Risk-reducing Surgery in BRCA mutation carriers

Risk-reducing Surgery in BRCA mutation carriers Daerim St. Mary s Hospital Department of Surgery, Breast Care Center Hereditary Breast Ovarian Cancer Clinic Sung-Won Kim, MD, PhD, FACS

Overview of HBOC Risk-reducing surgery Where are we in Asia Contents Patterns of HBOC Management in Korea Korean Hereditary Breast Cancer (KOHBRA) St udy

Hereditary Breast Ovarian Cancer New York Times (2013.5.14) My Medical Choice

BRCA carriers or Even Non-carriers TO REMOVE OR NOT TO REMOVE BREAST???? THAT IS THE PROBLEM!!!

Breast-Cancer Susceptibility Loci and Genes Foulkes et al. NEJM 2008

Breast and ovarian cancer risk in BRCA1/2 mutation carriers BRCA1 BRCA2 BRCA 1 BRCA 2 Breast cancer ( ) 65% (44%-78%) 45% (31%-56%) Ovarian cancer ( ) 39% (18%-54%) 11% (2.4%-7.9%) Antoniou et al. Am J Mum Genet 2003

Environmental modifiers of breast cancer risk among mutation carriers Breast feeding Late menarche Pregnancy Study BRCA1 BRCA2 Kotsopoulos et al., 2012 Jernstrom et al., 2004 Kotsopoulos et al., 2005 Cullinance et al., 2005 Kotsopoulos et al., 2007 Protective At least 1 year: 32% reduction, 2 years and more: 49% reduction Protective At least 1 year: 45% reduction Protective >14 y vs. 11 y: 54% reduction 4 births (only a modest protective effect) Early full-term birth: not protective No association No association No association Increase in cancer risk with each additional pregnancy (OR=1.17, 95%CI: 1.01-1.36) Early full-term birth: not protective

Genetic modifiers of breast cancer risk among mutation carriers SNPs associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers (GWAS) Milne & Antoniou. Ann Oncol 2011

Screening for breast cancer Kriege et al., NEJM 2004 MRI is more sensitive than MMG AUC for MMG: 0.686 AUC for MRI: 0.827 Warner et al., JCO 2011 Incidence of advanced breast cancer was decreased by 70% in women with MRI screening Early (0-I) Total Advanced (II-IV)

Chemoprevention of breast cancer King et al. JAMA 2001 NSABP P-1 trial, subset analysis Tamoxifen reduced breast cancer incidence only among healthy BRCA2 carriers Gronwald et al. Int J Cancer 2006 Tamoxifen and contralateral breast cancer in BRCA1/2 carriers (update)

Risk Reduction Intervention Risk reduction surgery - Risk-reduction mastectomy (RRM) - RRM: 90% BC risk-reduction in BRCA carriers No evidence of life-expectancy gain NCCN Breast Cancer Risk Reduction Panel supports the use of RRM for carefully selected women at high risk of breast cance r who desire this intervention women with a BRCA1/2, TP53, or PTEN mutation or, possibly, for women with a history of LCI S

Risk Reduction Intervention Risk reduction surgery - Bilateral salpingo-oophorectomy - Rationale for RRSO Absence of reliable methods of early detection Poor prognosis associated with advanced ovarian cancer RRSO 80% reduction in the risk of ovarian or fallopian tube cancer PPC: 3% residual risk of a primary peritoneal carcinoma Also reduce the risk of BC by approximately 50%.

PROSE Consortium Study Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations RRM: lower risk of breast cancer RRSO: lower risk of ovarian cancer, first diagnosis of breast cancer, allcause mortality, breast cancer specific mortality, and ovarian cancer specific mortality. RRSO and breast cancer risk in healthy carriers Risk reduction 1 (0.37-0.79) HR: 0.54 (0.41-0.96) HR: 0.63 (0.16-0.82) HR: 0.36 Domchek et al. JAMA 2010

PROSE Consortium Study Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations RRSO and all-cause mortality 1 (0.26-0.61) HR: 0.4 Risk reduction (0.22-1.23) (0.24-0.62) HR: 0.52 HR: 0.38 Domchek et al. JAMA 2010

Manchester Study Manchester Genetic Medicine DB 691 female healthy BRCA1/2 mutation carriers; 346 BRCA1 and 345 BRCA2. Ingham et al. BCRT 2013;142:611

Dutch Study 570 healthy female mutation carriers (405 BRC A1, 165 BRCA2) BRRM: 156 BRCA1 and 56 BRCA2 carriers HR of 0.29 (95% CI 0.02-2.61) for BC-specific m ortality. Heemskerk-Gerristsen et al. Ann Oncolo 2013;24:2029

Contralateral RRM Survival from the primary breast cancer in 105 contralateral risk-reducing mastectomy (CRRM) cases vs. 105 non-crrm controls Hazard ratio 0.37 (95% CI 0.17-0.80), p= 0.008 10-years survival: 89% in CRRM vs. 73% in no-crrm CRRM improves survival in women with BRCA1/2- associated breast cancer Evans et al. Breast Cancer Res Treat 2013

Contralateral RRM Contralateral mastectomy and survival after breast cancer in carr iers of BRCA1 and BRCA2 mutations: retrospective analysis 390 female (I, II BC) BRCA+ 181 CRRM Median f/u: 14.3 years 20 year survival rate 88% vs. 66% with CRRM HR: 0.52 (p=0.08) Metcalfe et al. BMJ 2014

Contralateral RRM Improved overall survival after contralateral risk-reducing mastec tomy in brca1/2 mutation carriers with a history of unilateral bre ast cancer: A prospective analysis Dutch multicentre cohort 583 BRCA-associated PBC patients (1980~2011) 242 pt. (42%) CRRM vs. 341 pt. (58%) Surveillance Median follow-up after PBC diagnosis was 11.4 years CBC incidence: CRRM (2%) vs. Surveillance (19%) (p < 0.001) Mortality: CRRM vs. Surveillance (9.6 and 21.6 per 1000 person-years of observatio n, respectively; adjusted hazard ratio 0.49, 95% confidence interval 0.29 0.82). Survival benefit was especially seen in young PBC patients (<40 years), in patients having a PBC with differentiation grade 1/2 and/or no triple-negative phenotype, a nd in patients not treated with adjuvant chemotherapy. Bernadette et al. Int J Cancer 2014

Contralateral RRM Bernadette et al. Int J Cancer 2014

Where are we in Asia

ABRCA (Asian BRCA Consortium) in 2009 Oct Participants Korea (KOHBRA study, headquarter), Japan, Hong Kong, Malaysia, Indonesia, China, Singapore Objectives To share the knowledge of HBOC in Asian country To improve the quality of care of HBOC patients in Asia To collaborate for researches on HBOC in Asia Research collaboration BRCA registry Blood and tissue banking Clinical practice guideline

Summary of Projects of ABRCA consortium WG1 BRCA spectrum in Asia Review on BRCA in Asia (mutation spectrum, founder mutation, VUS) Database of BRCA and other non-brca genes (next phase) Classification of selected VUS by multifactorial approach WG2 Genetic and environmental modifiers Estimation of penetrance in Asian BRCA carriers Lifestyle modifiers in Asian BRCA carriers: development of pan-asian questionnaire Calibrating risk assessment in Asians using BOADICEA WG3 Management of HBOC Descriptive paper on the status of genetic counseling and genetic testing in Asian countries Outcomes for Asian BRCA carriers

BMJ. 2013 May 22: Hurley R.

Ongoing ABRCA Project Asian mutation spectrum paper: Ava Kwong Genetic counseling and management in Asia: Seigo Nakamura Pan-Asian BRCA database: Sue K. Park

International consortium for HBOC

IBCCS (International BRCA1/2 Carrier Cohort study) Collaborative study of women and man carrying a deleterious mutation in BRCA1 or BRCA2 (1997~) Participating: 15 countries (19 groups) Specific aims 1. more precisely estimate the age-, sex-, and site-specific cancer risks due to mutations in the BRCA1 and BRCA2 genes; 2. assess the importance of risk factors as known in the general population, in determining the cancer risks in the BRCA1/2 mutation carriers; 3. examine the efficacy of prophylactic surgery and other screening/prevention options in these high risk women; 4. create an ongoing registry of gene carriers for potential use in future clinical trials

CIMBA (Consortium of investigators of modifiers of BRCA1/2) A collaborative group of researchers working on genetic modifiers of cancer in BRCA1 and BRCA2 mutation carriers The aim of CIMBA To provide sufficient sample sizes to allow large scale studies in order to evaluate reliably the effects of genetic modifiers Participating: 59 Study groups including KOHBRA Study 36 publications Polymorphism in IRS1 6p22.33 PHB 1630 C>T, MTHFR 677C>T

ENIGMA (Evidence-based network for the interpretation of germline mutant alleles) A consortium of investigators focused on determining the involvement of all unclassified variants (UV) in the BRCA1 and BRCA2 tumor suppressor genes The purpose To facilitate classification of variants through collaborative large-scale projects by sharing data and improving classification methods

Patterns of HBOC Management in Korea

Breast cancer; Age-Standardized Incidence Rate per 100,000 Most Common Cancer of Women GLOBOCAN 2012 32 Vary Between Areas Relatively Lower in Asia

Number 600 500 400 American White Japanese (2001) Korean (2006) 300 200 100 0-19 20-29 30-39 40-49 50-59 60-69 70-79 80- Age * patients number per 100,000 women SEER 17 data (2001-2004) Cancer statistics in Japan (2007)

Number 16000 13908 16398 14000 12000 9668 11275 10000 8000 6000 3801 4695 5401 7551 4000 2000 0 1996 1998 2000 2002 2004 2006 2008 2010 Year

BRCA Testing Reimbursement Since Aug 2005/Revised From May 2012 Breast or ovarian cancer patients who have more than one family members with breast or ovarian cancer Breast and ovarian cancer in one patient Early-onset breast cancer (age <40) Bilateral breast cancer Multiple organ cancer including breast cancer Male breast cancer Epithelial ovarian cancer Testing fee: 1,000 USD patient pays 100 USD

National Survey 2013 2013.May from 36 institutions Follow-up version of 2007 survey. (2007 KOHBRA start!) Annual summary (2012) Genetic counseling: 1858 cases Genetic testing: 1318 cases 2007 2013 97.2 100 100 81.4 39.5 55.6 48.8 58.1 Family history taking Pedigree drawing Genetic test availability Genetic test recommendation

Management of BRCA Mutation Carriers Recommendation N of hospitals % 1200 MRI Yes 23 63.9 No 11 30.6 Unknown 2 5.6 Tamoxifen Yes 13 36.1 No 21 58.3 Unknown 2 5.6 Oral pill Yes 5 13.9 No 28 77.8 Unknown 3 8.3 BPM Yes 15 41.7 No 19 52.8 Unknown 2 5.6 CPM Yes 10 27.8 No 24 66.7 Unknown 2 5.6 BSO Yes 19 52.8 No 14 38.9 Unknown 3 8.3 1000 800 600 400 200 0 1042 480 562 28 20 2 21 137 n=0-324

Genetic Counseling in SNUBH 2015.4.3 Genetic counseling 1132 Test acceptance (Overall) 982/1132 (86.7%) Test acceptance (Proband) 777/926 (83.9%) Test acceptance (Family member) 205/206 (99.5%) Test acceptance rate before and after reimbursement (only proband included) 2005.8.18 Before After 43/67 (64.2%) 734/859 (85.4%)

RRM rate in SNUBH NO cases of BRRM for 48 unaffected BRCA carriers CRRM: Of 102 unilateral BC female carriers Affected carriers: 8/102 (7.8%) Breast reconstruction: 5/8 (62.5%) CRRM date First Surgery First Surgery Name Genetic testing Test result 2007-07-12 2006-08-17 Rt. BCS+SLNB 2006-05-18 2007-01-19 2009-05-07 2008-11-20 Rt. BCS+SLNB 2008-11-19 2009-03-06 2009-11-17 2009-04-30 Rt. BCS+ALND 2009-04-27 2009-07-08 2010-11-19 2008-01-08 Lt. BCS+SLNB 2008-01-28 2008-08-01 2011-03-24 2010-10-27 Rt. TM+SLNB+TEI 2010-11-10 2011-03-04 2011-11-14 2009-05-28 Rt. BCS+ALND 2009-02-25 2009-04-29 2013-03-14 2007-05-08 Lt. BCS+ALND 2013-02-26 2013-03-13 2013-11-28 2008-12-16 Rt. BCS+SLNBx 2008-12-15 2009-03-17

RRSO rate in SNUBH N=145 (117 BC, 28 Healthy) BRCA mutation carriers (>35) RRSO rate Overall: 29.6% (43/145) for overall Affected carriers: 34.4% (41/119) Healthy carriers: 7.6% (2/26) Decision to undergo RRSO had been 16 months (range, 0 68 months) in the 43 carriers who had undergone RRSO

KOHBRA Study Overview

Korean Hereditary Breast Cancer Study (KOHBRA study) KOHBRA I : 2007.5.25-2010.5.24 KOHBRA II : 2010.6.1-2013.5.31 Multi-center study which is conducted by KBCS Grant: the National R&D Program for Cancer Control

KOHBRA Phase 1 Study aim: To define prevalence of BRCA1/2 mutation in Korea Korean Breast Cancer Study Group (KBCSG) Prospective nationwide study 2007.5.25~ Part I: Family Hx(+) Part II: FHx(-) & high risk group 1.Age at Dx.<40 2.Coexistence of ovary ca. 3.Male breast ca. 4.Bilateral breast ca. Part III: family member of BRCA(+) Part IV: Female from Part I, II, III (ovary ca prevalence)

Enrollment (2007.10.05~2013. 06.30) Subgroups Total Familial breast cancer patients 1342 High-risk non-familial breast cancer 1342 Family members of carriers 553 Total enrollment 3237 Banking (WB, DNA, Serum, Plasma) 3183 BRCA Carriers 684

KOHBRA cohort Demographic information Clinical information Bank of DNA, serum KOHBRA Phase 2

KOHBRA Phase 2 (2010.6~2013.5) Development of Korean BRCA Prediction Model Part I (Risk prediction) Part 2 (Treatment) Characterization of clinical phenotype and discovery of novel prognostic factors for BRCA associated breast cancer Development of nationwide network of genetic counseling Part 4 (Genetic counseling) Part 3 (Prevention) Identification of environmental and genetic modifiers of BRCA1/2 mutation

KOHBRA Study Novel Gene Penetrance Intervention study Segregation analysis Family association study Virtual Counselor Modifier gene assay Gene-Env. Interaction Clinical Practice Guideline BRCA Mutation Risk Pretest Prediction Model BRCA Carrier Cohort Prevalence Study

Acknowledgement ABRCA Members KOHBRA Members

Thank you.