Inherited Ovarian Cancer Diagnosis and Prevention Dr. Jacob Korach - Deputy director Gynecologic Oncology (past chair - Israeli Society of Gynecologic Oncology) Prof. Eitan Friedman - Head, Oncogenetics Sheba Medical Center Tel Hashomer, Israel
The Chaim Sheba Medical Center Largest in Israel Affiliated to Tel-Aviv University Almost 2000 beds (1000 Acute + 900 Chronic ) Geriatrics Rehab, Psychiatry, Ortho & Neuro Rehab 120 Departments and clinics (3 hospices, 4 hotels) >7,000 Employees 85,000 Admissions 750,000 OP visits 150,000 ER visits 35,000 Operations 10,000 Deliveries 850 MDs / 2000 RNs Copyright 2011. MSR, the Israel Center for Medical Simulation. All rights reserved.
Ovarian Cancer Ovarian cancer Fallopian tube cancer Primary peritoneal cancer
Incidence The less common Gynecologic malignancy Turkey - It is estimated that around 3,800 new cases are seen each year It has been reported that 69% of ovarian cancers are epithelial stromal tumors (Quintiles 2012) - i.e. - around 2700 cases a year US - 23000 cases a year Israel - 320 cases a year life time probability - 1.4% (1/70) Most lethal gyn malignancy - All stages 5 year survival - 50%
Risk Factors Familial history of ovarian cancer is the most significant risk factor First degree relative - 5% life time probability
Inherited Ovarian Cancer Worldwide - 5-10% of all cases General population - prevalence of disease related mutations - 1:300-1:800 Israel - 25-30% of all cases Prevalence of disease related mutations up to 1:40! (Ashkenazi Jews(
Both - Tumor suppressor genes - DNA repair genes Two hit theory loss of heterozygosity
Average cumulative risk of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. Mavaddat N et al. JNCI J Natl Cancer Inst 2013;105:812-822 The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
Ovarian cancer risk Ovarian Cancer Risk: BRCA1 vs. BRCA2 (carrier relatives of index cases) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Israel Breast Cancer Consortium Nov 2005 HR=2.1, p=.04* 0.5% 7% 25 30 35 40 45 50 55 60 65 70 75 0% 2% 28% 14% Age (years) 59% 51% 42% 54% BRCA1 BRCA2 * Controlled for year of birth, index case cancer site, 9 ascertainment
Criteria for Genetic Risk Assessment Patients with greater than an approximate 20 25% chance of having an inherited predisposition to breast cancer and ovarian cancer and for whom genetic risk assessment is recommended: Women with a personal history of both breast cancer and ovarian cancer* Women with ovarian cancer*and a close relative with ovarian cancer or premenopausal breast cancer or both Women with ovarian cancer*who are of Ashkenazi Jewish ancestry Women with breast cancer at age 50 years or younger and a close relative with ovarian cancer* or male breast cancer at any age Women of Ashkenazi Jewish ancestry in whom breast cancer was diagnosed at age 40 years or younger Women with a close relative with a known BRCA1 or BRCA2 mutation Patients with greater than an approximate 5 10% chance of having an inherited predisposition to breast cancer and ovarian cancer and for whom genetic risk assessment may be helpful: Women with breast cancer at age 40 years or younger Women with ovarian cancer, primary peritoneal cancer, or fallopian tube cancer of high grade, serous histology at any age Women with bilateral breast cancer (particularly if the first case of breast cancer was diagnosed at age 50 years or younger) Women with breast cancer at age 50 years or younger and a close relative with breast cancer at age 50 years or younger Women of Ashkenazi Jewish ancestry with breast cancer at age 50 years or younger Women with breast cancer at any age and two or more close relatives with breast cancer at any age (particularly if at least one case of breast cancer was diagnosed at age 50 years or younger) Unaffected women with a close relative that meets one of the previous criteria *Cancer of the peritoneum and fallopian tubes should be considered a part of the spectrum of the hereditary breast and ovarian cancer syndrome. Close relative is defined as a first-degree relative (mother, sister, daughter) or second-degree relative (grandmother, granddaughter, aunt, niece). ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome
NCCN Guidelines Version 2.2014 Hereditary Breast and/or Ovarian Cancer Syndrome Breast awareness at the age of 18 Clinical breast exam, every 6 12 mo, starting at age 25 y. Breast screening Age 25 29 y, annual breast MRI screening (preferred) or mammogram if MRI is unavailable or individualised based on earliest age of onset in family. Age 33 75 y, annual mammogram and breast MRI screening. Age >75 y, management should be considered on an individual basis. Discuss risk-reducing mastectomy
And what about ovarian cancer screening
BRCA mutation carrier surveillance - ovary There are data that show that annual trans-vaginal ultrasound and CA-125 are not effective strategies for screening for ovarian cancer in high-risk women There are limited data regarding the effectiveness of a six-month screening interval consensus groups have recommended periodic screening with CA 125 and trans-vaginal ultrasonography, beginning between the ages of 30 years and 35 years or 5 10 years earlier than the earliest age of first diagnosis of ovarian cancer in the family
Active management Chemo-prevention oral contraceptive Surgical prevention bilateral salpingo-oophorectomy Hysterectomy
general population oral contraceptive
oral contraceptive as ovarian cancer risk reducer General population The Cancer and Steroid Hormone Study 546 EOC vs 4228 control risk of EOC 0.6 among OC users 3-6months is enough??? lasts for 15 years independent of formulation N Engl J Med 1987 Mar 12;316(11):650 5.
general population cont d The Royal College of General Practitioners Oral Contraception study 46,000 women - OC users vs non users RR 0.54 in ever users Collaborative Group on Epidemiological Studies of Ovarian Cancer 23,257 EOC vs 87,303 controls the longer the usage the greater reduction of EOC OC usage provide long-term protection against EOC Beral V et al, Lancet 2008 Jan 26;371(9609):303 14.
general population cont d Beral V et al, Lancet 2008 Jan 26;371(9609):303 14.
100,000 deaths from disease prevented by OC Beral V et al, Lancet 2008 Jan 26;371(9609):303 14.
underlying mechanisms The old theory - Incessant ovulation (Fathalla 1971) The new theory fimbrial p53 signature etc (Kurman 2004) prevent invagination of Mullerian duct cells
chemo-prevention BRCA mut. population
OC and BRCA mutation carriers 6 studies since 1998 5 found risk reducing effect Modan et al N Engl J Med 2001;345:235 240 no benefit due to small number of OC users
OC and BRCA mutation carriers McLaughlin JR et al Lancet Oncol 2007;8:26 34 The largest study The use of OC was associated with highly significant risk reduction of ovarian cancer for mutation carriers"
risk reducing surgery BSO/BS+BO/H-BSO
risk reducing salpingo-oophorectomy After a preventive salpingo-oophorectomy, mutation carriers achieve an 80% reduction in subsequent ovarian, fallopian tube and peritoneal cancer Iryna Vyarvelska et al Gyn Onc 134 (2014) 219 221
NCCN Guidelines Version 2.2014 Hereditary Breast and/or Ovarian Cancer Syndrome Recommend risk-reducing salpingooophorectomy, ideally between 35 and 40 y, and upon completion of child bearing or individualised based on earliest age of onset of ovarian cancer in the family
Hysterectomy? Salpingectomy only first?
Hysterectomy Absolute risk of uterine cancer BRCA carriers Canada 4456BRCA women 17endometrial cancer Life time risk (35-75) 2.8% Tamoxifen users among BRCA women 4.3% General population 2.6% Segev Y, et al. The incidence of endometrial cancer in women with BRCA1 and BRCA2 mutations: an international prospective cohort study. Gynecol Oncol 2013;130:127 31.
To H or not to H pro hysterctomy con eliminate risk of endometrial cancer fallopian cornual portion small increments of endometrial cancer mainly in tamoxifen users fimbria should be removed tamoxifen w/o risk of endometrial cancer simplifies HRT peri-operative morbidity QOL issues eliminate risk of cervical cancer cost serous endometrial cancer and BRCA HRT is not c/i in BRCA there is no evidence for prognostic benefit of hysterectomy
Two steps BSO The fimbria is the origin of major portion of ovarian cancer Young age BSO carries higher risk of health and QOL disadvantages Pre menopause salpingectomy Post menopausal oophorectomy
salpingectomy 60% pelvic serous carcinomas (only 60 ) in a mathematical model: BSO offers the greatest risk reduction for breast and ovarian cancer when considering QOL is acceptable alternative for those unwilling to undergo BSO JS Kwon et al obstet gynecol VOL. 121, NO. 1, JANUARY 2013
Why risk reducing and not prophylactic? Occult TIC/occult cancer PPC post BSO
oophorectomy - cancer incidence and mortality Amy Finch et al J Clin Oncol 32:1547-1553
all cause mortality
Post BSO Follow up
Follow up post RSO Cedar Sinai RRSO series occult and subsequent gyn cancer following RRSO 2000-2013 258 cases 14 occult cancer 5%)) tubal - 9 TIC, 1 IA, 2 IC ovary - 1 IIIA, 1 IIB endometrioid endometrial carcinoma 4 subsequent serous carcinoma 1.6%)) PPC 2 post TIC (elevated CA 125 on FU) 2 post benign adnexa (abdominal distension) M. Zakhour, WAGO abstracts 2014, GynOnc Nov 2014
Summary familial history is the most significant risk factor no effective risk reducing surveillance schema OC should be considered for chemo-prevention BSO is the most effective risk reducing procedure women should continue follow up post BSO