Risk Reduction management for Ovarian Cancer in Women with BRCA1/2 Mutation Global Breast Cancer Conference 2018 2018. 4. 6 (Fri) Songdo, Incheon, Korea Hereditary Gynecologic Cancer Clinic Precision Medicine Center Comprehensive Gynecologic Cancer Center CHA Bundang Medical Center, Korea Min Chul Choi
Risk management for BRCA1/2 mutation carriers Surveillance Chemoprevention ( Risk Reduction Agents) Risk-Reducing Surgery For Breast cancer For Ovarian cancer Surveillance Mammogram TVS, CA125 Chemoprevention Tamoxifen/Raloxifen OCs RR surgery RR mastectomy RR SO NCCN Guidelines Genetic/Familial High-risk Assessment: Breast and Ovarian. 1 2018 ACOG Committee Opinion Hereditary cancer syndromes and risk assessment 2015 June, #634
Risk management of ovarian cancer for gbrca1/2 mut 1. Risk-Reducing Surgery (RRSO) 2. Chemoprevention and/or Surveillance NCCN Guidelines Genetic/Familial High-risk Assessment: Breast and Ovarian. 1. 2018 ACOG Committee Opinion Hereditary cancer syndromes and risk assessment 2015 June, #634
Contents Clinical features of Epithelial Ovarian Cancer (EOC) Surveillances Transvaginal sonogram (TVS) CA125 Chemoprevention Oral Contraceptives (OCs) Risk-reducing salpingo-oophorectomy (RRSO) Discussion
Types of Ovarian cancer https://www.aacc.org/publications/cln/articles/2013/march/ovarian-cancer
Types of Ovarian cancer http://popcultureworldnews.com/ovarian-cancer/types-of-ovarian-cancer-cells
Molecular-genetic classification of EOC (Epithelial Ovarian Cancer) Kurman et al. Hum Path 2011;42:918-31
Proportion & Survival of EOC by stage NIH, Surveillance, Epidemiology, and End Results Program (SEER) https://www.aacc.org/publications/cln/articles/2013/march/ovarian-cancer
Contents Clinical features of Epithelial Ovarian Cancer (EOC) Surveillances Transvaginal sonogram (TVS) CA125 Chemoprevention Oral Contraceptives (OCs) Risk-reducing salpingo-oophorectomy (RRSO) Discussion
Screening test for ovarian cancer <Transvaginal sonogram (TVS)> Sensitivity 89%, specificity 70% PPV by only TVS : 1.0% ~ 27% DePriest PD et al. Gynecol Oncol 1994;55:174-178 Van Nagell JR Jr et al. Cancer 2007;109:1887-1896 Limitations Considerable variation in interpret/scoring TVS image Poor reproducibility Inclusion criteria (at average risk/at high risk)
Screening test for ovarian cancer <Cancer Antigen 125 (CA-125; MUC16)> Elevated >80% in advanced stage ovarian cancer 1~2% in normal population Bast RC Jr et al NEJM 1983;309:883-887 Limitation Elevated <50% in stage I ovarian cancer Poor specificity Daniel L Clarke-Pearson NEJM 2009;361:170-177
Efforts to find the screening test for ovarian cancer with CA125/TVS (PLCO RCT) RCT 78216 women (55~74y) USA 10 centers, 1993.11 ~ 2001.7 CA125 (4y) + TVS (6y) annual screening (39,105 women) VS Routine medical care (39,111 women) f/u 12.4y (10.9~13.0y) Ovary/fallopian tube/peritoneal (POFT) cancer diagnosis 212 (5.7 per 10000 person*year) in intervention group VS 173 (4.7 per 10000 person*year) (RR 1.21; 95% CI, 0.99-1.48) Ovary (POFT) cancer mortality 118 (3.1 per 10000 person*year) in intervention group VS 100 (2.6 per 10000 person*year) (RR 1.18; 95% CI, 0.82-1.71) False positive results : 3285 women! Prostate, Lung, Colorectal and Ovarian (PLCO) cancer trial. Saundra S Buys et al. JAMA 2011;305:2295-2303
UKCTOCS (UK Collaborative Trial of Ovarian Cancer Screening) RCT RCT 202638 women (50~74y) England, Wales, Northern Ireland 13 centers, 2001.6 ~ 2005.10 Multimodal screening (MMS) with CA125 using risk of ov cancer algorithm (50640 women) VS TVS annual screening (50639 women) VS No screening (101359 women) f/u 11.1y (10.0~12.0y) Ovary(POFT) cancer diagnosis 338(0.7%) in MMS VS 314(0.6%) in TVS VS 1282(0.6%) in control Ovary(POFT) cancer mortality 148(0.29%) in MMS VS 154(0.30%) in TVS VS 347(0.34%) in control Ian J Jacobs et al. Lancet 2016;387:945-945
Recommendations for Ovarian cancer screening Daniel L Clarke-Pearson NEJM 2009;361:170-177 Effective Screening test X Early detection X More advanced stage & poor prognosis
Annual screening (46/F)
Contents Clinical features of Epithelial Ovarian Cancer (EOC) Surveillances Transvaginal sonogram (TVS) CA125 Chemoprevention Oral Contraceptives (OCs) Risk-reducing salpingo-oophorectomy (RRSO) Discussion
Oral contraceptives Mechanism Inhibition of follicular maturation & ovulation Inhibition of tubular motility Induction of endometrium atrophy Change of cervical mucus E + progesterone : Combined OCs Generations (ethinyl estradiol < 0.05mg, except 1 st G) 2 nd : Levonorgestrel 3 rd : Desogestrel/Gestodene/Cyproterone 4 th : Drospirenone
OCs cancer risks association with breast & ovarian cancer at-average risk population Ovarian cancer risk 30% ovarian cancer risk reduction in ever users Longer duration of use greater risk reduction Beral V et al. Ovarian cancer and oral contraceptives: Collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet 371:303-314, 2008 Breast cancer risk Modest increased OR 1.08 in ever users Higher risk for current/recent users Breast cancer and hormonal contraceptives: Collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies Collaborative Group n Hormonal Factors in Breast Cancer. Lancet 347:1713-1727, 1996
OCs cancer risks association with ovarian cancer in BRCA1/2 mut carriers Moorman et al. JCO 2013;31:4188-4198
OCs cancer risks association with breast cancer in BRCA1/2 mut carriers : conflicting results No RCT, just case-control studies (ethical problem) Criteria for defining the control population for the studies Non-BRCAmut carrier OR carrier without cancer diagnosis Consideration of family history of breast/ovarian cancer Baseline demographics of the population studied Nationality Ethnicity Geographic region Age group Age of onset of breast cancer Formulations (generation), duration of OCs used, or timing of OCs started NCCN Guidelines Genetic/Familial High-risk Assessment: Breast and Ovarian. 1. 2018
Matched Case-control study 2492 matched BRCA1mut Start OCs < 20y (OR 1.45; 95 % CI 1.20 1.75; P = 0.0001) 20 ~ 25y (OR 1.19; 95 % CI 0.99 1.42; P = 0.06) Limited effects to breast cancers diagnosed before age 40 (OR 1.40; 95 % CI 1.14 1.70; P = 0.001) Risk of early-onset breast cancer increased by 11 % with each additional year when < 20y (OR 1.11; 95 % CI 1.03 1.20; P = 0.008) Kotsopoulos et al. Breast Cancer Res Treat 2014;143:579-586
Kotsopoulos et al. Breast Cancer Res Treat 2014;143:579-586
Vulnerable age to OCs or others? Radiation exposure in young age with BRCA1/2 mut may be harmful Breast screening with mammogram : 25y 30y Andrieu et al. EMBRACE, GENEPSO, GEO-HEBON, IBCCS group. JCO 2006;24:3361-3366 Adolescence represents a time period of rapid cellular proliferation when the breast is susceptible to carcinogenic insult Russo J et al. 1981. In Vitro 17(10):877 884
Chemoprevention of ovarian cancer for gbrca1/2 mut Unanswered questions When to start oral pill? Till when? The dose and type of OCs? Start OCs at least after 25 years old in BRCA1mut? The overall benefit of OCs for ovarian cancer prevention in high-risk women must be weighed against the risk for breast cancer
Contents Clinical features of Epithelial Ovarian Cancer (EOC) Surveillances Transvaginal sonogram (TVS) CA125 Chemoprevention Oral Contraceptives (OCs) Risk-reducing salpingo-oophorectomy (RRSO) Discussion
Risk Reducing Salpingo-Oophorectomy 35~40 year or upon completion of child bearing Delayed until age 40-45y in BRCA2 80~85% risk reduction of ovary/tubal/peritoneal cancer 43~56% risk reduction of Br ca. Rebbeck TR et al. J Natl Caner Inst 2009;101:80-87 Kauff ND et al. JCO, 2008;26:1331-1337 Eisen A et al. JCO 2005;23:7491-7496 Rebbeck TR et al. NEJM 2002;346:1616-1622 Rebbeck TR et al. J Natl Caner Inst 2009;101:80-87 Incidentally detected cancer rate : 4.6 ~ 8.0% Sherman ME et al. JCO 2014;32:3275-3283 Crum et al. IJGC, 2012;22:S29-34
Risk management of ovarian cancer for gbrca1/2 mut NCCN Guidelines Genetic/Familial High-risk Assessment: Breast and Ovarian. 1. 2018
Conclusions Risk management of ovarian cancer for gbrca1/2 mut Primary prevention strategy for ovarian cancer RRSO : supported by national health insurance in Korea Other preventive strategies for ovarian cancer Chemoprevention with OCs Surveillance by clinician s discretion Alternatives less invasive, preserving ovary and fertility 1. For not complete childbearing 2. Who wish to avoid surgery (RRSO) Uptake rate of RRSO (13~54%) : 22~52% in Korea Wainberg S et al. J Cancer Epidemiol Biomarkers Prev 2004;13:1989-1995 Kim SI et al. J Cancer Res Clin Oncol 2016;142:333-340
Complication after RRSO Induced surgically menopause Oophorectomy before menopause leads to an abrupt decline in sex hormones Impaired Quality of Life(QoL) of patients Menopausal symptoms Night sweats Sleep disturbance Hot flushes Vaginal dryness, dyspareunia, loss of sex drive(libido) possible short-term HRT to a recommended maximum age of natural menopause Medical problems, increased risks Cardiovascular disease Stroke Dementia Cognitive impairment Osteoporosis, Lower life expectancy, Lung cancer Hamsen et al. BMC Cancer 2015;15:593
RSDO rather than RRSO Robert J Kurman and Ie-Ming Shih Human Pahtology 2011;42:918-931
RSDO rather than RRSO ClinicalTrials.gov https://clinicaltrials.gov/ct2/results?cond=salpingectomy+brca&term=&cntry=&state=&city=&dist