Global Breast Cancer Conference 2015 & 4th International Breast Cancer Symposium April 24 th, 2015 The Shilla Jeju Hotel, Jeju Island, Korea

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1 Global Breast Cancer Conference 2015 & 4th International Breast Cancer Symposium April 24 th, 2015 The Shilla Jeju Hotel, Jeju Island, Korea Dr. Steven A. Narod MD, FRCPC Canada Research Chair in Breast Cancer Director, Familial Breast Cancer Research Unit, Women s College Hospital Professor, University of Toronto

2 Prevent recurrence and death Prevent second primary breast cancer Prevent ovarian cancer 2

3 Chemotherapy. Which type? Oophorectomy Tamoxifen Radiotherapy Surgery Breast conserving surgery Unilateral Mastectomy Bilateral Mastectomy 3

4 820 women with Stage I or Stage II breast cancer Followed for up to 20 years Treatments reviewed Endpoints, death, second primary cancers 4

5 Characteristics by 820 study subjects Variable Year of birth Mean (range) ( ) Duration of follow-up Years (range) 11.1 (0.3-20) Mean age of diagnosis By age group: < Mutation BRCA1 BRCA2 Both mutations Tumour size cm cm Unknown Mean (range) ER status Positive Negative Unknown Nodal status Positive Negative Unknown 42.2 (21-65) 49 (6.0%) 314 (38.3%) 302 (36.8%) 155 (18.9%) 507 (61.8%) 301 (36.7%) 12 (1.5%) 508 (63.4%) 293 (36.6%) ( ) 271 (45.4%) 326 (54.6%) (35.6%) 525 (64.4%) 5 Mean (range) or frequency (percentage) 5

6 Treatments received by 820 study subjects Variable Initial surgery Lumpectomy Unilateral mastectomy Bilateral mastectomy Contralateral mastectomy No Yes, at initial surgery Yes, after initial surgery Chemotherapy Yes No Missing Radiotherapy Yes No Missing Tamoxifen Yes No Missing Oophorectomy Never Ever Missing Timing of Oophorectomy Before diagnosis At or after diagnosis Missing 396 (48.3%) 417 (50.9%) 7 (0.9%) (67.4%) 262 (32.6%) (52.8%) 381 (47.2%) (35.1%) 505 (64.9%) (38.2%) 496 (61.9%) Mean (range) or frequency (percentage) 6

7 Early age of diagnosis Family history of breast cancer Oophorectomy Tamoxifen 7

8 Years From Diagnosis All Subjects BRCA1 BRCA2 <50 Years at Diagnosis 5 Years 13.1% 13.7% 12.0% 14.2% 8.6% 10 Years 22.0% 23.8% 18.7% 23.9% 14.7% >50 Years at Diagnosis 15 Years 33.8% 36.1% 28.5% 37.6% 16.8% 8

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10 Breast Cancer Mortality BRCA mutation 5 years 10 years 15 years 20 years BRCA1 7% 15% 21% 30% BRCA2 4% 13% 20% 26% estimated by Kaplan-Meier method 10

11 Risk of death after diagnosis of breast cancer among BRCA carriers: Lumpectomy versus mastectomy 11

12 Risk of death after 10 years of diagnosis of breast cancer among BRCA carriers by first surgery: Lumpectomy versus Mastectomy 12

13 Risk of death after 10 years of diagnosis of breast cancer among BRCA carriers: Unilateral versus bilateral mastectomy N Ipsi / contra either first surgery * death No Bil PM / Lum, 154 UM 36 Bil PM 151 1/ Lum, 105 UM, 3 Bil M 2 * the 2 nd surgery of the 151: for the 43, 30 had BPM, 13 had contra PM; for the 105, 104 had contra PM and 1 had BPM, for the 3 had Bil M, no further surgery. 13

14 Optimum treatment is bilateral mastectomy at diagnosis Prevents local recurrence Prevents contralateral breast cancer Prevents death 14

15 Prevention of breast cancer Prevention of ovarian cancer Prevention of death after breast cancer 15

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17 North American Study Univariate RR (95% CI) P Multivariate a RR (95%CI) P Chemotherapy 0.97 ( ) ( ) 0.16 Oophorectomy b 0.62 ( ) ( ) 0.06 Ipsilateral Mastectomy (versus lumpectomy) 0.76 ( ) ( ) 0.59 Contralateral Mastectomy b 0.56 ( ) ( ) 0.02 a Adjusted for age at diagnosis, year of diagnosis, BRCA gene (BRCA1 or BRCA2), tumour size (cm), nodal status (positive/negative), ER status (+, -, missing), chemotherapy, tamoxifen, oophorectomy and contralateral mastectomy b Time-dependent variable 17

18 Univariate RR (95%CI) P Multivariate RR (95%CI) P All subjects 0.47 ( ) ( ) BRCA1 only BRCA2 only Age of diagnosis <50 50 Chemotherapy Yes No Stage I II ER-status Negative Positive 0.36 ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( )

19 Should all patients with breast cancer and a BRCA1 mutation receive chemotherapy? 3 databases merged Poland Israel North America 455 BRCA1 carriers node- negative 0-2 cm in size 19

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24 Treatment of BRCA1 associated breast cancers with neo-adjuvant cis- platinum 24

25 Regimen Number treated Number of PCR %PCR CMF % AC % FAC % AT % Cis-platinum % C: Cyclophosphamide M: methotrexate F: 5-flourouracil A: adriamycin (doxorubicin T: docetaxel CMF category includes four patients with CMFP and two patients with CMFVP 25

26 Neoadjuvant Cisplatinum in Poland No previous CHTH, no record of breast cancer BRCA1 carriers only PCR (60.2%) Total treated to date 108 No PCR Dec 2006-Apr Ooph No Ooph Ooph No Ooph Death Alive Death Alive Death Alive Death Alive Average follow-up 5 years

27 Optimal treatment is bilateral mastectomy Oophorectomy prevents recurrence, death, ovarian cancer, second primary breast cancer Benefit of extended surgery in second decade Chemotherapy for small node negative cancers Chemotherapy- more data on cis-platinum needed Combination of cis-platinum and oophorectomy 27

28 UNITED STATES: Fergus Couch Mary Daly Susan Domchek Charis Eng Judy Garber Claudine Isaacs Beth Karlan Henry Lynch Wendy McKinnon Susan Neuhausen Ken Offit Funmi Olopade Mark Robson Howard Saal Nadine Tung Jeffrey Weitzel Marie Wood Dana Zakalik Talia Donenberg Kevin Sweet Leaha Senter CANADA: Peter Ainsworth Ab Chudley Andrea Eisen William Foulkes Parviz Ghadirian Donna Gilchrist Charmaine Kim-Sing Ed Lemire Barry Rosen Amy Finch Joanne Kotsopoulos Kelly Metcalfe Ping Sun Christine Maugard Susan Armel Louise Bordeleau Ophira Ginsburg Seema Panchal Aletta Poll Wendy Meschino EUROPE: Jan Klijn Siranoush Manoukian Dominique Stoppa- Lyonnet Barbara Pasini Christian Singer Catharina Anne Speiss POLAND: Jacek Gronwald Jan Lubinski Cezary Cybulski Tomasz Huzarski Tomasz Byrski 28