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Ovarian Cancer
Stacey N. Akers, MD
July 14, 2015
Overview
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Ovarian cancer
Statistics
Risk factors
Inherited Syndromes
Prevention
Diagnosis
Staging
Treatment
Ovarian Cancer
Epidemiology
• 9th most common cancer among women
– 22,000 • 5th most common cause of cancer death
– 15,000 • Leading three malignancies among women: Breast, Lung, Colon
Jemal. Cancer Statistics 2012
Epithelial Ovarian Cancer (EOC)
• Most common type of ovarian cancer
– Epithelial (75%)
– Germ cell (15‐20%)
– Sex‐cord Stromal (5%)
• Median age of presentation 65 • Overall lifetime risk is 1 in 70
• 75‐80% of patients are diagnosed with Stage III or IV disease
Ovarian Cancer
• Risk Factors
– Poorly understood
– 85‐90% sporadic
• Screening
– General Population??
– Low prevalence in women <50 (40/10,000)
Risk Factors
 Family history (primarily 2 or more first degree relatives)
 Age (besides family history, this is the most important risk factor)
 Nulliparity
 Early menarche, late menopause
 Late childbirth (age >35)
 Environmental factors not yet defined
Lifetime Risk for Ovarian Cancer
Family History of Ovarian Cancer
None
1 first degree relative (parent, child, sibling)
2 first degree relatives Lifetime Risk
1.4%
5% 7% Symptoms of Ovarian Cancer
• Largely non‐specific
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Increase in abdominal girth (ascites)
Bloating
Fatigue
Abdominal pain
Early satiety
Indigestion
Constipation
Weight loss, unexplained
New onset of urinary frequency or incontinence
Risk Reduction
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Oral Contraceptive Pills
Breast Feeding
Tubal ligation
Risk reducing oophorectomy
THE DEVELOPMENT OF A
HEREDITARY CANCER
2 normal genes
1 damaged gene
1 normal gene
2 damaged genes
Tumor
develops
In hereditary cancer, one damaged gene is inherited.
1 damaged gene
1 normal gene
2 damaged genes
Tumor
develops
Myriad Genetics, Inc.
© 2006 Myriad Genetic Laboratories, Inc.
Cancer Syndromes
• Hereditary Breast Cancer Syndromes
– BRCA1/2
• Hereditary Colorectal Cancer Syndromes
– HNPCC SYNDROME
BRCA 1+ Women
Angelina’s mom was diagnosed with ovarian cancer at 56
She died in 2007
Recently underwent risk reducing mastectomy
And removal of both ovaries and fallopian tubes
Christina was diagnosed with breast cancer at age 36
Her mom is a breast cancer survivor
Hereditary Breast and Ovarian Cancer Syndromes
Hereditary Ovarian Cancer
• Account for 10‐15% of EOC
• BRCA1, BRCA2 (Hereditary Breast and Ovarian Cancer –HBOC)
– Estimated 1/300 to 1/800 individuals carry a BRCA 1 or 2 mutation
– Estimated 1/40 Ashkenazi Jews carry a BRCA 1 or 2 mutation
• Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
– Colorectal Cancer before age 50
– Endometrial cancer before age 50
Hereditary Ovarian Cancer
• BRCA 1 Germline Mutations
– Tumor suppressor gene
– Autosomal dominant
– 65 to 74% Breast Cancer risk
– 39‐46% Ovarian Cancer risk
ACOG Practice Bulletin #103, 2009.
Hereditary Ovarian Cancer
• BRCA2 Germline Mutations
– Tumor suppressor gene
– 65‐74% Breast Cancer risk
– 12‐20% Ovarian Cancer risk
Lifetime Risks in Patients with
Hereditary Gynecologic Cancers
Gene
Hereditary Cancer Lifetime Risk
BRCA 1
30‐40% risk of ovarian cancer
BRCA 2
15‐25% risk of ovarian cancer
Hereditary Ovarian Cancer Syndrome
Lynch
40%
40‐60% risk of uterine cancer
6‐20% risk of ovarian cancer
Hereditary Ovarian Cancer
• HNPCC
– Autosomal dominant
– 80% risk of developing colon cancer
– 60% risk of developing endometrial cancer
– 10‐15% risk of developing ovarian cancer
– Mismatch repair gene defects
RRSO for BRCA
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BRCA1
– Risk of cancer rises in late 30’s and early 40’s (2‐3%)
– Risk of ovarian cancer is 10‐21% by age 50
– Average age of ovarian cancer diagnosis 53 years
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BRCA2
– Risk of ovarian cancer is 2‐3% by age 50
– Risk of breast cancer is 26‐34% by age 50
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Women with BRCA1 and 2 mutations should be offered RRSO by age 40 or when child bearing is complete
RRSO reduces a woman’s risk of developing breast cancer by 40‐70% (the protective effect is strongest among premenopausal women)
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Finch et al. JAMA. 2006
RRSO for HNPCC
• Average age of ovarian cancer 42 years
• Average age of endometrial cancer is 50 years
• RRSO associated near 100% reduction in endometrial, ovarian, fallopian and primary peritoneal adenocarcinoma
• Women with HNPCC mutations should be offered hysterectomy/RRSO by age 35‐40 or when child bearing is complete
Who To Test?
Offer testing to every patient with epithelial ovarian cancer
Why Should I Test Everyone with Ovarian Cancer?
19‐44% of patients with BRCA 1&2 mutations do not have a family history
Standard of care is to refer all women with breast cancer under the age of 45
• Mutation risk is 4.7%
• Mutation risk is 7.7% for a single case of ovarian cancer
• At any age, regardless of family history
Berchuck A. Obstet Gynecol 2012;120(2):221-222. [Editorial to Schrader paper]
Schrader et al. Obstet Gynecol 2012;120(2):235-240
Alsop et al. JCO 2012;30(21):2654-2663
ACOG Guidelines: Genetic Referral and Testing Non Ashkenazi Jewish women
• 2 first degree relatives with breast cancer, one diagnosed before 50
• 3 or more first or second degree relatives with breast cancer at any age
• Combination of breast and ovarian cancer among first and second degree relatives
• First degree relative with bilateral breast cancer
• Two or more first or second degree relatives with ovarian cancer at any age
• A first or second degree relative with both breast and ovarian cancer at any age
• A male relative with breast cancer
ACOG Practice Bulletin #89 January 2008, reaffirmed 2012
Screening Guidelines for BRCA and HNPCC Patients
• BRCA
– Begin at age 30‐35 or 5‐10 years before earliest diagnosed cancer in family
– annual CA125
– annual TVS
• HNPCC
– Start at age 25 or 10 years before earliest diagnosed cancer in family
– annual EMB
– annual TVS
– annual Colonoscopy
Screening
• High risk patients
– Genetic counseling
– CA‐125 and pelvic ultrasound every six months
• No evidence for improved survival
• DO NOT RECOMMEND ROUTINE SCREENING
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US Preventive Service Task Force
American Cancer Society
American College of Obstetricians and Gynecologist
National Comprehensive Cancer Network
Screening for Ovarian Cancer
• There is no evidence that screening for Ovarian Cancer leads to earlier detection or improved survival…
• Nonetheless, the following have been or are being used
– TVS
– CA125
Screening (Multimodal)
• Simultaneous screening with CA125 and transvaginal ultrasound compared with usual care did not reduce ovarian cancer mortality
Misconceptions about genetic testing
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Testing is not covered by insurance. In most instances insurance
covers the cost of testing like any other medical expense.
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Testing is complicated. True and false – choosing the appropriate test
is not always simple, there are significant opportunities for
misinterpretation. Seek consultation with a health care provider (nurse
practitioner, genetic counselor, MD) specializing in hereditary cancer.
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Testing will cause you to lose your insurance. Concerns exist about
genetic discrimination, but after nearly 15 years of clinical testing, no
significant problems have been seen. Members of group health
insurance plans have protection under Federal Law (HIPPA, 1996).
GINA signed into law May 2008, extends protections from discrimination
based on genetic information to those with private health insurance
DISCRIMINATION
• FEDERAL AND STATE LAWS PROHIBIT THE USE OF GENETIC INFORMATION AS A PRE‐
EXISTING CONDITION
• NO DOCUMENTED CASES OF GENETIC DISCRIMINATION
NEJM 2008
Management of Adnexal Masses
• Adnexal masses often present both diagnostic and management dilemmas
• Need to determine:
– Malignant vs. benign
– Surgery vs. conservation
ACOG Practice Bulletin #83, 2007. Differential Diagnosis
 Gynecologic
– Benign
• Functional cyst
• Leiomyomata
• Endometrioma
• TOA
• Ectopic
• Teratoma
• Cystadenoma
– Malignant
• EOC
• Germ Cell
• Sex‐cord stromal
• Non‐gynecologic
– Benign
• Diverticular abscess
• Appendiceal abscess
• Nerve sheath tumors
• Pelvic Kidney
– Malignant
• Colon cancer
• Breast cancer
• Gastric cancer
Current GYN/Oncology referral guidelines for a pelvic mass
• ACOG committee
• Postmenopausal women with suspicious pelvic mass as suggested by at least one of the following:
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elevated CA125
ascites
nodular or fixed pelvic mass
evidence of distant metastasis
Current GYN/Oncology referral guidelines for a pelvic mass
• Premenopausal patient with pelvic mass suspicious for ovarian cancer as evidenced by the presence of one of the following:
• Very elevated CA125
• ascites
• evidence of metastasis
How is ovarian cancer diagnosed?
• Labs
• Imaging – CT, Ultrasound
• Surgery
FIGO Staging
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Stage I
– IA Tumor confined to a single ovary, negative washings, capsule intact, surface of ovary uninvolved
– IB Tumor found in both ovaries, negative washings, capsule intact, surface of ovary uninvolved
– IC Tumor on one or both ovaries, ruptured capsule, positive cytology or ovarian surface involvement
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Stage II
– IIA Extension or metastasis to uterus and/or tubes
– IIB Extension to other pelvic structures
– IIC Tumor on one or both ovaries, ruptured capsule, positive cytology or ovarian surface involvement
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Stage III
– IIIA Tumor on one or both ovaries with microscopic spread to abdominal peritoneal surface (ex. Liver serosa)
– IIIB Tumor implant <2cm to abdominal peritoneal surface
– IIIC Tumor implant >2cm to abdominal peritoneal surface and/or positive retroperitoneal or inguinal lymph nodes
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Stage IV – Distant metastasis
– Pleural effusion with positive cytology
– Parenchymal liver metastasis
Survival Rates for Ovarian Cancer Need to be Improved
Ovarian Cancer 5-yr Survival Rate by Stage
Stage Distribution
at Diagnosis
Survival Rate
Stage I
20-27%
73-93%
Stage II
5-10%
45-70%
Stage III
52-58%
21-37%
Stage IV
11-17%
11-25%
Heintz APM, et al. FIGO Annual Report on the Results of Treatment in Gynecologic Cancers. 2000; 24 :107-138.
Holschneider CH, Berek JS. Semin Surg Oncol. 2000;19:3-10.
Histology
Histology
Incidence
Serous
40-50%
Most common
Endometrioid
15-25%
2nd most common
Mucinous
6-16%
Clear Cell
5-11%
Other
Principles of Ovarian Cancer Surgery
• Purpose of Surgery
– Staging of disease
• Prognosis and treatment depend upon surgical findings and subsequent stage
– Debulking (cytoreduction)
• Overall reduction of tumor burden to less than 1 cm (preferably no gross residual disease) improves survival
Principles of Ovarian Cancer Surgery
• In most cases, hysterectomy with bilateral salpingo‐oophorectomy is indicated
Treatment
• Surgery
• Chemotherapy
Advanced ovarian cancer (Stage III, Stage IV)
• Despite the best efforts at early detection, 70‐
80% of women will be diagnosed with advanced epithelial ovarian cancer
• Prognosis is poor 25‐35% 5‐year survival, 10% 10‐
year survival
• Maximal effort/time/expense has been dedicated to better screening and more effective therapy
• Over the past 20 years, we have not been successful in changing the survival rate…