Each year in the U.S. alone:

1. Magnetic Resonance Imaging (MRI) Screening for High Risk PatientsEllen Warner M.D. Division of Medical OncologySunnybrook & Women’s College Health Sciences CenterToronto, 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 no family mutation general population

7. High Risk Screening Guidelines

8. 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 Mammography Screening for High Risk Women

9. Limitations of Mammographyfor ‘High Risk’ Screening • young age = dense breasts

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

12. Limitations of Mammographyfor 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 Studiesfor 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 Studiesfor 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 • 45 evaluable cancers • 39 invasive, 6 DCIS • 50% in carriers • 50% 1st screen • 4 (9%) interval cancers!

19. Dutch Study: Results Sensitivity of Individual Modalities

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

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

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

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

24. 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 Genetics Steven NarodM.D. Sandra MessnerM.D. Wendy MeschinoM.D. Andrea Eisen M.D. Pathology John WongM.D. Judit Zubovits M.D. General Surgery Glen Taylor M.D. Claire HollowayM.D. Frances Wright M.D. Study Co-ordinator Kimberley Hill, BSc The Toronto Study Nurse Examiner MargCutraraR.N. Biostatistics Gerrit DeBoer PhD Alice Chung BSc Funding CBCRA NBCF Amersham Health Papoff Family

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

26. Toronto Study: Results Sensitivity of Individual Modalities

27. Toronto Study: Results Sensitivity of CombinedModalities

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

32. Toronto Study: Results Sensitivity by Age

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

34. Toronto Study: Results False Positives: Recalls

35. Toronto Study: Results False Positives: Biopsies

36. Invasive Tumour Size

37. Toronto Study:Results Tumor Stage by Year Yr.# cancersDCISMean Invasive SizeNode + 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 No recurrences to date. Median f/u 3yrs. (range 1 to 7)

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

39. Cost-Benefit Analysis

40. $$$ 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 Cost-Benefit Estimate $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