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