Breast Cancer Screening and Prevention

1. Breast Cancer Screening and Prevention

2. What factors put persons at higher risk for breast cancer? • History of chest radiation (RR 26.0) • History of breast cancer (RR varies) • Extremely dense breasts compared with fatty breasts (RR 4.5) • History biopsy with atypical hyperplasia 3.7 • Two 1st-degree relatives with breast cancer vs none (RR 3.5) • One 1st-degree relative with breast cancer vs none (RR 2.5) • Menopause >55 y compared with <45 y (RR 2.0) • Nulliparity or 1st full-term pregnancy ≥30 y (RR 2.0) • History benign breast biopsy vs no breast biopsy (RR 1.7) continued…

3. Menarche before age 12 years compared with >14 y (RR 1.5) • Postmenopausal obesity vs normal weight (RR 1.5) • Heterogeneously dense or extremely dense breasts compared with fatty or fibroglandular breasts (RR 1.3) • Current use of combination menopausal hormone therapy vs never users (RR 1.2) • Moderate alcohol use compared with abstention (RR 1.1)

4. Are there tools that can help patients and physicians judge the risk? • NCI Breast Cancer Risk Assessment Tool • Less accurate for women with markedly positive family histories and women over 70 years • Main limitation: omits breast density as risk factor • Breast Cancer Surveillance Consortium • Illustrates importance of breast density and age • Ontario Family History Assessment tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, Family History Screen 7 • All useful for women with family histories of breast cancer

5. Decision aids • Help clinicians and patients understand risk estimates • Use to facilitate conversations, not to make decisions • Example: www.breastscreeningdecisions.com • Helps women 40–49 years visualize effect of screening mammography • Creates a summary of personal values about breast cancer screening

6. CLINICAL BOTTOM LINE: Risk Assessment... • Breast cancer is common among U.S. women • Risk factors: older age, increased duration of endogenous estrogen, increased breast density, presence of proliferative breast disease, family history of breast cancer • Genetic mutations substantially increase risk • Online calculators can help assess risk • Periodic risk assessment can mitigate high risk and develop individualized screening plan

7. Who should be screened for breast cancer? • We use age-based protocols to determine who to screen • Strong connection between age and breast cancer risk • Many women who develop breast cancer do not fall into a clear high-risk group • Protocols may be modified for high-risk women • No low-risk groups (other than young age) have been identified in which screening can clearly be omitted

8. Is screening effective in reducing mortality? • Screening reduces breast cancer mortality 15%-20% • Women 40-59 y: reduction in breast cancer mortality smaller magnitude and less statistically significant • Women 60-69 y, reduction highly significant • Women 70-74 y, reduction has not been shown to be significant  • Screening has not been shown to reduce all-cause mortality

9. What are the harms? • False positive results • Unnecessary follow-up tests and biopsies • Anxiety and psychological distress • Overdiagnosis • Cancer that would never have progressed to clinical importance in absence of screening • Harms of treatment without any benefit • Once a cancer is diagnosed, no way to determine whether it is a case of overdiagnosis • Radiation exposure (may be a small risk)

10. What is the current evidence for screening women in their 40s? • USPSTF: 8% reduced risk breast cancer mortality • ACS: 15% reduced risk breast cancer mortality • Initiating screening at age 40 averts about 1 breast cancer death per 1000 women screened • Most averted deaths among women aged 45–49 • Harms include false-positive results and overdiagnosis

11. When should average-risk patients stop screening? • Breast cancer incidence increases with age • 26% breast cancer deaths attributed to diagnosis at >74y • Continue biennial screening until the remaining life expectancy is about 10 years  • Biennial screening estimated to reduce breast cancer deaths and harms for women in their 70s • Benefit of screening is low among women ≥80

12. How frequently should patients be screened? • Annual screening recommended • Women with higher risk of breast cancer • Women who value a greater mortality benefit even at expense of higher likelihood of false positive result or overdoagnosis • Biennial screening maintains about 80% mortality benefits of annual screening

13. What are the performance characteristics of various approaches to screening? • Digital mammography • Sensitivity and specificity increases with age and decreases with increasing breast density • 3-D mammography (tomosynthesis+ digital mammography) • May improve sensitivity and specificity • Contrast-enhanced MRI • Women at very high risk • More sensitive but less specific than mammography

14. How should clinicians and patients select from the different screening methods? • Mammography: for average-risk women • Tomosynthesis: wheh breast cancer risk is increased • MRI: lack of evidence for effectiveness in average-risk women, because of excessive false-positives, high cost • Ultrasonography: no evidence it improves results over mammography screening for average-risk women • Breast self-exam: instructing average-risk women does not improve mortality, causes excess benign biopsies

15. Should persons with above-average risk be screened differently from average-risk persons? • Moderately increased risk • Reasonable to initiate screening at younger age • Screen with annual mammography, tomosynthesis • Another reasonable strategy: follow screening recommendations for average risk women • Very high risk • More aggressive screening strategies are appropriate • Start mammography at age 25 or 5-10 years before youngest person with breast cancer in the family • Add breast MRI screening as adjunct to mammography

16. CLINICAL BOTTOM LINE: Screening... • Screening mammography reduces breast cancer mortality • Harms: false-positive results, overdiagnosis, radiation • Biennial screening averts 80% deaths averted by annual screening • Decisions about screening: consider woman’s values and her personal level of risk • Annual screening and digital breast tomosynthesis most appropriate for women with extremely dense breasts and those with 1-2 first degree family members with breast cancer • Reserve MRI for women at very high risk

17. How should a patient at increased risk for breast cancer be counseled about personal risk? What is the role of the genetic counselor? • Genetic counseling reduces worry about breast cancer and increases the accuracy of risk perception • USPSTF (2014) • Offer genetic counseling and testing to women with ≥1 family members with BRCA1 / BRCA2 mutation • Refer only high-risk women for genetic counseling and testing • No recommendation for a specific risk level as threshold for referral

18. What are the options for prevention in eligible women? • Healthy lifestyle, chemoprevention, and prophylactic mastectomy • Healthy behaviors reduce breast cancer risk • Physical activity reduces breast cancer risk about 12% • Diets high in fruits and vegetables modestly reduce risk • Alcohol use increases risk in a dose-response effect • Vitamins E and D do not reduce breast cancer risk • For women with hereditary breast cancer mutations, prophylactic bilateral mastectomy is an effective alternative to chemoprophylaxis

19. What are the benefits of chemoprevention? • Selective Estrogen Receptor Modulators (SERMs) • Tamoxifen, raloxifene: stimulate some estrogen receptors while blocking others • Reduce risk for ER+ invasive breast cancer • Tamoxifen appears slightly more effective than raloxifene after 7 y, but adverse effects differ • No difference in osteoporotic fracture rates • Aromatase Inhibitors (AIs) • Anastrazole, exemestane: inhibit the enzyme aromatase, which converts androgens to estrogens • AIs have not been compared to each other • SERMs have not been directly compared to AIs

20. What are the harms from chemoprevention? • SERMs • Tamoxifen: endometrial cancer and VTE (RR 2.0) for women ≥50 y • Raloxifene: VTE risk but not endometrial cancer risk • ? stroke risk (not significant in USPSTF meta-analysis) • Aromatase Inhibitors • Anastrozole: musculoskeletal side effects, hypertension, vaginal dryness, vasomotor symptoms • Exemestane: joint pain, diarrhea, vasomotor symptoms continued…

21. Comparing chemoprevention agents • Tamoxifen (compared to raloxifine) • women more likely to remain sexually active and to have less difficulty with sexual interest and enjoyment • more vasomotor symptoms, bladder problems, leg cramps • Raloxifene (compared to tamoxifen) • reduced risk for uterine cancer and slightly lower risk for VTE • more musculoskeletal problems, dyspareunia, and weight gain

22. How should clinicians choose among the chemoprevention strategies? • No chemoprevention drugs known to improve survival • If estimated 5-y breast cancer risk ≥3%, consider SERM • SERMs but not AIs are FDA-approved for prevention • Tamoxifencan be used in all eligible women • Avoid AIs in premenopausal women (ovarian stimulation) • Do not use tamoxifen in postmenopausal women • In postmenopausal women choice depends mainly on QOL effects and cost

23. How long should women receive chemoprevention to prevent breast cancer? • Optimum duration not established • Protective effect of 5-year course of tamoxifen lasts a median of 16 years • 10-year course may confer additional benefit, but differential in benefit and risk is not defined

24. For which women is chemoprevention or surgery more cost-effective? • Chemoprevention • Younger women • Women at highest risk • Women without a uterus and at low risk for VTE • Prophylactic bilateral mastectomy • Women at high-risk because of genetic mutations • More cost effective when combined with bilateral oophorectomy

25. CLINICAL BOTTOM LINE: Prevention... • Healthy behaviors reduce breast cancer risk • Genetic counseling and testing guides decisions about screening and prevention for women at high risk • Depending on the level of risk, prevention options include: • Chemoprevention • Prophylactic mastectomy (with or without oophorectomy) • For women with BRCA mutations, surgery may confer greatest benefit and be most cost effective