Post on 06-Aug-2020
GYNECOLOGIC CANCERS
JANUARY 17, 2017Dr. Stacey N. Akers
US MORTALITY, 2014
Source: US Mortality Data 2014, National Center for Health Statistics, Centers for Disease Control and Prevention, 2012.
1. Heart Diseases 611,105
2. Cancer 584,881
3. Chronic lower respiratory diseases 149,205
4. Cerebrovascular diseases 128,978
5. Accidents 130,557
6. Alzheimer disease 84,767
7. Diabetes mellitus 75,578
8. Nephritis* 47,112
9. Influenza & pneumonia 56,979
10. Suicide 41,149
Rank Cause of DeathNo. of deaths
CANCER
All cancer involves changes in genes….
During mitosis & DNA replication
mutations occur in the cell’s genetic code
Mutations are normally corrected by DNA repair
mechanisms
If repair mechanism or cell cycle regulation damaged
Cell accumulates too many mutations
→ reaches ‘threshold’
→ tumor development
SPORADIC CANCER
All cancer arises from changes in genes….
But NOT all cancer is inherited
Most cancer is sporadic ~ 80%
Due to mutations acquired over a person’s lifetime:
Cause unknown – multifactorial
Age
Environment
lifestyle (obesity, alcohol)
chance
Sporadic cancer generally has a later onset
CLUSTERING OF CANCER IN FAMILIES
10 -15% of breast/ovarian cancer is familial: Due to some factor in the family
Undiscovered gene mutation
Generally not eligible for genetic testing
5-10% of breast/ovarian cancer is hereditary: Inherited gene mutation which causes increased risk for cancer
Variety of cancer syndromes
About 2/3 of these - BRCA 1 or BRCA 2 mutations
May be eligible for genetic testing
RISK FACTORS
Family History
Lifestyle
Environment
Genetics (10 % of cancers)
Aging
Chance
RISK FACTORS FOR HEREDITARY CANCER
YOUNG Breast <45, Colon <50
RARE Ovarian
Male Breast
Pancreatic
MULTIPLE Two or more different cancers in the same person
FAMILY Two or more family members with the same or related
types of cancer Breast/Ovary
OBJECTIVES
Discuss epidemiological, medical and surgical,
preventative, and future treatment of:
Ovarian cancer
Endometrial cancer
OVARIAN CANCER
SYMPTOMS:
Bloating
Reflux
Weight loss
Abdominal pain/fullness
Pelvic pain/pressure
Urinary frequency
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)
Median age of presentation 65
Overall lifetime risk is 1 in 70
1 first degree relative 5%
2 first degree relatives 7%
75-80% of patients are diagnosed with Stage III
or IV disease
OVARIAN CANCER
Risk Factors
Poorly understood
85% sporadic
Screening
General Population??
Low prevalence in women <50 (40/10,000)
RISK FACTORS OVARIAN CANCER
Family history (MOST IMPORTANT)
primarily 2 or more first degree relatives
Age
Nulliparity
Early menarche, late menopause
Late childbirth (age >35)
Environmental factors not yet defined
SURVIVAL RATES FOR OVARIAN
CANCER NEED TO BE IMPROVED
Ovarian Cancer 5-yr Survival Rate by Stage
Stage Distribution
at DiagnosisSurvival 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.
TREATMENT
Surgery
Chemotherapy
ADVANCED OVARIAN CANCER
(STAGE III, STAGE IV)
Prognosis is poor 25-35% 5-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…
DIAGNOSIS AND TREATMENT OF UTERINE
CANCER
UTERINE CANCER
Abnormal uterine
bleeding
Post menopausal
bleeding
Obesity
Unopposed estrogen
Diabetes
Chronic anovulation
Genetic syndrome
LYNCH
Symptoms Risk Factors
EVALUATION AND TREATMENT
Endometrial biopsy
Hysteroscopy with Dilation and Curettage
Total hysterectomy with bilateral salpingo-oophorectomy, selective pelvic and para-aortic lymph node dissection (+/-Adjuvant therapy)
ENDOMETRIAL CANCER SURVIVAL RATES
Stage 5 Year Survival (%)
I 81-91
II 71-78
III 52-60
IV 14-17
GENETICS
CHROMOSOMES
THE DEVELOPMENT OF A HEREDITARY CANCER
1 damaged gene1 normal gene
Tumordevelops2 normal genes 2 damaged genes
In hereditary cancer, one damaged gene is inherited.
1 damaged gene1 normal gene
Tumordevelops2 damaged genes
© 2006 Myriad Genetic Laboratories, Inc.
Myriad Genetics, Inc.
GENETICS
Genetics can help us identify the people who have
risks for disease that go far above the general
risks
Who are the people who have such a risk for
cancer that they should take extra steps to detect
or prevent this disease?
GENE MUTATIONS INCREASING RISK FOR
OVARIAN CANCER
•Hereditary breast and ovarian
cancer syndrome
BRCA1, BRCA2
•Lynch syndrome
MLH1, MSH2, MSH6,
PMS2, EPCAM
• BARD1
• BRIP1
• CDH1
• CHEK2
• MRE11A
• MUTYH
• NBN
• PALB2
• RAD50
• RAD51C
• RAD51D
• STK11
• TP53
BRCA1 AND BRCA2
WHAT HAPPENS WHEN THEIR FUNCTION IS
COMPROMISED ?
Both genes are tumor suppressors (autosomal
dominant):
Regulation of cell growth
Maintenance of cell cycle
Mutation leads to:
Inability to regulate cell death
Uncontrolled growth, cancer
CANCER SYNDROMES
Hereditary Breast Cancer Syndromes BRCA1/2
Hereditary Colorectal Cancer Syndromes LYNCH SYNDROME (HNPCC)
Colon (<50)
Endometrial (<50)
Ovarian cancer
Account for 10-15% of EOC
HEREDITARY OVARIAN CANCER
BRCA 1 Germline Mutations
65-74% Breast Cancer risk
39-46% Ovarian Cancer risk
BRCA2 Germline Mutations
65-74% Breast Cancer risk
12-20% Ovarian Cancer risk
ACOG Practice Bulletin #103, 2009.
SCREENING GUIDELINES FOR BRCA
PATIENTS
BRCA
Begin at age 30-35 or 5-10 years before earliest diagnosed cancer in family
annual CA125
annual TVS
NO evidence improved overall survival
RRSO FOR BRCA
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
BRCA2
Risk of ovarian cancer is 2-3% by age 50
Risk of breast cancer is 26-34% by age 50
RRSO reduces a woman’s risk of developing breast cancer by 40-70% (the protective effect is strongest among premenopausal women)
Finch et al. JAMA. 2006
RISK REDUCTION
Oral Contraceptive Pills
Breast Feeding
Tubal ligation
Risk reducing salpingo-oophorectomy
LYNCH SYNDROME
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
Testing in women <50 with endometrial cancer
Mismatch Repair Genes
Repair mistakes that are made in the course of normal cell division MLH1
MSH2
MSH6
PMS2
SCREENING GUIDELINES FOR HNPCC
PATIENTS
HNPCC
Start at age 25 or 10 years before earliest diagnosed cancer in family
annual EMB
annual TVS
annual Colonoscopy
RRSO FOR LYNCH SYNDROME
Average age of ovarian cancer 42 years
Average age of endometrial cancer 50 years
RRSO associated near 100% reduction in endometrial, ovarian, fallopian and primary peritoneal carcinoma
Women with HNPCC mutations should be offered hysterectomy/RRSO by age 35-40 or when child bearing is complete
WHO TO TEST?
All patients with a diagnosis of ovarian cancer
20-40% of patients with a mutation will have no
family history of cancer
NCCN
HEREDITARY BREAST AND OVARIAN
CANCER SYNDROME: BRCA1 AND BRCA2
Prevalence in the general population: ~1 in 400
Prevalence in the Ashkenazi Jewish population: ~ 1 in 40
Consider when history includes one of the following:
• Ovarian cancer at any age
• Breast cancer at or before age 50
• Triple negative breast cancer at or before age 60
• Two primary breast cancers in the same person or on the same side of family
• Breast and ovarian cancer in the same person
• ≥3 relatives with breast, ovarian, pancreatic cancer and/or aggressive prostate cancer on the same side of family
• Ashkenazi Jewish Ancestry and a personal or family history of breast, ovarian or pancreatic cancer
• Male breast cancer
LYNCH SYNDROME: MLH1, MSH2,
MSH6, PMS2, EPCAM
Consider when history includes one of the following:
• Colon cancer before age 50
• Uterine cancer before age 50
• ≥ 2 Lynch cancers in the same person
• ≥ 2 relatives with a Lynch cancer, one <50 years old
• ≥ 3 relatives with a Lynch cancer at any age
MISCONCEPTIONS ABOUT GENETIC
TESTING
1. Testing is not covered by insurance.
2. Testing is complicated. choosing the appropriate test is not always simple, there are significant opportunities for misinterpretation. Seek consultation with a health care provider specializing in hereditary cancer.
3. 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.
INSURANCE COVERAGE
• Covered benefit if medical criteria is met (NCCN criteria). Some insurance have their own criteria.
• Always pre-authorized by the genetic testing lab
• Out of pocket cost depends on your insurance plan
• Discounted prices for those without insurance coverage
PSYCHOLOGICAL ASPECTS TO CONSIDER
Motivation for genetic testing:
Reduce uncertainty
Learn about risk for children
Explore further surveillance/treatment options
RESULTS FROM GENETIC TESTING
Positive
Negative
Variant of unknown significance
RISKS AND BENEFITS OF GENETIC TESTING
POSITIVE TEST RESULT
Potential Benefits:
Clinical intervention may
improve outcome
Family members at risk
can be identified
Positive health behavior
can be reinforced
Reduction of uncertainty
Potential Risks:
Adverse psychological
reaction
Family issues/distress
Uncertainty -incomplete
penetrance
Confidentiality issues
Intervention carries risk
RISKS AND BENEFITS OF GENETIC TESTING
NEGATIVE TEST RESULT
Potential Benefits:
Avoidance of
unnecessary clinical
interventions
Emotional - relief
Children can be
reassured
Avoidance of higher
insurance premiums
Potential Risks:
Complacent attitude to
health
WHY?
We're trying to predict the
future so we can maybe change
the future