Force (USPSTF) sparked a nationwide controversy when it announced that it was recommending against routine screening mammography for women younger than age 50.1 Indeed, that’s a recommendation that many other organizations, including the American Cancer Society (ACS),2 the American College of Obstetricians and Gynecologists (ACOG),3 and the National Comprehensive Cancer Network (NCCN),4 disagree with. But the age at which women should begin routine mammography isn’t the only controversial question. Experts disagree on the benefits of breast self-examination, the optimal frequency of clinical breast exams, and the use of digital mammography—among other issues. This evidence-based review can help you cut through the confusion.
CASE Carrie, a 39-year-old woman who has never been pregnant, comes in for an annual Pap smear and gynecologic exam. She has a negative past medical history, but a positive family history for breast cancer—both her mother and 1 of her sisters had the disease. How would you assess Carrie’s risk of breast cancer, and what preventive measures would you recommend?
Use this predictive model to pinpoint your patient’s risk
When making decisions regarding primary prevention of and screening for breast cancer, an accurate assessment of risk is critical. Many predictive models have been developed with that in mind. The most widely studied, the Gail model, incorporates a number of important risk factors (TABLE 1), including age; race; family history; reproductive factors such as age of menarche, menopause, and first childbirth; and previous history of breast biopsy and atypical findings, to calculate a woman’s 5-year risk.5
A risk calculator (the Breast Cancer Risk Assessment Tool) based on the Gail model is available on the National Cancer Institute’s Web site, at http://www.cancer.gov/bcrisktool. Generally, a score ≥1.66%,5 which indicates that a patient has at least a 1.66% chance of developing breast cancer over the next 5 years, is considered high risk.6,7
CASE Carrie’s 2 first-degree relatives affected by breast cancer and her nulliparous status place her at increased risk. Further questioning reveals a particularly strong family history, as both relatives were diagnosed before the age of 50 (her mom at 45 years of age and her sister, at 39). Carrie’s 5-year risk is 1.8%.
TABLE 1
Risk factors for breast cancer5,29
|
| *African American and Caucasian women are at higher risk compared with Asian, Hispanic, and Native American women. |
| †1 drink/day results in minimal increase in risk; 2-5 drinks/day result in 1.5 increased risk compared with nondrinkers. |
| HRT, hormone replacement therapy; LCIS, lobular carcinoma in situ. |
All women can benefit from these preventive measures
As primary care physicians, we have a responsibility to stress lifestyle modification as the mainstay of breast cancer prevention. Whether or not a woman is at high risk, advise her that maintaining a normal weight, exercising vigorously, limiting alcohol consumption, and breastfeeding are evidence-based methods of primary prevention. Diets low in fat and high in fiber may be associated with a lower risk of invasive breast cancer, but there is no conclusive evidence to support specific dietary interventions to reduce the risk.8-11 Nor has a link between active or passive smoking, antioxidants, or fruit and vegetable intake been firmly established.12
There is a clear association between prolonged estrogen exposure and breast cancer, however. Many reproductive factors, such as early menarche, late menopause, later age at time of first full-term pregnancy, and nulliparity, increase a woman’s exposure to endogenous estrogen—and her risk of developing breast cancer.12,13
Exposure to exogenous estrogen is also linked to the development of breast cancer. In 2002, the Women’s Health Initiative (WHI) was stopped early after a report was released stating that the risks of hormone replacement therapy (HRT)—a higher incidence of cardiovascular events, stroke, and venous thromboembolism, as well as breast cancer—outweighed the benefits.14 Subsequent analyses have found a relationship between the declining incidence of breast cancer and the marked decrease in HRT use prompted by the WHI report. While causality has not been firmly established, multiple studies strongly suggest it.15,16
The association between oral contraceptives (OCs) and breast cancer is more controversial. Some studies have found an increased breast cancer risk among OC users, but both the relative risk and absolute risk were found to be very small and to dissipate 10 years after stopping OC use. More recent studies with newer formulations containing lower doses of estrogen have failed to show an increased risk.8
Breast cancer screening: The parameters have changed
Various organizations have published guidelines for breast cancer screening (TABLE 2), and all are somewhat different. Here’s what you need to know.
Breast self-examination (BSE), which women were previously advised to perform monthly, has not been shown to improve mortality in any age group, and is no longer routinely recommended.17 While both the USPSTF and the Canadian Task Force on Preventive Health Care recommend against teaching women BSE, the ACS, ACOG, and NCCN encourage self-examination—particularly among women older than 40 years.1-4,17,18
Clinical breast examination has an average sensitivity of 50% and detects approximately 5% of mammographically occult cancers.19 It is still not clear whether clinical breast exams save lives, however—a finding that is reflected in the USPSTF’s “I” (insufficient evidence to assess the benefits and harms) recommendation.1 Other consensus guidelines still recommend clinical breast examination, albeit at varying frequencies.
Screening mammography decreases mortality rates by anywhere from 28% to 65%, depending on the statistical model used.20 The benefit is greatest in women between the ages of 50 and 69 years, however, and most groups agree that mammography every 1 to 2 years is advisable for this age group. (There is limited data on the value of mammography for women 70 years of age and older, and no consensus on the age at which to stop screening.1,21) But because the mortality benefit from screening mammography is lower for women aged 40 to 49, guidelines for this age group are more controversial.
Mammography’s sensitivity is affected by a variety of factors, including age and menopausal status, prior breast surgery or radiation, breast density, and the experience of the radiologist. Women in their 40s have denser breast tissue than older women, making mammography less sensitive for this age group. Because of that, and because the overall incidence of breast cancer is lower for women younger than 50, some argue that screening mammography for women between the ages of 40 and 49 years leads to unacceptably high false-positive rates (9.8% annually22) and that the harm associated with mammography may outweigh the benefit. Others counter that tumors in younger women tend to be more aggressive and faster growing, making early detection even more critical than for older women.
What should you advise women in this age group? You might point out that the USPSTF recommends against routine screening, but indicates that the decision to begin (or defer) routine mammography before age 50 should be individualized, based on the needs and values of each patient.1
Digital mammography. A recent study of more than 43,000 women demonstrated that digital mammography is more accurate than film—but only for certain groups: These include women <50 years of age, women with dense breasts, and pre- and perimenopausal women. 23 Because it is still not clear whether the increased accuracy will translate into a mortality benefit, more research is needed before digital mammography is widely adopted. The USPSTF maintains that there is insufficient evidence to assess the benefits and harms of using either digital mammography or magnetic resonance imaging (MRI) rather than film mammography to screen for breast cancer.1
MRI. In 2007, the ACS published guidelines on the use of MRI as an adjunct to mammography for breast cancer screening in high-risk women.24 According to ACS guidelines, screening MRI should be offered to patients with a known BRCA 1 or 2 mutation (5%-10% of all breast cancers are associated with a mutation in the BRCA 1 or BRCA 2 gene, which is transmitted in an autosomal dominant pattern6). It also should be offered to those with a strong family history, or a lifetime risk of developing breast cancer that is >20% to 25%. And finally, MRI should be offered to women who had chest wall radiation when they were between the ages of 10 and 30 years—another significant risk factor for breast cancer—and those with other genetic syndromes that increase their lifetime risk of breast cancer.24
Evidence is insufficient for or against MRI screening for women with a personal history of breast cancer, atypical hyperplasia, or lobular carcinoma in situ, however, and neither breast ultrasound (which is generally used diagnostically, not for screening purposes) nor MRI has been shown to be helpful as a screening tool in women with <15% lifetime risk of developing breast cancer.24,25
TABLE 2
Guidelines for breast cancer screening for women with average risk
| Organization | Age (years) | Breast self-exam | Clinical breast exam | Mammography |
|---|---|---|---|---|
| American Cancer Society2 | 20-40 | Optional | Every 3 y | NA |
| >40 | Encourages | Annually | Annually | |
| American College of Obstetricians and Gynecologists3 | 40-49 | Encourages | Annually | 1-2 y |
| 50-69 | Encourages | Annually | Annually | |
| Canadian Task force on Preventive Health Care18 | 40-49 | Recommends against teaching | Insufficient evidence | Insufficient evidence |
| 50-69 | Recommends against teaching | 1-2 y | 1-2 y | |
| National Comprehensive Cancer Network4 | 20-40 | Encourages | 1-3 y | NA |
| >40 | Encourages | Annually | Annually | |
| US Preventive Services Task Force1 | 40-49 | Recommends against teaching | Insufficient evidence | Not routinely recommended |
| 50-74 | Recommends against teaching | Insufficient evidence | Every 2 y | |
| NA, not addressed. | ||||
When to consider chemoprevention
For women like Carrie, who are at high risk of developing breast cancer, selective estrogen receptor modulator (SERM) therapy and surgical interventions may be options to consider. The Breast Cancer Prevention Trial demonstrated the efficacy of tamoxifen as a preventive agent. This landmark trial showed that for high-risk women older than 35, 5 years of tamoxifen therapy can reduce the incidence of invasive breast cancer by nearly 50%.26
Women with the BRCA 1 or 2 mutation—all of whom should be offered genetic counseling—were included in the study. Tamoxifen reduced the incidence of breast cancer in BRCA 2 carriers by 62%, the researchers found, but did not reduce risk in carriers of the BRCA 1 gene. This is likely due to the high prevalence of estrogen receptor-negative breast cancers among BRCA 1 carriers.26
More recently, the Study of Tamoxifen and Raloxifene (STAR) trial compared the efficacy of tamoxifen and raloxifene, a second-generation SERM, in high-risk postmenopausal women ages 35 and older. The drugs were found to be equally effective in reducing the risk of invasive breast cancer, but raloxifene had a better side effect profile, with a lower incidence of thromboembolism and cataracts. 27
What the guidelines call for. In 2003, the USPSTF recommended that clinicians discuss chemoprevention with women at high risk for breast cancer and low risk for adverse effects of SERMs.28
The most recent update to the NCCN breast cancer risk reduction guidelines recommends that clinicians offer tamoxifen to premenopausal women with a 5-year projected breast cancer risk ≥1.7% and offer tamoxifen or raloxifene to high-risk postmenopausal women.29 It is worth noting, however, that SERMs can have significant adverse effects, including venous thromboembolism, stroke, cataracts, uterine malignancy, and hot flashes, while lifestyle modifications and the avoidance of HRT have few, if any, negative effects.
CASE After consultation with a genetic counselor, Carrie underwent testing for both the BRCA 1 and BRCA 2 mutations. She tested negative for both. She declined chemoprevention and prophylactic surgery, opting for enhanced screening with yearly mammography and MRI and lifestyle modification instead.
When a mass is found
For women ages 30 or older with palpable masses or solid masses ≥2 cm found on imaging, core needle biopsy is recommended.30,31 Biopsy is indicated for women younger than 30 as well, if the mass is >2 cm or imaging is suspicious. In general, a needle biopsy read as benign is considered adequate for diagnostic purposes only if the lesion appeared benign on imaging.
For lesions shown to be cystic on imaging, recommendations for follow-up or additional testing are based on the characteristics of the cyst. For simple cysts, 2- to 4-month follow up for stability, followed by routine screening, is adequate.21 Additional evaluation of complex cysts is indicated, including aspiration for complicated cysts and biopsy for complex cysts. After aspiration, surgical excision of bloody aspirates or persistent masses is recommended.30,31
Staging using the TNM system
The TNM (tumor, node, metastases) classification system is used for the staging of breast cancer:
- T refers to the tumor type, size, and extent of local involvement
- N describes regional lymph node involvement
- M refers to distant metastases.
The TNM classifications are also grouped by stage (I through IV).,
Lumpectomy and sentinel node mapping with excision is the preferred method for staging of early-stage breast cancer without palpable lymphadenopathy—provided that the surgical team has documented experience with sentinel node biopsy.32 Sentinel node biopsy is preferred because of its safety, low (<10%) false negative rate, and decreased morbidity compared with full axillary dissection, although dissection is recommended for patients with more advanced cancer or a positive sentinel node.32 The comparative effects of sentinel node biopsy vs axillary node dissection on tumor recurrence and patient survival are not known.33
Testing for tumor markers such as estrogen and progesterone receptors and human epidermal growth factor receptor 2 (HER2) expression status in biopsy-proven breast cancer is now the standard of care. Seventy percent of breast cancers are estrogen receptor-positive, with increasing frequency associated with older age.34 Estrogen/progesterone receptor positivity is associated with a more favorable outcome, and multiple hormonal therapies can be aimed at these receptors.34 While HER2 overexpression—which occurs in 15% to 30% of newly diagnosed breast cancers35—is associated with more aggressive tumors, women with this type of tumor cell can benefit from trastuzumab, an anti-HER2 drug.36
Key factors that affect prognosis
Important factors affecting prognosis and treatment of localized breast cancer are tumor size, age and menopausal status, tumor expression of hormone receptors and/ or the HER2 protein, as well as the status of the draining axillary nodes. Factors that predict a greater chance of recurrence include the spread of disease to axillary nodes, larger tumor size, invasive histology, inflammatory pathology, lack of estrogen/progesterone receptors, and age <50 years or premenopausal status.
Treatment options include surgical resection, radiation, and systemic adjuvant therapy in the form of chemotherapy, endocrine therapy, or anti-HER2 monoclonal antibodies.37 (For more on treatment, see “Surgery, radiation, and systemic therapy: Making the most of what’s in our arsenal” at jfponline.com.)
Don’t overlook quality-of-life issues
Follow-up of breast cancer patients should go beyond treatment and work-up for recurrence and metastatic disease to focus on health and lifestyle issues, such as stress reduction, mood, smoking cessation, diet and exercise, treatment of hot flashes, sexual dysfunction, and bone health. A recent study found both reduced recurrence and increased survival in women receiving psychological interventions to improve quality-of-life measures after an 11-year follow-up.38
Refer women to targeted Web sites such as the National Breast Cancer Awareness Month organization (http://www.nbcam.org/), the National Breast Cancer Foundation (http://community.nationalbreastcancer.org/), and the Susan G. Komen Breast Cancer Foundation (http://ww5.komen.org/). Offer treatment for bothersome symptoms. Hot flashes and depression, for example, often related to endocrine therapy, can be treated with selective serotonin reuptake inhibitors (SSRIs). That said, some SSRIs decrease the active metabolite of tamoxifen by inhibiting CYP2D6 enzyme and must, therefore, be used with caution. However, venlafaxine and citalopram are less likely to alter tamoxifen metabolism than other SSRIs.39
CASE When Carrie was 47, she had an abnormal MRI of the left breast. Core needle biopsy and pathology of the lesion revealed an estrogen and progesterone receptor-positive tumor that was negative for HER2 overexpression. She underwent lumpectomy, which revealed a 1.5 cm tumor, followed by a negative sentinel node biopsy, and was diagnosed with stage I (T1N0M0) breast cancer. Carrie had radiation after surgery; she did not require chemotherapy, but was told to take tamoxifen for 5 years. This adjuvant endocrine therapy led to hot flashes and depression, both of which were successfully treated with venlafaxine. Carrie is currently cancer-free and participates in a breast cancer survivor program that includes regular visits with her primary physician and her oncologist.
CORRESPONDENCE Denise Sur, MD, 1920 Colorado Avenue, Santa Monica, CA 90404; [email protected]
Surgery, radiation, and systemic therapy: Making the most of what’s in our arsenal
Breast cancer surgery has changed dramatically over the years. Multiple studies have shown that breast-conserving therapy (lumpectomy followed by radiation) for carefully selected women is comparable to mastectomy for local recurrence and survival. While there has been much interest in determining whether a subset of patients could forego radiation after lumpectomy, a meta-analysis by the Early Breast Cancer Trialists Collaborative Group demonstrated that radiation after lumpectomy provides an absolute local recurrence risk reduction of 19%, and a 5.4% absolute reduction in 15-year breast cancer mortality rates compared with lumpectomy without radiation.1 Thus, radiation after lumpectomy remains the standard of care for all women undergoing breast-conserving therapy, regardless of tumor characteristics.
In certain women with a high risk of recurrence (≥4 positive nodes), radiation is also recommended after mastectomy. Women undergoing mastectomy have numerous options for immediate or delayed breast reconstruction. Consultation with a multidisciplinary team, including a plastic surgeon, prior to any surgical intervention is advised.2
Multiple systemic chemotherapy regimens have been shown to be beneficial in carefully selected patients with breast cancer. Systematic reviews have demonstrated that an anthracycline-based regimen can decrease annual breast cancer mortality by 38% in women <50 years old and by 20% in women ages 50 to 69 years.1 in more recent randomized controlled trials, the addition of taxanes to anthracycline-based regimens has produced promising results.3
Numerous hormonal therapies benefit women with estrogen or progesterone receptor-positive breast cancer. Tamoxifen blocks the activity of estrogen on receptors located in breast cancer tissue, for example; aromatase inhibitors block the conversion of androgens to estrogen; and gonadotropin-releasing hormone (GnRH) analogs such as leuprolide and goserelin suppress ovarian production of estrogen.
For postmenopausal women, options include an aromatase inhibitor alone or tamoxifen followed by an aromatase inhibitor.
In premenopausal women, aromatase inhibitors are not very effective, as decreasing peripheral estrogen stimulates the ovaries to produce more estrogen. Thus, for these patients, adjuvant endocrine therapy consists of tamoxifen, with ovarian ablation (via surgery or radiation) or ovarian suppression with a GnRH analog. If the patient goes through menopause as a result of this therapy, she may benefit from aromatase inhibitors at that time.4,5
Women with breast cancer that overexpresses the HER2 gene benefit from adjuvant treatment with trastuzumab, an anti-HER2 antibody.6 While current guidelines advise treatment for 1 year, multiple studies are evaluating dosing schedules and optimal duration of treatment. for now, patients should be monitored for signs of cardiotoxicity at baseline and every 3 months thereafter until completion of therapy.4
References
1. Early Breast Caner Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;265:1687-1717.
2. Codeiro P. Breast reconstruction after surgery for breast cancer. N Engl J Med. 2008;359:1590-1601.
3. DeLaurentiis M, Cancello G, D’Agostino D, et al. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol. 2008;26:44-53.
4. National Comprehensive Cancer Network. Breast cancer risk reduction clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2003;1:280-296.
5. Baum M, Budzar AU, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002;359:2131-2139.
6. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Herceptin adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-1672.
1. US Preventive Services Task Force Screening for breast cancer. Available at: http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm. Accessed September 2, 2010.
2. American Cancer Society. American Cancer Society guidelines for the early detection of cancer. Available at: http://www.cancer.org/Healthy/FindCancerEarly/CancerScreeningGuidelines/american-cancer-society-guidelines-for-the-early-detection-of-cancer. Accessed September 2, 2010.
3. American College of Obstetricians and Gynecologists. Response of the American College of Obstetricians and Gynecologists to the new breast cancer screening recommendations from the US Preventive Services Task Force. Available at: http://www.acog.org/from_home/misc/uspstfresponse.cfm. Accessed September 2, 2010.
4. National Comprehensive Cancer Network. Breast cancer screening and diagnosis. Clinical Practice Guidelines in Oncology-V.1.2010. Fort Washington, Pa: National Comprehensive Cancer Network: November 3, 2009. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed September 17 , 2010.
5. National Cancer Institute. Breast cancer risk assessment tool. Available at: http://www.cancer.gov/bcrisktool/. Accessed September 2, 2010
6. Robson M, Offit K. Clinical practice. Management of an inherited predisposition to breast cancer. N Engl J Med. 2007;357:154-162.
7. 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.
8. Cummings SR, Tice JA, Bauer S, et al. Prevention of breast cancer in postmenopausal women: approaches to estimating and reducing risk. J Natl Cancer Inst. 2009;18:101,-384-398.
9. Prentice RL, Caan B, Chlebowski RT, et al. Low-fat dietary pattern and risk of invasive breast cancer: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006;295:629-642.
10. 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 Women’s Healthy Eating and Living (WHEL) randomized trial. JAMA. 2007;298:289-298.
11. Chlebowski RT, Blackburn GL, Thomson CA, et al. Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention Nutrition Study (WINS). J Natl Cancer Inst. 2006;98:1767-1776.
12. PDQ Cancer Information Summary. Breast Cancer Prevention (PRQ) – Health Professional. Date last modified April 30, 2009. Available at: http://www.cancer.gov/cancertopics/pdq/prevention/breast/healthprofessional. Accessed May 12, 2009.
13. Hulka BS, Moorman PG. Breast cancer: hormones and other risk factors. Maturitas. 2001;38:103-113.
14. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.
15. Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med. 2007;356:1670-1674.
16. Chlebowski RT, Kuller LH, Prentice RL, et al. WHI Investigators. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med. 2009;360:573-587.
17. Kosters JP, Gotzsche PC. Regular self-examination or clinical examination for early detection of breast cancer. Cochrane Database Syst Rev. 2003;(2):CD003373.-
18. Canadian Task Force on the Periodic Health Examination Ottawa, Canada: Health Canada; 1994:788-795 (reaffirmed by the Canadian Task Force on the Periodic Health Examination 1999, 2001).Available at: http://www.ctfphc.org/index/html. Accessed August 12, 2009.
19. Green BB, Taplin SH. Breast cancer screening controversies. J Am Board Fam Pract. 2003;16:233-241.
20. Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005;353:1784-1792.
21. Tice JA, Kerlikowske K. Screening and prevention of breast cancer in primary care. Prim Care. 2009;36:533-558.
22. US Preventive Services Task Force. Screening for breast cancer. Systematic evidence review update for the US Preventive Services Task Force. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=es74. Accessed September 2, 2010.
23. Pisano ED, Gatsonis C, Hendrick E, et al. Digital Mammographic Imaging Screening Trial (DMIST) Investigators Group. Diagnostic performance of digital versus film mammography for breast-cancer screening. N Engl J Med. 2005;353:1773-1783.
24. Saslow D, Boetes C, Burke W, et al. American Cancer Society Breast Cancer Advisory Group. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57:75-89.
25. Berg W, Blume J, Cormack J, et al. Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer. JAMA. 2008;299:2151-2163.
26. King M, Wieand S, Hale K, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001;286:2251-2256.
27. 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;295:2727-2741.
28. Berg AO. US Preventive Services Task Force. Chemoprevention of breast cancer: recommendations and rationale. Am J Nurs. 2003;103:107-113.
29. National Comprehensive Cancer Network. Breast cancer risk reduction. Clinical Practice Guidelines in Oncology-V.2.2010. Fort Washington, Pa: National Comprehensive Cancer Network; August 7, 2010. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed September 17, 2010.
30. Sickles EA, Filly RA, Cllen PW. Benign breast lesions: ultrasound detection and diagnosis. Radiology. 1984;151:467.-
31. Beavers TB, Anderson BO, Bonaccio E, et al. NCCN clinical practice guidelines in oncology: breast cancer screening and diagnosis. J Natl Compr Canc Netw. 2009;7:1060-1096.
32. Mansel RE, Fallowfield L, Kissin M, et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC trial. J Natl Canc Inst. 2006;98:599-609
33. Lyman GH, Guiliano AE, Somerfield MR, et al. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early- stage breast cancer. J Clin Oncol. 2005;23:7703-7720.
34. Turner N, Jones A. Management of breast cancer-Part II. BMJ. 2008;337:a540.-
35. Harris L, Fritsche H, Mennel R, et al:. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer J Clin Oncol. 2007;25:5287-5312.
36. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Herceptin adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-1672.
37. PDQ Cancer Information Summary Breast cancer treatment– health professional. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/breast/HealthProfessional. Accessed May 12, 2009.
38. Anderson BL, Yang HC, Farrar WB, et al. Psychologic intervention improves survival for breast cancer patients: a randomized clinical trial. Cancer. 2008;113:3450-3458.
39. 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;97:30-39.
• Offer screening magnetic resonance imaging (MRI) to patients with a known BRCA 1 or 2 mutation, a strong family history of breast cancer, or a lifetime risk of breast cancer >20% to 25%. B
• For early-stage breast cancer, lumpectomy and sentinel node mapping with excision is the preferred method for staging. A
• Monitor patients receiving tamoxifen for signs and symptoms of venous thromboembolism, cataracts, and uterine malignancy, and patients on aromatase inhibitors for the development of osteoporosis. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Late last year, the US Preventive Services Task Force (USPSTF) sparked a nationwide controversy when it announced that it was recommending against routine screening mammography for women younger than age 50.1 Indeed, that’s a recommendation that many other organizations, including the American Cancer Society (ACS),2 the American College of Obstetricians and Gynecologists (ACOG),3 and the National Comprehensive Cancer Network (NCCN),4 disagree with. But the age at which women should begin routine mammography isn’t the only controversial question. Experts disagree on the benefits of breast self-examination, the optimal frequency of clinical breast exams, and the use of digital mammography—among other issues. This evidence-based review can help you cut through the confusion.
CASE Carrie, a 39-year-old woman who has never been pregnant, comes in for an annual Pap smear and gynecologic exam. She has a negative past medical history, but a positive family history for breast cancer—both her mother and 1 of her sisters had the disease. How would you assess Carrie’s risk of breast cancer, and what preventive measures would you recommend?
Use this predictive model to pinpoint your patient’s risk
When making decisions regarding primary prevention of and screening for breast cancer, an accurate assessment of risk is critical. Many predictive models have been developed with that in mind. The most widely studied, the Gail model, incorporates a number of important risk factors (TABLE 1), including age; race; family history; reproductive factors such as age of menarche, menopause, and first childbirth; and previous history of breast biopsy and atypical findings, to calculate a woman’s 5-year risk.5
A risk calculator (the Breast Cancer Risk Assessment Tool) based on the Gail model is available on the National Cancer Institute’s Web site, at http://www.cancer.gov/bcrisktool. Generally, a score ≥1.66%,5 which indicates that a patient has at least a 1.66% chance of developing breast cancer over the next 5 years, is considered high risk.6,7
CASE Carrie’s 2 first-degree relatives affected by breast cancer and her nulliparous status place her at increased risk. Further questioning reveals a particularly strong family history, as both relatives were diagnosed before the age of 50 (her mom at 45 years of age and her sister, at 39). Carrie’s 5-year risk is 1.8%.
TABLE 1
Risk factors for breast cancer5,29
|
| *African American and Caucasian women are at higher risk compared with Asian, Hispanic, and Native American women. |
| †1 drink/day results in minimal increase in risk; 2-5 drinks/day result in 1.5 increased risk compared with nondrinkers. |
| HRT, hormone replacement therapy; LCIS, lobular carcinoma in situ. |
All women can benefit from these preventive measures
As primary care physicians, we have a responsibility to stress lifestyle modification as the mainstay of breast cancer prevention. Whether or not a woman is at high risk, advise her that maintaining a normal weight, exercising vigorously, limiting alcohol consumption, and breastfeeding are evidence-based methods of primary prevention. Diets low in fat and high in fiber may be associated with a lower risk of invasive breast cancer, but there is no conclusive evidence to support specific dietary interventions to reduce the risk.8-11 Nor has a link between active or passive smoking, antioxidants, or fruit and vegetable intake been firmly established.12
There is a clear association between prolonged estrogen exposure and breast cancer, however. Many reproductive factors, such as early menarche, late menopause, later age at time of first full-term pregnancy, and nulliparity, increase a woman’s exposure to endogenous estrogen—and her risk of developing breast cancer.12,13
Exposure to exogenous estrogen is also linked to the development of breast cancer. In 2002, the Women’s Health Initiative (WHI) was stopped early after a report was released stating that the risks of hormone replacement therapy (HRT)—a higher incidence of cardiovascular events, stroke, and venous thromboembolism, as well as breast cancer—outweighed the benefits.14 Subsequent analyses have found a relationship between the declining incidence of breast cancer and the marked decrease in HRT use prompted by the WHI report. While causality has not been firmly established, multiple studies strongly suggest it.15,16
The association between oral contraceptives (OCs) and breast cancer is more controversial. Some studies have found an increased breast cancer risk among OC users, but both the relative risk and absolute risk were found to be very small and to dissipate 10 years after stopping OC use. More recent studies with newer formulations containing lower doses of estrogen have failed to show an increased risk.8
Breast cancer screening: The parameters have changed
Various organizations have published guidelines for breast cancer screening (TABLE 2), and all are somewhat different. Here’s what you need to know.
Breast self-examination (BSE), which women were previously advised to perform monthly, has not been shown to improve mortality in any age group, and is no longer routinely recommended.17 While both the USPSTF and the Canadian Task Force on Preventive Health Care recommend against teaching women BSE, the ACS, ACOG, and NCCN encourage self-examination—particularly among women older than 40 years.1-4,17,18
Clinical breast examination has an average sensitivity of 50% and detects approximately 5% of mammographically occult cancers.19 It is still not clear whether clinical breast exams save lives, however—a finding that is reflected in the USPSTF’s “I” (insufficient evidence to assess the benefits and harms) recommendation.1 Other consensus guidelines still recommend clinical breast examination, albeit at varying frequencies.
Screening mammography decreases mortality rates by anywhere from 28% to 65%, depending on the statistical model used.20 The benefit is greatest in women between the ages of 50 and 69 years, however, and most groups agree that mammography every 1 to 2 years is advisable for this age group. (There is limited data on the value of mammography for women 70 years of age and older, and no consensus on the age at which to stop screening.1,21) But because the mortality benefit from screening mammography is lower for women aged 40 to 49, guidelines for this age group are more controversial.
Mammography’s sensitivity is affected by a variety of factors, including age and menopausal status, prior breast surgery or radiation, breast density, and the experience of the radiologist. Women in their 40s have denser breast tissue than older women, making mammography less sensitive for this age group. Because of that, and because the overall incidence of breast cancer is lower for women younger than 50, some argue that screening mammography for women between the ages of 40 and 49 years leads to unacceptably high false-positive rates (9.8% annually22) and that the harm associated with mammography may outweigh the benefit. Others counter that tumors in younger women tend to be more aggressive and faster growing, making early detection even more critical than for older women.
What should you advise women in this age group? You might point out that the USPSTF recommends against routine screening, but indicates that the decision to begin (or defer) routine mammography before age 50 should be individualized, based on the needs and values of each patient.1
Digital mammography. A recent study of more than 43,000 women demonstrated that digital mammography is more accurate than film—but only for certain groups: These include women <50 years of age, women with dense breasts, and pre- and perimenopausal women. 23 Because it is still not clear whether the increased accuracy will translate into a mortality benefit, more research is needed before digital mammography is widely adopted. The USPSTF maintains that there is insufficient evidence to assess the benefits and harms of using either digital mammography or magnetic resonance imaging (MRI) rather than film mammography to screen for breast cancer.1
MRI. In 2007, the ACS published guidelines on the use of MRI as an adjunct to mammography for breast cancer screening in high-risk women.24 According to ACS guidelines, screening MRI should be offered to patients with a known BRCA 1 or 2 mutation (5%-10% of all breast cancers are associated with a mutation in the BRCA 1 or BRCA 2 gene, which is transmitted in an autosomal dominant pattern6). It also should be offered to those with a strong family history, or a lifetime risk of developing breast cancer that is >20% to 25%. And finally, MRI should be offered to women who had chest wall radiation when they were between the ages of 10 and 30 years—another significant risk factor for breast cancer—and those with other genetic syndromes that increase their lifetime risk of breast cancer.24
Evidence is insufficient for or against MRI screening for women with a personal history of breast cancer, atypical hyperplasia, or lobular carcinoma in situ, however, and neither breast ultrasound (which is generally used diagnostically, not for screening purposes) nor MRI has been shown to be helpful as a screening tool in women with <15% lifetime risk of developing breast cancer.24,25
TABLE 2
Guidelines for breast cancer screening for women with average risk
| Organization | Age (years) | Breast self-exam | Clinical breast exam | Mammography |
|---|---|---|---|---|
| American Cancer Society2 | 20-40 | Optional | Every 3 y | NA |
| >40 | Encourages | Annually | Annually | |
| American College of Obstetricians and Gynecologists3 | 40-49 | Encourages | Annually | 1-2 y |
| 50-69 | Encourages | Annually | Annually | |
| Canadian Task force on Preventive Health Care18 | 40-49 | Recommends against teaching | Insufficient evidence | Insufficient evidence |
| 50-69 | Recommends against teaching | 1-2 y | 1-2 y | |
| National Comprehensive Cancer Network4 | 20-40 | Encourages | 1-3 y | NA |
| >40 | Encourages | Annually | Annually | |
| US Preventive Services Task Force1 | 40-49 | Recommends against teaching | Insufficient evidence | Not routinely recommended |
| 50-74 | Recommends against teaching | Insufficient evidence | Every 2 y | |
| NA, not addressed. | ||||
When to consider chemoprevention
For women like Carrie, who are at high risk of developing breast cancer, selective estrogen receptor modulator (SERM) therapy and surgical interventions may be options to consider. The Breast Cancer Prevention Trial demonstrated the efficacy of tamoxifen as a preventive agent. This landmark trial showed that for high-risk women older than 35, 5 years of tamoxifen therapy can reduce the incidence of invasive breast cancer by nearly 50%.26
Women with the BRCA 1 or 2 mutation—all of whom should be offered genetic counseling—were included in the study. Tamoxifen reduced the incidence of breast cancer in BRCA 2 carriers by 62%, the researchers found, but did not reduce risk in carriers of the BRCA 1 gene. This is likely due to the high prevalence of estrogen receptor-negative breast cancers among BRCA 1 carriers.26
More recently, the Study of Tamoxifen and Raloxifene (STAR) trial compared the efficacy of tamoxifen and raloxifene, a second-generation SERM, in high-risk postmenopausal women ages 35 and older. The drugs were found to be equally effective in reducing the risk of invasive breast cancer, but raloxifene had a better side effect profile, with a lower incidence of thromboembolism and cataracts. 27
What the guidelines call for. In 2003, the USPSTF recommended that clinicians discuss chemoprevention with women at high risk for breast cancer and low risk for adverse effects of SERMs.28
The most recent update to the NCCN breast cancer risk reduction guidelines recommends that clinicians offer tamoxifen to premenopausal women with a 5-year projected breast cancer risk ≥1.7% and offer tamoxifen or raloxifene to high-risk postmenopausal women.29 It is worth noting, however, that SERMs can have significant adverse effects, including venous thromboembolism, stroke, cataracts, uterine malignancy, and hot flashes, while lifestyle modifications and the avoidance of HRT have few, if any, negative effects.
CASE After consultation with a genetic counselor, Carrie underwent testing for both the BRCA 1 and BRCA 2 mutations. She tested negative for both. She declined chemoprevention and prophylactic surgery, opting for enhanced screening with yearly mammography and MRI and lifestyle modification instead.
When a mass is found
For women ages 30 or older with palpable masses or solid masses ≥2 cm found on imaging, core needle biopsy is recommended.30,31 Biopsy is indicated for women younger than 30 as well, if the mass is >2 cm or imaging is suspicious. In general, a needle biopsy read as benign is considered adequate for diagnostic purposes only if the lesion appeared benign on imaging.
For lesions shown to be cystic on imaging, recommendations for follow-up or additional testing are based on the characteristics of the cyst. For simple cysts, 2- to 4-month follow up for stability, followed by routine screening, is adequate.21 Additional evaluation of complex cysts is indicated, including aspiration for complicated cysts and biopsy for complex cysts. After aspiration, surgical excision of bloody aspirates or persistent masses is recommended.30,31
Staging using the TNM system
The TNM (tumor, node, metastases) classification system is used for the staging of breast cancer:
- T refers to the tumor type, size, and extent of local involvement
- N describes regional lymph node involvement
- M refers to distant metastases.
The TNM classifications are also grouped by stage (I through IV).,
Lumpectomy and sentinel node mapping with excision is the preferred method for staging of early-stage breast cancer without palpable lymphadenopathy—provided that the surgical team has documented experience with sentinel node biopsy.32 Sentinel node biopsy is preferred because of its safety, low (<10%) false negative rate, and decreased morbidity compared with full axillary dissection, although dissection is recommended for patients with more advanced cancer or a positive sentinel node.32 The comparative effects of sentinel node biopsy vs axillary node dissection on tumor recurrence and patient survival are not known.33
Testing for tumor markers such as estrogen and progesterone receptors and human epidermal growth factor receptor 2 (HER2) expression status in biopsy-proven breast cancer is now the standard of care. Seventy percent of breast cancers are estrogen receptor-positive, with increasing frequency associated with older age.34 Estrogen/progesterone receptor positivity is associated with a more favorable outcome, and multiple hormonal therapies can be aimed at these receptors.34 While HER2 overexpression—which occurs in 15% to 30% of newly diagnosed breast cancers35—is associated with more aggressive tumors, women with this type of tumor cell can benefit from trastuzumab, an anti-HER2 drug.36
Key factors that affect prognosis
Important factors affecting prognosis and treatment of localized breast cancer are tumor size, age and menopausal status, tumor expression of hormone receptors and/ or the HER2 protein, as well as the status of the draining axillary nodes. Factors that predict a greater chance of recurrence include the spread of disease to axillary nodes, larger tumor size, invasive histology, inflammatory pathology, lack of estrogen/progesterone receptors, and age <50 years or premenopausal status.
Treatment options include surgical resection, radiation, and systemic adjuvant therapy in the form of chemotherapy, endocrine therapy, or anti-HER2 monoclonal antibodies.37 (For more on treatment, see “Surgery, radiation, and systemic therapy: Making the most of what’s in our arsenal” at jfponline.com.)
Don’t overlook quality-of-life issues
Follow-up of breast cancer patients should go beyond treatment and work-up for recurrence and metastatic disease to focus on health and lifestyle issues, such as stress reduction, mood, smoking cessation, diet and exercise, treatment of hot flashes, sexual dysfunction, and bone health. A recent study found both reduced recurrence and increased survival in women receiving psychological interventions to improve quality-of-life measures after an 11-year follow-up.38
Refer women to targeted Web sites such as the National Breast Cancer Awareness Month organization (http://www.nbcam.org/), the National Breast Cancer Foundation (http://community.nationalbreastcancer.org/), and the Susan G. Komen Breast Cancer Foundation (http://ww5.komen.org/). Offer treatment for bothersome symptoms. Hot flashes and depression, for example, often related to endocrine therapy, can be treated with selective serotonin reuptake inhibitors (SSRIs). That said, some SSRIs decrease the active metabolite of tamoxifen by inhibiting CYP2D6 enzyme and must, therefore, be used with caution. However, venlafaxine and citalopram are less likely to alter tamoxifen metabolism than other SSRIs.39
CASE When Carrie was 47, she had an abnormal MRI of the left breast. Core needle biopsy and pathology of the lesion revealed an estrogen and progesterone receptor-positive tumor that was negative for HER2 overexpression. She underwent lumpectomy, which revealed a 1.5 cm tumor, followed by a negative sentinel node biopsy, and was diagnosed with stage I (T1N0M0) breast cancer. Carrie had radiation after surgery; she did not require chemotherapy, but was told to take tamoxifen for 5 years. This adjuvant endocrine therapy led to hot flashes and depression, both of which were successfully treated with venlafaxine. Carrie is currently cancer-free and participates in a breast cancer survivor program that includes regular visits with her primary physician and her oncologist.
CORRESPONDENCE Denise Sur, MD, 1920 Colorado Avenue, Santa Monica, CA 90404; [email protected]
Surgery, radiation, and systemic therapy: Making the most of what’s in our arsenal
Breast cancer surgery has changed dramatically over the years. Multiple studies have shown that breast-conserving therapy (lumpectomy followed by radiation) for carefully selected women is comparable to mastectomy for local recurrence and survival. While there has been much interest in determining whether a subset of patients could forego radiation after lumpectomy, a meta-analysis by the Early Breast Cancer Trialists Collaborative Group demonstrated that radiation after lumpectomy provides an absolute local recurrence risk reduction of 19%, and a 5.4% absolute reduction in 15-year breast cancer mortality rates compared with lumpectomy without radiation.1 Thus, radiation after lumpectomy remains the standard of care for all women undergoing breast-conserving therapy, regardless of tumor characteristics.
In certain women with a high risk of recurrence (≥4 positive nodes), radiation is also recommended after mastectomy. Women undergoing mastectomy have numerous options for immediate or delayed breast reconstruction. Consultation with a multidisciplinary team, including a plastic surgeon, prior to any surgical intervention is advised.2
Multiple systemic chemotherapy regimens have been shown to be beneficial in carefully selected patients with breast cancer. Systematic reviews have demonstrated that an anthracycline-based regimen can decrease annual breast cancer mortality by 38% in women <50 years old and by 20% in women ages 50 to 69 years.1 in more recent randomized controlled trials, the addition of taxanes to anthracycline-based regimens has produced promising results.3
Numerous hormonal therapies benefit women with estrogen or progesterone receptor-positive breast cancer. Tamoxifen blocks the activity of estrogen on receptors located in breast cancer tissue, for example; aromatase inhibitors block the conversion of androgens to estrogen; and gonadotropin-releasing hormone (GnRH) analogs such as leuprolide and goserelin suppress ovarian production of estrogen.
For postmenopausal women, options include an aromatase inhibitor alone or tamoxifen followed by an aromatase inhibitor.
In premenopausal women, aromatase inhibitors are not very effective, as decreasing peripheral estrogen stimulates the ovaries to produce more estrogen. Thus, for these patients, adjuvant endocrine therapy consists of tamoxifen, with ovarian ablation (via surgery or radiation) or ovarian suppression with a GnRH analog. If the patient goes through menopause as a result of this therapy, she may benefit from aromatase inhibitors at that time.4,5
Women with breast cancer that overexpresses the HER2 gene benefit from adjuvant treatment with trastuzumab, an anti-HER2 antibody.6 While current guidelines advise treatment for 1 year, multiple studies are evaluating dosing schedules and optimal duration of treatment. for now, patients should be monitored for signs of cardiotoxicity at baseline and every 3 months thereafter until completion of therapy.4
References
1. Early Breast Caner Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;265:1687-1717.
2. Codeiro P. Breast reconstruction after surgery for breast cancer. N Engl J Med. 2008;359:1590-1601.
3. DeLaurentiis M, Cancello G, D’Agostino D, et al. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol. 2008;26:44-53.
4. National Comprehensive Cancer Network. Breast cancer risk reduction clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2003;1:280-296.
5. Baum M, Budzar AU, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002;359:2131-2139.
6. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Herceptin adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-1672.
• Offer screening magnetic resonance imaging (MRI) to patients with a known BRCA 1 or 2 mutation, a strong family history of breast cancer, or a lifetime risk of breast cancer >20% to 25%. B
• For early-stage breast cancer, lumpectomy and sentinel node mapping with excision is the preferred method for staging. A
• Monitor patients receiving tamoxifen for signs and symptoms of venous thromboembolism, cataracts, and uterine malignancy, and patients on aromatase inhibitors for the development of osteoporosis. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Late last year, the US Preventive Services Task Force (USPSTF) sparked a nationwide controversy when it announced that it was recommending against routine screening mammography for women younger than age 50.1 Indeed, that’s a recommendation that many other organizations, including the American Cancer Society (ACS),2 the American College of Obstetricians and Gynecologists (ACOG),3 and the National Comprehensive Cancer Network (NCCN),4 disagree with. But the age at which women should begin routine mammography isn’t the only controversial question. Experts disagree on the benefits of breast self-examination, the optimal frequency of clinical breast exams, and the use of digital mammography—among other issues. This evidence-based review can help you cut through the confusion.
CASE Carrie, a 39-year-old woman who has never been pregnant, comes in for an annual Pap smear and gynecologic exam. She has a negative past medical history, but a positive family history for breast cancer—both her mother and 1 of her sisters had the disease. How would you assess Carrie’s risk of breast cancer, and what preventive measures would you recommend?
Use this predictive model to pinpoint your patient’s risk
When making decisions regarding primary prevention of and screening for breast cancer, an accurate assessment of risk is critical. Many predictive models have been developed with that in mind. The most widely studied, the Gail model, incorporates a number of important risk factors (TABLE 1), including age; race; family history; reproductive factors such as age of menarche, menopause, and first childbirth; and previous history of breast biopsy and atypical findings, to calculate a woman’s 5-year risk.5
A risk calculator (the Breast Cancer Risk Assessment Tool) based on the Gail model is available on the National Cancer Institute’s Web site, at http://www.cancer.gov/bcrisktool. Generally, a score ≥1.66%,5 which indicates that a patient has at least a 1.66% chance of developing breast cancer over the next 5 years, is considered high risk.6,7
CASE Carrie’s 2 first-degree relatives affected by breast cancer and her nulliparous status place her at increased risk. Further questioning reveals a particularly strong family history, as both relatives were diagnosed before the age of 50 (her mom at 45 years of age and her sister, at 39). Carrie’s 5-year risk is 1.8%.
TABLE 1
Risk factors for breast cancer5,29
|
| *African American and Caucasian women are at higher risk compared with Asian, Hispanic, and Native American women. |
| †1 drink/day results in minimal increase in risk; 2-5 drinks/day result in 1.5 increased risk compared with nondrinkers. |
| HRT, hormone replacement therapy; LCIS, lobular carcinoma in situ. |
All women can benefit from these preventive measures
As primary care physicians, we have a responsibility to stress lifestyle modification as the mainstay of breast cancer prevention. Whether or not a woman is at high risk, advise her that maintaining a normal weight, exercising vigorously, limiting alcohol consumption, and breastfeeding are evidence-based methods of primary prevention. Diets low in fat and high in fiber may be associated with a lower risk of invasive breast cancer, but there is no conclusive evidence to support specific dietary interventions to reduce the risk.8-11 Nor has a link between active or passive smoking, antioxidants, or fruit and vegetable intake been firmly established.12
There is a clear association between prolonged estrogen exposure and breast cancer, however. Many reproductive factors, such as early menarche, late menopause, later age at time of first full-term pregnancy, and nulliparity, increase a woman’s exposure to endogenous estrogen—and her risk of developing breast cancer.12,13
Exposure to exogenous estrogen is also linked to the development of breast cancer. In 2002, the Women’s Health Initiative (WHI) was stopped early after a report was released stating that the risks of hormone replacement therapy (HRT)—a higher incidence of cardiovascular events, stroke, and venous thromboembolism, as well as breast cancer—outweighed the benefits.14 Subsequent analyses have found a relationship between the declining incidence of breast cancer and the marked decrease in HRT use prompted by the WHI report. While causality has not been firmly established, multiple studies strongly suggest it.15,16
The association between oral contraceptives (OCs) and breast cancer is more controversial. Some studies have found an increased breast cancer risk among OC users, but both the relative risk and absolute risk were found to be very small and to dissipate 10 years after stopping OC use. More recent studies with newer formulations containing lower doses of estrogen have failed to show an increased risk.8
Breast cancer screening: The parameters have changed
Various organizations have published guidelines for breast cancer screening (TABLE 2), and all are somewhat different. Here’s what you need to know.
Breast self-examination (BSE), which women were previously advised to perform monthly, has not been shown to improve mortality in any age group, and is no longer routinely recommended.17 While both the USPSTF and the Canadian Task Force on Preventive Health Care recommend against teaching women BSE, the ACS, ACOG, and NCCN encourage self-examination—particularly among women older than 40 years.1-4,17,18
Clinical breast examination has an average sensitivity of 50% and detects approximately 5% of mammographically occult cancers.19 It is still not clear whether clinical breast exams save lives, however—a finding that is reflected in the USPSTF’s “I” (insufficient evidence to assess the benefits and harms) recommendation.1 Other consensus guidelines still recommend clinical breast examination, albeit at varying frequencies.
Screening mammography decreases mortality rates by anywhere from 28% to 65%, depending on the statistical model used.20 The benefit is greatest in women between the ages of 50 and 69 years, however, and most groups agree that mammography every 1 to 2 years is advisable for this age group. (There is limited data on the value of mammography for women 70 years of age and older, and no consensus on the age at which to stop screening.1,21) But because the mortality benefit from screening mammography is lower for women aged 40 to 49, guidelines for this age group are more controversial.
Mammography’s sensitivity is affected by a variety of factors, including age and menopausal status, prior breast surgery or radiation, breast density, and the experience of the radiologist. Women in their 40s have denser breast tissue than older women, making mammography less sensitive for this age group. Because of that, and because the overall incidence of breast cancer is lower for women younger than 50, some argue that screening mammography for women between the ages of 40 and 49 years leads to unacceptably high false-positive rates (9.8% annually22) and that the harm associated with mammography may outweigh the benefit. Others counter that tumors in younger women tend to be more aggressive and faster growing, making early detection even more critical than for older women.
What should you advise women in this age group? You might point out that the USPSTF recommends against routine screening, but indicates that the decision to begin (or defer) routine mammography before age 50 should be individualized, based on the needs and values of each patient.1
Digital mammography. A recent study of more than 43,000 women demonstrated that digital mammography is more accurate than film—but only for certain groups: These include women <50 years of age, women with dense breasts, and pre- and perimenopausal women. 23 Because it is still not clear whether the increased accuracy will translate into a mortality benefit, more research is needed before digital mammography is widely adopted. The USPSTF maintains that there is insufficient evidence to assess the benefits and harms of using either digital mammography or magnetic resonance imaging (MRI) rather than film mammography to screen for breast cancer.1
MRI. In 2007, the ACS published guidelines on the use of MRI as an adjunct to mammography for breast cancer screening in high-risk women.24 According to ACS guidelines, screening MRI should be offered to patients with a known BRCA 1 or 2 mutation (5%-10% of all breast cancers are associated with a mutation in the BRCA 1 or BRCA 2 gene, which is transmitted in an autosomal dominant pattern6). It also should be offered to those with a strong family history, or a lifetime risk of developing breast cancer that is >20% to 25%. And finally, MRI should be offered to women who had chest wall radiation when they were between the ages of 10 and 30 years—another significant risk factor for breast cancer—and those with other genetic syndromes that increase their lifetime risk of breast cancer.24
Evidence is insufficient for or against MRI screening for women with a personal history of breast cancer, atypical hyperplasia, or lobular carcinoma in situ, however, and neither breast ultrasound (which is generally used diagnostically, not for screening purposes) nor MRI has been shown to be helpful as a screening tool in women with <15% lifetime risk of developing breast cancer.24,25
TABLE 2
Guidelines for breast cancer screening for women with average risk
| Organization | Age (years) | Breast self-exam | Clinical breast exam | Mammography |
|---|---|---|---|---|
| American Cancer Society2 | 20-40 | Optional | Every 3 y | NA |
| >40 | Encourages | Annually | Annually | |
| American College of Obstetricians and Gynecologists3 | 40-49 | Encourages | Annually | 1-2 y |
| 50-69 | Encourages | Annually | Annually | |
| Canadian Task force on Preventive Health Care18 | 40-49 | Recommends against teaching | Insufficient evidence | Insufficient evidence |
| 50-69 | Recommends against teaching | 1-2 y | 1-2 y | |
| National Comprehensive Cancer Network4 | 20-40 | Encourages | 1-3 y | NA |
| >40 | Encourages | Annually | Annually | |
| US Preventive Services Task Force1 | 40-49 | Recommends against teaching | Insufficient evidence | Not routinely recommended |
| 50-74 | Recommends against teaching | Insufficient evidence | Every 2 y | |
| NA, not addressed. | ||||
When to consider chemoprevention
For women like Carrie, who are at high risk of developing breast cancer, selective estrogen receptor modulator (SERM) therapy and surgical interventions may be options to consider. The Breast Cancer Prevention Trial demonstrated the efficacy of tamoxifen as a preventive agent. This landmark trial showed that for high-risk women older than 35, 5 years of tamoxifen therapy can reduce the incidence of invasive breast cancer by nearly 50%.26
Women with the BRCA 1 or 2 mutation—all of whom should be offered genetic counseling—were included in the study. Tamoxifen reduced the incidence of breast cancer in BRCA 2 carriers by 62%, the researchers found, but did not reduce risk in carriers of the BRCA 1 gene. This is likely due to the high prevalence of estrogen receptor-negative breast cancers among BRCA 1 carriers.26
More recently, the Study of Tamoxifen and Raloxifene (STAR) trial compared the efficacy of tamoxifen and raloxifene, a second-generation SERM, in high-risk postmenopausal women ages 35 and older. The drugs were found to be equally effective in reducing the risk of invasive breast cancer, but raloxifene had a better side effect profile, with a lower incidence of thromboembolism and cataracts. 27
What the guidelines call for. In 2003, the USPSTF recommended that clinicians discuss chemoprevention with women at high risk for breast cancer and low risk for adverse effects of SERMs.28
The most recent update to the NCCN breast cancer risk reduction guidelines recommends that clinicians offer tamoxifen to premenopausal women with a 5-year projected breast cancer risk ≥1.7% and offer tamoxifen or raloxifene to high-risk postmenopausal women.29 It is worth noting, however, that SERMs can have significant adverse effects, including venous thromboembolism, stroke, cataracts, uterine malignancy, and hot flashes, while lifestyle modifications and the avoidance of HRT have few, if any, negative effects.
CASE After consultation with a genetic counselor, Carrie underwent testing for both the BRCA 1 and BRCA 2 mutations. She tested negative for both. She declined chemoprevention and prophylactic surgery, opting for enhanced screening with yearly mammography and MRI and lifestyle modification instead.
When a mass is found
For women ages 30 or older with palpable masses or solid masses ≥2 cm found on imaging, core needle biopsy is recommended.30,31 Biopsy is indicated for women younger than 30 as well, if the mass is >2 cm or imaging is suspicious. In general, a needle biopsy read as benign is considered adequate for diagnostic purposes only if the lesion appeared benign on imaging.
For lesions shown to be cystic on imaging, recommendations for follow-up or additional testing are based on the characteristics of the cyst. For simple cysts, 2- to 4-month follow up for stability, followed by routine screening, is adequate.21 Additional evaluation of complex cysts is indicated, including aspiration for complicated cysts and biopsy for complex cysts. After aspiration, surgical excision of bloody aspirates or persistent masses is recommended.30,31
Staging using the TNM system
The TNM (tumor, node, metastases) classification system is used for the staging of breast cancer:
- T refers to the tumor type, size, and extent of local involvement
- N describes regional lymph node involvement
- M refers to distant metastases.
The TNM classifications are also grouped by stage (I through IV).,
Lumpectomy and sentinel node mapping with excision is the preferred method for staging of early-stage breast cancer without palpable lymphadenopathy—provided that the surgical team has documented experience with sentinel node biopsy.32 Sentinel node biopsy is preferred because of its safety, low (<10%) false negative rate, and decreased morbidity compared with full axillary dissection, although dissection is recommended for patients with more advanced cancer or a positive sentinel node.32 The comparative effects of sentinel node biopsy vs axillary node dissection on tumor recurrence and patient survival are not known.33
Testing for tumor markers such as estrogen and progesterone receptors and human epidermal growth factor receptor 2 (HER2) expression status in biopsy-proven breast cancer is now the standard of care. Seventy percent of breast cancers are estrogen receptor-positive, with increasing frequency associated with older age.34 Estrogen/progesterone receptor positivity is associated with a more favorable outcome, and multiple hormonal therapies can be aimed at these receptors.34 While HER2 overexpression—which occurs in 15% to 30% of newly diagnosed breast cancers35—is associated with more aggressive tumors, women with this type of tumor cell can benefit from trastuzumab, an anti-HER2 drug.36
Key factors that affect prognosis
Important factors affecting prognosis and treatment of localized breast cancer are tumor size, age and menopausal status, tumor expression of hormone receptors and/ or the HER2 protein, as well as the status of the draining axillary nodes. Factors that predict a greater chance of recurrence include the spread of disease to axillary nodes, larger tumor size, invasive histology, inflammatory pathology, lack of estrogen/progesterone receptors, and age <50 years or premenopausal status.
Treatment options include surgical resection, radiation, and systemic adjuvant therapy in the form of chemotherapy, endocrine therapy, or anti-HER2 monoclonal antibodies.37 (For more on treatment, see “Surgery, radiation, and systemic therapy: Making the most of what’s in our arsenal” at jfponline.com.)
Don’t overlook quality-of-life issues
Follow-up of breast cancer patients should go beyond treatment and work-up for recurrence and metastatic disease to focus on health and lifestyle issues, such as stress reduction, mood, smoking cessation, diet and exercise, treatment of hot flashes, sexual dysfunction, and bone health. A recent study found both reduced recurrence and increased survival in women receiving psychological interventions to improve quality-of-life measures after an 11-year follow-up.38
Refer women to targeted Web sites such as the National Breast Cancer Awareness Month organization (http://www.nbcam.org/), the National Breast Cancer Foundation (http://community.nationalbreastcancer.org/), and the Susan G. Komen Breast Cancer Foundation (http://ww5.komen.org/). Offer treatment for bothersome symptoms. Hot flashes and depression, for example, often related to endocrine therapy, can be treated with selective serotonin reuptake inhibitors (SSRIs). That said, some SSRIs decrease the active metabolite of tamoxifen by inhibiting CYP2D6 enzyme and must, therefore, be used with caution. However, venlafaxine and citalopram are less likely to alter tamoxifen metabolism than other SSRIs.39
CASE When Carrie was 47, she had an abnormal MRI of the left breast. Core needle biopsy and pathology of the lesion revealed an estrogen and progesterone receptor-positive tumor that was negative for HER2 overexpression. She underwent lumpectomy, which revealed a 1.5 cm tumor, followed by a negative sentinel node biopsy, and was diagnosed with stage I (T1N0M0) breast cancer. Carrie had radiation after surgery; she did not require chemotherapy, but was told to take tamoxifen for 5 years. This adjuvant endocrine therapy led to hot flashes and depression, both of which were successfully treated with venlafaxine. Carrie is currently cancer-free and participates in a breast cancer survivor program that includes regular visits with her primary physician and her oncologist.
CORRESPONDENCE Denise Sur, MD, 1920 Colorado Avenue, Santa Monica, CA 90404; [email protected]
Surgery, radiation, and systemic therapy: Making the most of what’s in our arsenal
Breast cancer surgery has changed dramatically over the years. Multiple studies have shown that breast-conserving therapy (lumpectomy followed by radiation) for carefully selected women is comparable to mastectomy for local recurrence and survival. While there has been much interest in determining whether a subset of patients could forego radiation after lumpectomy, a meta-analysis by the Early Breast Cancer Trialists Collaborative Group demonstrated that radiation after lumpectomy provides an absolute local recurrence risk reduction of 19%, and a 5.4% absolute reduction in 15-year breast cancer mortality rates compared with lumpectomy without radiation.1 Thus, radiation after lumpectomy remains the standard of care for all women undergoing breast-conserving therapy, regardless of tumor characteristics.
In certain women with a high risk of recurrence (≥4 positive nodes), radiation is also recommended after mastectomy. Women undergoing mastectomy have numerous options for immediate or delayed breast reconstruction. Consultation with a multidisciplinary team, including a plastic surgeon, prior to any surgical intervention is advised.2
Multiple systemic chemotherapy regimens have been shown to be beneficial in carefully selected patients with breast cancer. Systematic reviews have demonstrated that an anthracycline-based regimen can decrease annual breast cancer mortality by 38% in women <50 years old and by 20% in women ages 50 to 69 years.1 in more recent randomized controlled trials, the addition of taxanes to anthracycline-based regimens has produced promising results.3
Numerous hormonal therapies benefit women with estrogen or progesterone receptor-positive breast cancer. Tamoxifen blocks the activity of estrogen on receptors located in breast cancer tissue, for example; aromatase inhibitors block the conversion of androgens to estrogen; and gonadotropin-releasing hormone (GnRH) analogs such as leuprolide and goserelin suppress ovarian production of estrogen.
For postmenopausal women, options include an aromatase inhibitor alone or tamoxifen followed by an aromatase inhibitor.
In premenopausal women, aromatase inhibitors are not very effective, as decreasing peripheral estrogen stimulates the ovaries to produce more estrogen. Thus, for these patients, adjuvant endocrine therapy consists of tamoxifen, with ovarian ablation (via surgery or radiation) or ovarian suppression with a GnRH analog. If the patient goes through menopause as a result of this therapy, she may benefit from aromatase inhibitors at that time.4,5
Women with breast cancer that overexpresses the HER2 gene benefit from adjuvant treatment with trastuzumab, an anti-HER2 antibody.6 While current guidelines advise treatment for 1 year, multiple studies are evaluating dosing schedules and optimal duration of treatment. for now, patients should be monitored for signs of cardiotoxicity at baseline and every 3 months thereafter until completion of therapy.4
References
1. Early Breast Caner Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;265:1687-1717.
2. Codeiro P. Breast reconstruction after surgery for breast cancer. N Engl J Med. 2008;359:1590-1601.
3. DeLaurentiis M, Cancello G, D’Agostino D, et al. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol. 2008;26:44-53.
4. National Comprehensive Cancer Network. Breast cancer risk reduction clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2003;1:280-296.
5. Baum M, Budzar AU, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002;359:2131-2139.
6. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Herceptin adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-1672.
1. US Preventive Services Task Force Screening for breast cancer. Available at: http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm. Accessed September 2, 2010.
2. American Cancer Society. American Cancer Society guidelines for the early detection of cancer. Available at: http://www.cancer.org/Healthy/FindCancerEarly/CancerScreeningGuidelines/american-cancer-society-guidelines-for-the-early-detection-of-cancer. Accessed September 2, 2010.
3. American College of Obstetricians and Gynecologists. Response of the American College of Obstetricians and Gynecologists to the new breast cancer screening recommendations from the US Preventive Services Task Force. Available at: http://www.acog.org/from_home/misc/uspstfresponse.cfm. Accessed September 2, 2010.
4. National Comprehensive Cancer Network. Breast cancer screening and diagnosis. Clinical Practice Guidelines in Oncology-V.1.2010. Fort Washington, Pa: National Comprehensive Cancer Network: November 3, 2009. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed September 17 , 2010.
5. National Cancer Institute. Breast cancer risk assessment tool. Available at: http://www.cancer.gov/bcrisktool/. Accessed September 2, 2010
6. Robson M, Offit K. Clinical practice. Management of an inherited predisposition to breast cancer. N Engl J Med. 2007;357:154-162.
7. 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.
8. Cummings SR, Tice JA, Bauer S, et al. Prevention of breast cancer in postmenopausal women: approaches to estimating and reducing risk. J Natl Cancer Inst. 2009;18:101,-384-398.
9. Prentice RL, Caan B, Chlebowski RT, et al. Low-fat dietary pattern and risk of invasive breast cancer: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006;295:629-642.
10. 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 Women’s Healthy Eating and Living (WHEL) randomized trial. JAMA. 2007;298:289-298.
11. Chlebowski RT, Blackburn GL, Thomson CA, et al. Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention Nutrition Study (WINS). J Natl Cancer Inst. 2006;98:1767-1776.
12. PDQ Cancer Information Summary. Breast Cancer Prevention (PRQ) – Health Professional. Date last modified April 30, 2009. Available at: http://www.cancer.gov/cancertopics/pdq/prevention/breast/healthprofessional. Accessed May 12, 2009.
13. Hulka BS, Moorman PG. Breast cancer: hormones and other risk factors. Maturitas. 2001;38:103-113.
14. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.
15. Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med. 2007;356:1670-1674.
16. Chlebowski RT, Kuller LH, Prentice RL, et al. WHI Investigators. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med. 2009;360:573-587.
17. Kosters JP, Gotzsche PC. Regular self-examination or clinical examination for early detection of breast cancer. Cochrane Database Syst Rev. 2003;(2):CD003373.-
18. Canadian Task Force on the Periodic Health Examination Ottawa, Canada: Health Canada; 1994:788-795 (reaffirmed by the Canadian Task Force on the Periodic Health Examination 1999, 2001).Available at: http://www.ctfphc.org/index/html. Accessed August 12, 2009.
19. Green BB, Taplin SH. Breast cancer screening controversies. J Am Board Fam Pract. 2003;16:233-241.
20. Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005;353:1784-1792.
21. Tice JA, Kerlikowske K. Screening and prevention of breast cancer in primary care. Prim Care. 2009;36:533-558.
22. US Preventive Services Task Force. Screening for breast cancer. Systematic evidence review update for the US Preventive Services Task Force. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=es74. Accessed September 2, 2010.
23. Pisano ED, Gatsonis C, Hendrick E, et al. Digital Mammographic Imaging Screening Trial (DMIST) Investigators Group. Diagnostic performance of digital versus film mammography for breast-cancer screening. N Engl J Med. 2005;353:1773-1783.
24. Saslow D, Boetes C, Burke W, et al. American Cancer Society Breast Cancer Advisory Group. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57:75-89.
25. Berg W, Blume J, Cormack J, et al. Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer. JAMA. 2008;299:2151-2163.
26. King M, Wieand S, Hale K, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001;286:2251-2256.
27. 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;295:2727-2741.
28. Berg AO. US Preventive Services Task Force. Chemoprevention of breast cancer: recommendations and rationale. Am J Nurs. 2003;103:107-113.
29. National Comprehensive Cancer Network. Breast cancer risk reduction. Clinical Practice Guidelines in Oncology-V.2.2010. Fort Washington, Pa: National Comprehensive Cancer Network; August 7, 2010. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed September 17, 2010.
30. Sickles EA, Filly RA, Cllen PW. Benign breast lesions: ultrasound detection and diagnosis. Radiology. 1984;151:467.-
31. Beavers TB, Anderson BO, Bonaccio E, et al. NCCN clinical practice guidelines in oncology: breast cancer screening and diagnosis. J Natl Compr Canc Netw. 2009;7:1060-1096.
32. Mansel RE, Fallowfield L, Kissin M, et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC trial. J Natl Canc Inst. 2006;98:599-609
33. Lyman GH, Guiliano AE, Somerfield MR, et al. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early- stage breast cancer. J Clin Oncol. 2005;23:7703-7720.
34. Turner N, Jones A. Management of breast cancer-Part II. BMJ. 2008;337:a540.-
35. Harris L, Fritsche H, Mennel R, et al:. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer J Clin Oncol. 2007;25:5287-5312.
36. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Herceptin adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-1672.
37. PDQ Cancer Information Summary Breast cancer treatment– health professional. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/breast/HealthProfessional. Accessed May 12, 2009.
38. Anderson BL, Yang HC, Farrar WB, et al. Psychologic intervention improves survival for breast cancer patients: a randomized clinical trial. Cancer. 2008;113:3450-3458.
39. 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;97:30-39.
1. US Preventive Services Task Force Screening for breast cancer. Available at: http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm. Accessed September 2, 2010.
2. American Cancer Society. American Cancer Society guidelines for the early detection of cancer. Available at: http://www.cancer.org/Healthy/FindCancerEarly/CancerScreeningGuidelines/american-cancer-society-guidelines-for-the-early-detection-of-cancer. Accessed September 2, 2010.
3. American College of Obstetricians and Gynecologists. Response of the American College of Obstetricians and Gynecologists to the new breast cancer screening recommendations from the US Preventive Services Task Force. Available at: http://www.acog.org/from_home/misc/uspstfresponse.cfm. Accessed September 2, 2010.
4. National Comprehensive Cancer Network. Breast cancer screening and diagnosis. Clinical Practice Guidelines in Oncology-V.1.2010. Fort Washington, Pa: National Comprehensive Cancer Network: November 3, 2009. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed September 17 , 2010.
5. National Cancer Institute. Breast cancer risk assessment tool. Available at: http://www.cancer.gov/bcrisktool/. Accessed September 2, 2010
6. Robson M, Offit K. Clinical practice. Management of an inherited predisposition to breast cancer. N Engl J Med. 2007;357:154-162.
7. 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.
8. Cummings SR, Tice JA, Bauer S, et al. Prevention of breast cancer in postmenopausal women: approaches to estimating and reducing risk. J Natl Cancer Inst. 2009;18:101,-384-398.
9. Prentice RL, Caan B, Chlebowski RT, et al. Low-fat dietary pattern and risk of invasive breast cancer: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006;295:629-642.
10. 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 Women’s Healthy Eating and Living (WHEL) randomized trial. JAMA. 2007;298:289-298.
11. Chlebowski RT, Blackburn GL, Thomson CA, et al. Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention Nutrition Study (WINS). J Natl Cancer Inst. 2006;98:1767-1776.
12. PDQ Cancer Information Summary. Breast Cancer Prevention (PRQ) – Health Professional. Date last modified April 30, 2009. Available at: http://www.cancer.gov/cancertopics/pdq/prevention/breast/healthprofessional. Accessed May 12, 2009.
13. Hulka BS, Moorman PG. Breast cancer: hormones and other risk factors. Maturitas. 2001;38:103-113.
14. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.
15. Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med. 2007;356:1670-1674.
16. Chlebowski RT, Kuller LH, Prentice RL, et al. WHI Investigators. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med. 2009;360:573-587.
17. Kosters JP, Gotzsche PC. Regular self-examination or clinical examination for early detection of breast cancer. Cochrane Database Syst Rev. 2003;(2):CD003373.-
18. Canadian Task Force on the Periodic Health Examination Ottawa, Canada: Health Canada; 1994:788-795 (reaffirmed by the Canadian Task Force on the Periodic Health Examination 1999, 2001).Available at: http://www.ctfphc.org/index/html. Accessed August 12, 2009.
19. Green BB, Taplin SH. Breast cancer screening controversies. J Am Board Fam Pract. 2003;16:233-241.
20. Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005;353:1784-1792.
21. Tice JA, Kerlikowske K. Screening and prevention of breast cancer in primary care. Prim Care. 2009;36:533-558.
22. US Preventive Services Task Force. Screening for breast cancer. Systematic evidence review update for the US Preventive Services Task Force. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=es74. Accessed September 2, 2010.
23. Pisano ED, Gatsonis C, Hendrick E, et al. Digital Mammographic Imaging Screening Trial (DMIST) Investigators Group. Diagnostic performance of digital versus film mammography for breast-cancer screening. N Engl J Med. 2005;353:1773-1783.
24. Saslow D, Boetes C, Burke W, et al. American Cancer Society Breast Cancer Advisory Group. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57:75-89.
25. Berg W, Blume J, Cormack J, et al. Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer. JAMA. 2008;299:2151-2163.
26. King M, Wieand S, Hale K, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001;286:2251-2256.
27. 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;295:2727-2741.
28. Berg AO. US Preventive Services Task Force. Chemoprevention of breast cancer: recommendations and rationale. Am J Nurs. 2003;103:107-113.
29. National Comprehensive Cancer Network. Breast cancer risk reduction. Clinical Practice Guidelines in Oncology-V.2.2010. Fort Washington, Pa: National Comprehensive Cancer Network; August 7, 2010. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed September 17, 2010.
30. Sickles EA, Filly RA, Cllen PW. Benign breast lesions: ultrasound detection and diagnosis. Radiology. 1984;151:467.-
31. Beavers TB, Anderson BO, Bonaccio E, et al. NCCN clinical practice guidelines in oncology: breast cancer screening and diagnosis. J Natl Compr Canc Netw. 2009;7:1060-1096.
32. Mansel RE, Fallowfield L, Kissin M, et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC trial. J Natl Canc Inst. 2006;98:599-609
33. Lyman GH, Guiliano AE, Somerfield MR, et al. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early- stage breast cancer. J Clin Oncol. 2005;23:7703-7720.
34. Turner N, Jones A. Management of breast cancer-Part II. BMJ. 2008;337:a540.-
35. Harris L, Fritsche H, Mennel R, et al:. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer J Clin Oncol. 2007;25:5287-5312.
36. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Herceptin adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-1672.
37. PDQ Cancer Information Summary Breast cancer treatment– health professional. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/breast/HealthProfessional. Accessed May 12, 2009.
38. Anderson BL, Yang HC, Farrar WB, et al. Psychologic intervention improves survival for breast cancer patients: a randomized clinical trial. Cancer. 2008;113:3450-3458.
39. 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;97:30-39.