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Breast Cancer Screening: Handling the Trade-Offs

Breast Cancer Screening: Handling the Trade-Offs. Lisle Nabell MD Associate Professor of Medicine UAB Comprehensive Cancer Center. Ten Leading Cancer Types for Estimated New Cancer Cases and Deaths, by Sex, United States, 2009. From Jemal, A. et al. CA Cancer J Clin 2009;59:225-249.

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Breast Cancer Screening: Handling the Trade-Offs

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  1. Breast Cancer Screening: Handling the Trade-Offs Lisle Nabell MD Associate Professor of Medicine UAB Comprehensive Cancer Center

  2. Ten Leading Cancer Types for Estimated New Cancer Cases and Deaths, by Sex, United States, 2009 From Jemal, A. et al. CA Cancer J Clin 2009;59:225-249.

  3. Age-specific Breast Cancer Incidence Among Females by Age Group and Race/Ethnicity, United States, 2002 to 2004 From Mahoney, M. C. et al. CA Cancer J Clin 2008;58:347-371.

  4. Breast Cancer Disease Progression 0 5 10 Years of growth* 1012 1010 108 106 104 102 10 cm Very early breast cancer (undetectable) Clinicalbreast cancer 1 cm Number of cells DCIS 1 mm 0 5 10 15 20 25 30 35 40 Number of cell doublings DCIS = Ductal carcinoma in situ. *Note: 90-day doubling  40 doublings = 3,600 days (approximately 10 years). Harris JR, et al, eds. Breast Diseases, 2nd ed. Philadelphia: JB Lippincott; 1991:165-189.

  5. Mammography Screening for Breast Cancer • Screening mammogram entails 2 x-ray images of each breast: one taken from the top (craniocaudal or CC) and the other from the side (mediolateral oblique MLO) • Randomized trials suggest an overall sensitivity of 75%, lower in women with dense breast tissue and in women harboring BRCA mutations • Digital mammography allows for digital storage and manipulation of images; may be somewhat better with regard to detections of lesions in younger women

  6. Mammography Screening for Breast Cancer • Single-view mammography is less sensitive than 2-view mammography. In a UK NHS comparison, sites using single-view films were 19% less successful in detecting breast cancer compared to 2-view (76% versus 95%) – especially among smaller cancers Young et al Br J Raadiol 1997;70:482-488 Blanks et al Clin Radiol 2005;60:674-680

  7. Breast density patterns Cummings, S. R. et al. J. Natl. Cancer Inst. 2009 101:384-398

  8. Illustration of the quantitative estimation of breast density from a digitized image of a mammogram Cummings, S. R. et al. J. Natl. Cancer Inst. 2009 101:384-398

  9. Magnetic Resonance Imaging (MRI) • MRI utilizes magnetic fields to produce cross-sectional images of tissue structures; requires dedicated breast MRI coils and experience • Overall, the sensitivity of MRI is superior to mammography but specificity is lower, resulting in a higher false-positive rate • Strongest data for use is in high-risk women Leach et al Lancet. 2005;365:1769-1778 Port et al Ann Surg Oncol. 2007;14:1051-1057. Kuhl et al JCO 201028:1450-1457.

  10. Prospective Study of Women with Elevated Breast Cancer Risk: The EVA Trial • Study of 687 women at elevated risk of breast cancer development • Annual screening with CBE, mammography, US, and MRI over a 3 year time period • Mean age of 44; 72% were premenopausal • 63% had a family history of breast cancer • 27 of these women (3.9%) developed breast cancer during the study period with 21/27 having Tis or invasive cancer < 10 mm

  11. Cancer yield of the different imaging methods, used alone or in combination Kuhl, C. et al. J Clin Oncol; 28:1450-1457 2010

  12. ACS Guidelines for Screening Average Risk Women • Clinical breast exam every 1-3 years starting at age 20 and annually after age 40 • Annual mammography beginning at age 40; no upper age limit • Breast “awareness” Consensus Statement from ACS and NCI in 1997 with updates

  13. ACS Guidelines for Screening High Risk Women Definition: Life-time risk of Breast Cancer of ~20% • Known or suspected inherited susceptibility for breast/ovarian cancer • Women over age 35 with increased risk of breast cancer development • Having undergone mantle irradiation at a young age for Hodgkin’s (10-30 years of age); maybe less with current RT techniques

  14. Cumulative incidence (middle line) of breast cancer as a function of age of the cohort of female survivors of Hodgkin's disease, with 95% CIs (upper and lower curves) Bhatia, S. et al. J Clin Oncol; 21:4386-4394 2003

  15. Estimating Risk of Cancer Development or BRCA1/2 Status • Risk Factor Models: • Gail model using age, race, personal history of atypical hyperplasia, reproductive history, number of biopsies: components are in www.cancer.gov/bcrisktool • Claus model includes information on up to 2 first/second degree relatives with breast cancer, age of onset; most helpful for women with a family history • Cuzick-Tryer model assesses FH, hormonal factors, low-penetrantgenes and benign breast disease J Med Genetics 2003;40:807-814. • BRCAPRO incorporates data on BRCA1/2 mutation prevalence: http://astor.som.jhmi.edu/BayesMendel/brcapro.html • BOADICEA model of genetic susceptibility in Br J Cancer 2004;91:1580-1590

  16. ACS Guidelines for Screening: High Risk Women Known or Suspected Mutation Carrier or Radiation Exposure or Elevated Lifetime Risk > ~20% • Annual screening mammography and MRI beginning at age 30 • Clinical breast exam every 6-12 months • Breast awareness

  17. Guidelines from the US Preventative Services Task Force (USPSTF) • Independent body established in 1984 comprised of nonfederal experts in primary care and preventive medicine • The USPSTF examined the effectiveness of 5 screening modalities with regard to benefit and harm of screening and used population modeling to compare expected health outcomes and resource requirements

  18. Guidelines from the US Preventative Services Task Force (USPSTF) Rating system: • A, recommendation for the service, with expectation of high benefit; • B, recommendation for the service, with expectation that the net benefit is moderate; • C, recommendation against routinely providing the service; • D, recommendation against the service; • I, insufficient evidence to recommend for or against the service

  19. Nelson H D et al. Ann Intern Med 2009;151:727-737

  20. Mammography Screening Trials For Women Age 40-49 Included in Meta-analysis. Nelson H D et al. Ann Intern Med 2009;151:727-737

  21. Pooled relative risk for breast cancer mortality from mammography screening trials compared with control for women aged 39 to 49 years.CNBSS-1 = Canadian National Breast Screening Study-1; CrI = credible interval; HIP = Health Insurance Plan of Greater New York.* Swedish Two-County trial. Nelson H D et al. Ann Intern Med 2009;151:727-737

  22. Pooled RRs for Breast Cancer Mortality From Mammography Screening Trials for All Ages. Nelson H D et al. Ann Intern Med 2009;151:727-737

  23. Age-Specific Screening Results From the BCSC. Nelson H D et al. Ann Intern Med 2009;151:727-737

  24. Screening for Breast Cancer: SummaryUSPSTF Ann Int Med, 2009;151:716-726

  25. The Age Trial • The new trial added to the group (Age Trial) studied women aged 39 to 41 were invited to annual mammography or usual care through age 48(Lancet 2006;368:2053-2060) • A study of breast cancer mortality in 23 NHS centers in UK, Scotland, and Wales • First mammogram performed utilized two-view film, was not digital • Subsequent annual mammogram was performed in MLO only • Compliance was relatively poor with 41% of the invited group attending all screening rounds

  26. The Age Trial • 10 years of follow-up demonstrated a RR of 0.83 or 17% reduction in mortality in women invited to screen (CI of 0.66-1.04) • Those who attended screening the RR was 0.76 with CI of 0.51-1.01

  27. Randomized Controlled Trial Assessment • Mortality reduction from breast cancer is assessed in the intervention group as compared to controls – is this the optimal goal? • Should other data outside of randomized controlled trials that assess efficacy be employed to avoid noncompliance or contamination? • Is mammography the best screening tool? Should there be a standard for usage? • What is the chance of being diagnosed with breast cancer if you are a 40 year old woman?

  28. Breast Cancer Detection Rate from a Single Mammogram/1000 Breast Cancer Surveillance Consortium (BCSC) 1996-2007 http://breastsceening.cancer/gov/data/performance

  29. Mammography as the Standard • Mammography alone will miss approximately 20% of cancers – rates that are further decreased in women with dense breast tissue • Digital mammography results in better tissue contrast, improving cancer detection • MRI may prove to be superior but is unproven in women of average risk and while more sensitive, has a higher recall rate Pisano et al NEJM 2005;353:1773-1783

  30. Mammography as the Standard Rosenburg et al Radiology 2006;241;55-66

  31. Lifetime Risk of Breast Cancer Following Mammogram BEIR VII, Phase 2 Washington DC: National Academies Press 2006

  32. Observational Studies that Support Mammography • Observational Studies of women who undergo screening mammography have been performed in Sweden and British Columbia • In Sweden, screening may occur at age 40 or age 50; once started it continues every 18 months through age 54 • Across all age groups, with 20 years of follow-up, there was a 44% decrease in risk of death from breast cancer Coldman et al Int J Cancer 2007;120(5):1076-1080 Tabar et al Lancet 2003;361:1405-1410

  33. Cumulative 20-year Mortality from Incident Tumors in Women aged 40-69 Tabar et al Lancet 2003;361:1405-1410

  34. Observational Studies • These observational studies are biased by self-selection for screening, and the possibility that smaller tumors are detected (equating longer survival) • While neither the Sweden nor British Columbia trials separate mammography from CBE effects, both suggest a reduction of 30%-40% in women aged 40-49 Coldman et al Int J Cancer 2007;120:1076-1080 Tabar et al Lancet 2003;361:1405-1410

  35. Harms Associated with Mammography Screening • Radiation Exposure: • Screening 2-view films average 7 mGy of low-energy radiation. • Overdiagnosis • Pain During Procedure • Anxiety, Distress • False-Positive and False-negative Results

  36. USPSTF Breast Cancer Screening Recommendations • The USPSTF did not recommend against women having mammograms: “The USPSTF recommends against routine screening mammography in women aged 40-49 years. The decision to start…should be an individual one and take patient context into account, including the patient’s values regarding specific benefits and harms.” • USPSTF changed the recommended screening interval for women 50-74 from 1-2 years to biennial screening and noted that there was insufficient evidence for or against screening women > 75 years (I level). USPSTF Ann Int Med, 2009;151:716-726

  37. USPSTF Breast Cancer Screening Recommendations • The USPSTF did not oppose insurance coverage for mammography • The USPSTF did not oppose breast self-examination but recommended against teaching standardized examination procedures (D rating)

  38. Analysis of the Data Set • Methodology of the randomized controlled trials used in the meta-analysis used only fair data troubled by noncompliance & contamination with the “Age” trial adding a substandard method of screening • CBE will add little and rightly was not recommended • Majority of women have no clear identifiable risk factors for breast cancer development

  39. Benefits and Harms of Mammography Screening “Take the test, not the chance” has become the mantra for advocacy groups, physician report cards, celebrities and others How do we balance the trade-offs?

  40. Summary of Benefits and Harms Mandelblatt et al Ann Int Med 2009;151(10):738-747 Elmore JG et al N Engl J Med 1998;338(16):1089-1096 Woloshin et al JAMA 2010;303(2):164-165

  41. Assessing Breast Cancer Risk

  42. Factors Influencing Breast Cancer Development Breast Cancer Risk • Modifiable • Diet • Body mass index • Exercise • Smoking • Exogenous estrogen usage • Alcohol consumption • Not Modifiable • Genetics/Family History • Radiation as an adolescent • Atypical Ductal Hyperplasia • LCIS • Age • Race • Ethnicity • Age at menarche • Potentially Modifiable • Age at first birth • Breast feeding

  43. Prevention of Breast Cancer in Women: Reducing Risk in Modifiable Factors • Surveillance • Chemoprevention options with SERMs (tamoxifen or raloxifene) • Prophylactic surgery • Lifestyle modification

  44. ASCO Tech Assessment 2009 • NCI breast cancer risk assessment tool: www.cancer.gov/bcrisktool • ASCO 2009 Prevention Guidelines May 26, 2009

  45. Current Randomized Trials for Br Ca Prevention

  46. Strategies for Breast Cancer Risk Reduction • SERM therapy; ongoing trials of AI underway • Prophylactic surgery • Influence of postmenopausal hormonal therapy • Diet/Nutrition • Body size/Body mass index

  47. Association of Food/Nutrients and Breast Cancer Risk

  48. The Conundrum: Obesity, Diet, & Alcohol • There is compelling evidence that a high BMI (BMI of ~25 kg/m2)in postmenopausal women is associated with an increased risk of breast cancer • Estimated 15% of breast cancer within the NHS attributable to weight gain after menopause • Long term weight loss (10 kg or more) in menopause may be protective in breast cancer development; weak links to physical activity • Biological data suggests that exposure in early life may be important in predicting later breast cancer risk

  49. Survival from Breast Cancer in Physically Active Women • Prospective study in 1500 women with early-stage breast cancer between 1991-2000 studied by dietary and activity recall • Vegetables and fruits (V/F) were lumped into low (< 5 servings daily) or high (>5 servings) • Physical activity (PA) was divided into low (<540 metabolic equivalent tasks per week) or high (>540 MET) based on duration, intensity, and frequency • Measured BMI JCO 2007;25:2345-52.

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