1. Magnetic Resonance Imaging (MRI) Screening for High Risk Patients Ellen Warner M.D. Division of Medical Oncology Sunnybrook & Women’s College Health Sciences Center Toronto, Ontario, Canada

2. Each year in the U.S. alone: 5.3 million affected 40,000 deaths

3. Motor Vehicle Injuries Breast Cancer Primary Prevention: obey traffic laws tamoxifen don’t drink & drive oophorectomy Secondary Prevention: seat belts  air bags breast screening

4. Is MRI Screening of the Breast an Effective Seat Belt For High Risk Women?

5. Definition of ‘High Risk’ Known BRCA mutation carrier or Close relative of mutation carrier or Family history suggestive of inherited predisposition

6. Cumulative Risk of Breast Cancer 1. Antoniou et al. Am J Hum Genet, 2003 2. SEER Cancer Stats Review, 2004. BRCA1 BRCA1 + oophorectomy general population no family mutation

7. High Risk Screening Guidelines

8. Mammography Screening for High Risk Women The Ideal 100% sensitivity DCIS invasive  1cm, node -ve The Reality 50% sensitivity DCIS rarely found 50% > 1 cm 40% node +ve Brekelmans et al. JCO, 2001 Scheuer et al. JCO, 2002 Komenaka et al. Cancer, 2004

9. Limitations of Mammography for ‘High Risk’ Screening young age = dense breasts

11. Mammographic Visibility of Palpable Breast Cancers Chang Lancet, ‘99 Goffin JNCI ‘01 Tilanus -Linthorst Int J Cancer ‘02 P=.03 P=.01

12. Limitations of Mammography for HBC Surveillance young age = dense breasts tumour pathology (BRCA1) – less DCIS – fleshy, ‘pushing’ borders

13. Advantages of Breast MRI Contrast agent concentrates in areas of tumor angiogenesis tomographic images (3-D) less influenced by breast density no ionizing radiation

14. Disadvantages of MRI $$$ lower specificity biopsy more difficult logistics –menstrual phase –weight claustrophobia

15. Breast MRI Screening Studies for High Risk Women Kriege et al.The Netherlands Kuhl, et al.Bonn, Germany Leach et al. U.K. Podo et al. Italy Schnall, Lehman et al.U.S. Warner, Plewes, et al.Toronto, Canada

16. Breast MRI Screening Studies for High Risk Women Similarities prospective, non-randomized not restricted to mutation carriers annual mammography + MRI Differences single / multiple centers patient population additional modalities MRI technique

17. Dutch National Study Kriege et al. NEJM 351: 427, 2004. 6 centers unaffected women ages 25-70  15% lifetime risk MRI + mammography + CBE

18. Dutch National Study : Results 1909 women –358 mutation carriers – mean age 40 – mean # screens = 2 4 (9%) interval cancers! 45 evaluable cancers 39 invasive, 6 DCIS 50% in carriers 50% 1 st screen

19. Sensitivity of Individual Modalities Dutch Study: Results

20. Sensitivity: Invasive vs. In-Situ Dutch Study: Results n=39 n=6

21. False Positives RecallsBiopsies MRI 10% 5.8% Mammography 5% 1.7% Dutch Study: Results

22. Invasive Tumor Stage Dutch Study: Results n=45n=1500n=45 21% node + 52% node + 56% node +

23. Toronto Study Warner et al. JAMA 292: 1317, 2004 single center affected & unaffected women ages 25 - 65 >25% lifetime risk MRI + mammography + CBE + US

24. The Toronto Study Medical Biophysics Donald Plewes PhD. Martin Yaffe PhD. Elizabeth Ramsay MSc Cameron Piron MSc Medical Imaging Petrina Causer M.D. Roberta Jong M.D. Belinda Curpen M.D. Joan Glazier MRT Garry Detzler MRT Caron Murray MRT Joanne Muldoon MRT Study Co-ordinator Kimberley Hill, BSc Genetics Steven Narod M.D. Sandra Messner M.D. Wendy Meschino M.D. Andrea Eisen M.D. Pathology John Wong M.D. Judit Zubovits M.D. General Surgery Glen Taylor M.D. Claire Holloway M.D. Frances Wright M.D. Biostatistics Gerrit DeBoer PhD Alice Chung BSc Funding CBCRA NBCF Amersham Health Papoff Family Nurse Examiner Marg Cutrara R.N.

25. Toronto Study : Results 437 women –318 BRCA mutation carriers –mean age 43 – mean # screens = 3 Only 1 interval cancer! 37 cancers – 32 in carriers – mean age 48 (34-64) – 28 invasive (2 lobular), 9 DCIS

26. Sensitivity of Individual Modalities Toronto Study: Results

27. Sensitivity of Combined Modalities Toronto Study: Results

28. Sensitivity: Invasive vs. In-Situ Toronto Study: Results n=28 n=9

32. Sensitivity by Age Toronto Study: Results

33. Toronto Study: : Results Sensitivity by Year of Screening

34. False Positives: Recalls Toronto Study : Results

35. False Positives: Biopsies Toronto Study : Results

36. Invasive Tumour Size

37. Toronto Study: Results Yr. # cancers DCIS Mean Invasive Size Node + 1 18 22% 1.1 (0.4 - 3.0) cm 3 2 9 11% 1.2 (0.4 - 2.0) cm 1 3-5 9 44% 0.8 (0.7 - 1.0) cm 0 Tumor Stage by Year No recurrences to date. Median f/u 3yrs. (range 1 to 7)

38. Effect of MRI Screening on Survival M e t s MRI mammo

39. Cost-Benefit Analysis

40. Cost-Benefit Estimate $$$ 62 million women ages 30-60 in U.S. 1% high risk (620,000) $1200 per screen ____________________ $744 million/year 620,000 high risk 1% (6,200) have cancer mortality 30%  10% 1240 more cured mean years saved = 25 ________________________ 31,000 life years saved $24,000 / year of life saved

41. Summary Breast MRI for high risk women: most sensitive screening modality finds cancers at an earlier stage has acceptable specificity saves lives?

42. Other Research Questions Optimal MRI screening schedule for subgroups? –age –mutation status –breast density Role of other screening modalities? Role of MRI for other high risk women? –Atypical hyperplasia, LCIS –Chest irradiation < age 30 –Very dense breasts