Radiological screening for Breast Cancer. Brittany Lee, HMS IV Dr. Gillian Lieberman Radiology clerkship 11/07 Beth Israel

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1 Radiological screening for Breast Cancer Brittany Lee, HMS IV Radiology clerkship 11/07 Beth Israel

2 Our patient: 54F presents for screening mammography Why screen for breast cancer? Does screening reduce breast cancer mortality? How should average risk women be screened? When do we start screening? Is there a difference between digital and film mammography? When is breast MR appropriate? Is there a role for MRI to screen the contralateral breast in patients with a new diagnosis of breast cancer? Is breast MRI better for screening high risk women?

3 Screening Criteria The Condition Must be important health problem. Epidemiology and natural history of the disease should be adequately understood. Must have a detectable risk factor, disease marker, latent period d or early symptomatic stage. The Test Simple, safe, precise and validated screening test. Acceptable to the population Treatment The treatment/intervention for patients identified through screening must be effective and early treatment must improve outcomes compared to late treatment. Agreed policy on who to treat. Screening program RCT must demonstrate that screening reduced morbidity and mortality. The benefit of screening must outweigh the risks/side effects from the screening. Facilities for diagnosis and treatment should be available. The total cost of finding a case should be economically balanced in relation to medical expenditure as a whole. Case-finding should be a continuous process. Wilson and Jungner 1968

4 Breast Cancer Incidence and Epidemiology As a Public Health issue: In the US in 2007: 178,480 women will be diagnosed 40,460 women will die Lifetime risk of breast cancer is 1:6 overall, and 1:8 for invasive breast cancer Trends Increasing incidence since the 1940 s is attributed to: Introduction of screening Higher lifetime exposure to estrogen Decreased mortality since the 1990 s is attributed to:? Both screening and introduction of adjuvant therapy Jemal et al. CA Cancer J Clin

5 Early evidence for screening Trial HIP* Two Country Location Year Age N= Median follow-up RR reduction Absolute risk reduction New York ,000 pairs 16 years 21% 0.14% Sweden ,000 Study 56,000 Control 17 years 32% 0.18% *Health Insurance Plan The decision to embark on national screening programs in the US and UK were based on the RR reduction in breast cancer specific mortality of these two early trials. Gotzsche and Nielsen. Cochrane Review Humphrey et al. Ann Intern Med

6 Current evidence for screening Humphrey et al. Ann Intern Med Meta-analyses analyses of seven RCT (Edinburgh excluded) concluded mammography reduces breast cancer mortality rates in women age 40-74

7 Relative vs. Absolute Risk Example: A patient with cancer is trying to decide whether to undergo radiation treatment (XRT) to reduce their risk of a recurrence. Besides the side effects of treatment, XRT is cumbersome requiring treatments s 5 days a week for 6 weeks. XRT reduces the risk of recurrence by 75%!! A relative risk reduction of 75% is relative to the risk of recurrence. If the risk of recurrence without XRT is 20%: Risk of recurrence with XRT = 20% - 20% * 0.75 = 5% Absolute risk reduction of XRT = 20% - 5% = 15% If the risk of recurrence without XRT is 4%: Risk of recurrence with XRT = 4% - 4% * 0.75 = 1% Absolute risk reduction of XRT = 4% - 1% = 3%

8 Mammography vs. Adjuvant Chemotherapy Berry et al. NEJM Since the variability between the models was greater for screening than treatment, there is greater uncertainty when estimating the benefit of screening.

9 Mammography vs. Adjuvant Chemotherapy Berry et al. NEJM Reduction in mortality with adjuvant tx alone No reduction in mortality with screening alone Screening only has a benefit if followed by adjuvant treatment

10 Screening Questioned Gotzsche and Nielsen. Cochrane Review Meta-analysis analysis of the seven RCTs (same Humphrey) The Edinburgh trial was excluded Two trials were adequately randomized ( best ) Four trials were suboptimally randomized Overall RR reduction = 20% For the best trials: RR reduction = 15% Absolute risk reduction is 0.05% Screening leads to overdiagnosis and overtreatment: RR increase = 30% Absolute risk increase = 0.5%

11 Conclusion: Screening Questioned Gotzsche and Nielsen. Cochrane Review For every 2000 women screened over 10 years, one will have her life prolonged and 10 healthy women will be diagnosed with breast cancer and treated unnecessarily. It is not clear whether screening does more good than harm.

12 Guidelines for screening For average risk women with lifetime risk <15%: Age 40-50: clinicians should discuss the risks and benefits to mammography screening with their patients and use patients values to make an individual decision Age 50-70: screen with mammography every yrs Age > 70: screen with mammography if life expectancy is >10 yrs For high risk women with lifetime risk >20-25%: 25%: Includes BRCA1/BRCA2 mutations, women with a strong FHx of breast or ovarian cancer, and women who were treated with mantle radiation for Hodgkins lymphoma Screen with MRI as adjunct to mammography starting at age 40 or 10 years before the diagnosis of a first degree relative Saslow et al. CA Cancer J Clin

13 Cost-effectiveness of screening Age Cost per year of life saved $105, $21,400 >65 to 75 or 80 $34,000-$88,000 $88,000 For the and the age group, screening is cost-effective Screening is cost-effective in the oldest age group if the women are healthy. Salzmann et al. Ann Intern Med Mandelblatt et al. Ann Intern Med. 2003

14 Digital vs. Film Mammography Study Design: Pisano et al. NEJM Prospective study: 49,528 asymptomatic women underwent both digital and film screening mammography Methods: Mammograms were interpreted by using the BIRADS system and malignancy scale Breast cancer status was ascertained by breast biopsy or by f/u mammography at > 10 m. Sensitivity and specificity was calculated at 365 and 455 days. For malignancy scale, ROC analysis was performed. Results/Conclusion: The accuracy of digital mammography was significantly higher than film for women < 50 yo, women with dense breasts on mammography and pre- and perimenopausal women

15 Our patient: 54F presents for screening mammography Her risk factors for breast cancer: Gender and ethnicity Estrogen exposure: Menarche at age 11 P2G2 with first pregnancy at age 34 Premenopausal No personal history of breast cancer Family history of post-menopausal breast cancer in mother and paternal aunt, not Ashkenazi ethnicity By the Gail Model, her lifetime risk of BC is 17.6% Case courtesy of Dr. Valerie Fein-Zachary

16 Is mammography appropriate screening for this patient? Yes, her lifetime risk is <20% and therefore, she is average risk.

17 Her mammogram is negative heterogeneously dense glandular pattern with punctate benign calcifications seen bilaterally. BI-RADS 2

18 BI-RADS mammography categories 0: Need additional imaging 1: Negative, routine follow-up 2: Benign, routine follow-up 3: Probably benign finding Follow-up with diagnostic view of the suspicious lesion in six months Probability of malignancy is 2 percent 4: Suspicious Core-needle biopsy or needle localization biopsy as soon as possible >2 to 95 percent risk of malignancy Stratified further as: (a) Low-risk (b) Intermediate-risk risk (c) Moderate to high-risk 5: Highly suggestive of malignancy Core-needle biopsy or needle localization biopsy as soon as possible >95 percent risk of malignancy 6: Biopsy-proven proven carcinoma

19 Fletcher. UpToDate

20 4 m later, she palpates a mass in her left breast Mammography is repeated:

21 4 m later, she palpates a mass in her left breast Mammography is repeated: BI-RADS 4c

22 DDx of a breast mass Carcinoma of the breast Phyllodes tumor Fibroadenoma Adenoma of the nipple Intraductal papilloma DDx of a calcifications on o mammography Carcinoma of the breast Benign calcifications in: Skin Arteries Cysts Fibroadenoma with dense popcorn-like calcifications Foreign body post-trauma trauma

23 An ultrasound guided core biopsy reveals a infiltrating ductal carcinoma and DCIS

24 Use of MRI to screen the contralateral breast after an initial BC diagnosis Study design: Lehman et al. NEJM Prospective study of 969 women with a recent diagnosis of unilateral breast cancer, who had no abnormalities on clinical exam or mammography in the contralateral breast, underwent breast MR Results: 12.5% had positive MRI findings 25% with a positive MRI were positive for cancer 3.1% had contralateral BC detected by MRI Conclusion: MRI can detect clinically and mammographically occult BC in the contralateral breast after a new diagnosis of breast cancer.

25 Breast MRI technique Without contrast: Density, architecture, fluid- filled structures and implants Contrast, gadolinium, is used to maximize cancer detection. Contrast agents improve detection since malignant tumors are hypervascular and enhance early (before normal breast tissue) after contrast is given.

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27 Benign breast findings on MRI Fibroadenoma Lactating breast Implant with bubble T2 Post-contrast T1 No contrast T1 Post-contrast

28 Malignant findings on MRI T1 Pre-contrast IDC T1 Post-contrast IDC T1 Pre-contrast DCIS T1 Post-contrast DCIS

29 Our patient s breast MRI Right Breast Left Breast

30 Breast MRI is better for screening high risk women Multiple studies demonstrate that breast MR is more sensitive than mammography for high risk women* Kriege et al. NEJM 2004: 1909 women with lifetime risk >15% were screened every 6 month with clinical breast exam (CBE) and every year with mammography (M) and MRI Median f/u of 2.9 years Results: Sensitivity was 79.5% MRI, 33.3% M and 17.9% CBE Specificity was 89.8% MRI, 95% M and 98.1% CBE Conclusion: MRI is more sensitive than mammography in detecting tumors in women with an inherited susceptibility to breast cancer. *Leach et al. Lancet Lehman et al. Radiology Kriege et al. NEJM Kuhl et al. J Clin Oncol

31 Our patient: Summary 54F with average risk for breast cancer had a benign findings on a screening mammogram 4 months later, she p/w a left breast mass U/S guided bx of the L lesion revealed IDC and DCIS Breast MRI of the contralateral breast showed a suspicious lesion in the right posterior breast MR-guided bx the R lesion revealed IDC and DCIS No evidence of metastatic disease was seen on full-body CT and bone scan Underwent bilateral mastectomy: Right total mastectomy with sentinel node biopsy Left modified radical mastectomy since grossly positive axillary nodes were found intraoperatively Pathology: Right: IDC 0.9 cm, grade I with LVI positive and 1:1 sentinel nodes positive. Histology was ER/PR+ and HER-2/neu negative. Left: IDC >7 cm, grade 3 with LVI positive and 5:9 axillary nodes positive. Histology was ER/PR+ and HER-2/neu positive. Case courtesy of Dr. Valerie Fein-Zachary

32 Conclusion Does screening reduce breast cancer mortality? Uncertain since although 7 RCTs show that screening reduces the relative risk of breast cancer mortality by 15-20%, not all of these trials were randomized well and the absolute risk reduction was only % 0.1% How should average risk women be screened? Guidelines suggest to consider mammography screening at age 40 and a recommends to start everyone at age 50. Digital mammography is more accurate at detecting breast cancer than film When do I use breast MRI? Screening for women >20% lifetime risk of breast cancer Evaluation of the ipsilateral breast for synchronous lesions in a women with a newly diagnosed breast cancer that is believed to be more extensive than seen on standard imaging Evaluation of the contralateral breast for occult disease in women with a unilateral breast cancer that had no clinical or mammographic abnormalities on the opposite side Women with mammographically occult primary disease with an adenocarcinoma of unknown primary site in the axillary nodes

33 References Berry DA, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. NEJM ; 17: Boyd NF, et al. Mammographic density and the risk and Detection of Breast Cancer. NEJM ; 3: Fletcher SW. Report of the International Workshop on Screening for f Breast Cancer. J Natl Cancer Inst ; 20: Fletcher SW. Screening average risk women for breast cancer UptoDate. Glass AG, et al. Breast cancer incidence, : combined roles of menopausal hormone therapy, screening mammography, and estrogen receptor status. J Natl Cancer Inst ; 15: Gotzsche PC and Nielsen M. Screening for breast cancer with mammography. Cochrane Database of Systematic Review Humphrey LL, et al. Breast cancer screening: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med ; 5 Part 1: Jemal A, et al. Cancer statistics from SEER, CA Cancer J Clin ; 1: Kriege M, et al. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. NEJM ; 5: Lehman CD, et al. MRI Evaluation of the contralateral breast in women with recently diagnosed breast cancer. NEJM ; 13: Mandelblatt J, et al. The cost-effectiveness of screening mammography beyond age 65. Ann Intern Med :835. Macura KJ, et al. Patterns of Enhancement on Breast MR Images: Interpretation etation and Imaging Pitfalls. Radiographics : Pisano ED, et al. Diagnostic performance of digital vs. film mammography mography for breast-cancer screening. NEJM ; 17: Ravdin PM, et al. The decrease in breast-cancer incidence in 2003 in the United States. NEJM ; 16: Salzmann P, et al. Cost-effectiveness of extending screening mammography guidelines to include i women years of age. Ann Intern Med :955. Saslow D, et al. American cancer society guidelines for breast screening ng with MRI as an adjunct to mammography. CA Cancer J Clin ; 2:

34 Residents: Acknowledgements Katie Krajewski Anne Kim Senthil Palaniappun Andrew Bennett Dr. Valerie Fein-Zachary Maria Levantakis