1. Dr. Stacey Akers, MD
Cancer accounts for nearly one-quarter of deaths in the United States, exceeded only by heart diseases. In 2010, there were 574,743 cancer deaths in the US.

2. US Mortality, 2014 Cause of Death No. of deaths 2. Cancer 584,881
1. Heart Diseases ,105
2. Cancer ,881
3. Chronic lower respiratory diseases 149,205
4. Cerebrovascular diseases 128,978
5. Accidents ,557
6. Alzheimer disease ,767
7. Diabetes mellitus ,578
8. Nephritis* ,112
9. Influenza & pneumonia 56,979
10. Suicide ,149
Cancer accounts for nearly one-quarter of deaths in the United States, exceeded only by heart diseases. In 2010, there were 574,743 cancer deaths in the US.
Source: US Mortality Data 2014, National Center for Health Statistics, Centers for Disease Control and Prevention, 2012.

3. 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
Slide 4:
Cancer1
All cancer is genetic because it is caused by an accumulation of mutations in the cell’s genetic code (genes) that lead to tumour development.
Threshold effect: During the cell cycle, as the cell goes through DNA replication and mitosis, mistakes or mutations occur in the cell’s genetic code. These mistakes are normally corrected by a class of genes known as DNA mismatch & repair genes. Our cells have a series of checks and balances to maintain the rate of new cell growth and cell death. This balance is maintained by several classes of genes: tumour suppressors, oncogenes, DNA mismatch & repair genes.
A cell accumulates mutations either by chance or environmental exposures or due to an inherited defect in the normal DNA repair system.
When there are too many changes in the cell’s genetic code, the cell is unable to repair the mutations and/or regulate cell growth. At this point, irreversible changes in the cell’s DNA lead to an atypical cell - with uncontrolled proliferation, this can lead to the development of a tumor.

4. 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
Interaction of: age environment, lifestyle (obesity, alcohol), chance, unknown factors
Sporadic cancer generally has a later onset
Slide 5:
Sporadic Cancer
In cases of sporadic cancer, mutations in the cell’s genetic code occur after birth.
Breast cancer is multifactorial – it is caused by the interaction of many factors such as age, lifestyle, environmental exposures, genetic or chance/unknown factors.
Sporadic cancer generally has a later onset as it takes time for a cell to acquire multiple mutations in the genetic code leading to tumour development.
Common Question: What are the risk factors for breast cancer?
Risk factors with > 2x increased risk for breast cancer: 2
Age
Atypical hyperplasia or LCIS diagnosed by breast biopsy.
Risk factors associated with breast cancer with < 2x increased risk for developing breast cancer:2
Menarche before age 12 years
Menopause after age 55 years
First live birth after age 30 years
Nulliparity
Previous history of breast biopsies
Postmenopausal obesity
Alcohol use
Hormone replacement therapy
Excessive radiation exposure

5. Clustering of Cancer in Families
11% lifetime risk of developing breast cancer
~20% of women with breast cancer have a family history:
10 -15% of breast/ovarian cancer is familial:
Due to some factor in the family
Environmental
Undiscovered gene mutation
Chance
Generally not eligible for genetic testing
5-10% of breast/ovarian cancer is hereditary:
Caused by an 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
Slide 6:
Clustering of Cancer in Families
Approximately 20% of all breast cancer cases are familial. That is, 20% of women with breast cancer have a first, second or third degree relative who has also been diagnosed with cancer.
10 – 15% of familial breast cancer could be due to:
- Rare genetic syndromes associated with an increased risk of cancer.
- Common (unidentified) familial susceptibility cancer genes
- Common environment exposures
- Common lifestyle
- Chance: Approximately 1 women in 9 or 11% of Canadian women will develop breast cancer in their lifetime.3
5-10% of breast cancer is hereditary – in these cases a person is born with an inherited predisposition to cancer. About two-thirds of these hereditary cases are due to an inherited mutation in BRCA1 or BRCA2 genes.

6. Genetics (10 % of cancers) Aging Chance
Risk Factors
Family History
Lifestyle
Environment
Genetics (10 % of cancers)
Aging
Chance

7. 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
Breast/Thyroid/Uterine
Breast/Sarcoma/Brain

8. Epidemiological, medical and surgical, preventative, and future treatment of Ovarian and Endometrial cancer

9. Symptoms of Ovarian Cancer
Bloating
Reflux
Weight loss
Abdominal pain/fullness
Pelvic pain/pressure
Urinary frequency

10. 9th most common cancer among women 22,000
Statistics
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

11. 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

12. Low prevalence in women <50 (40/10,000)
Ovarian Cancer
Risk Factors
Poorly understood
85% sporadic
Screening
General Population??
Low prevalence in women <50 (40/10,000)

13. 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

14. 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%
We know that women who are diagnosed with early stage disease are fundamentally curable.
And the 5-year survival rate for Stage 1 ovarian cancer is as high as 93%.
However, the majority of women – more than 70 % -- will have advanced stage ovarian cancer at the time of their diagnosis and we see the survival rate dramatically decreases to about 40% for these women
So how can we affect survival for women who will be diagnosed with ovarian cancer?
Heintz APM, et al. FIGO Annual Report on the Results of Treatment in Gynecologic Cancers. 2000; 24 :
Holschneider CH, Berek JS. Semin Surg Oncol. 2000;19:3-10. 14

15. Treatment
Surgery
Chemotherapy

16. 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…

17. Diagnosis and Treatment of Uterine Cancer
Sonogram
Endometrial biopsy

18. Uterine cancer Abnormal uterine bleeding Post menopausal bleeding
Symptoms
Risk Factors
Abnormal uterine bleeding
Post menopausal bleeding
Obesity
Unopposed estrogen
Diabetes
Chronic anovulation
Genetic syndrome
LYNCH

19. 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)

20. Endometrial Cancer Survival Rates
Stage
5 Year Survival (%) I
81-91 II
71-78
III
52-60 IV
14-17

21. GENETICS

22. Chromosomes

23. Genes

24. THE DEVELOPMENT OF A HEREDITARY CANCER
Tumor
develops
2 normal genes
1 damaged gene
1 normal gene
2 damaged genes
In hereditary cancer, one damaged gene is inherited.
BRCA1/2 function as tumor suppressor genes, helping repair DNA damage.
In a cell with two functional copies of a specific tumor suppressor gene, if only one copy of the gene is damaged, the cell will still function properly as the second “back up” copy of the gene is still functional. If the other copy of the gene is damaged within the same cell, the tumor suppressor function of the gene is taken away and the cell can become cancerous.
This damage can occur through lifestyle, environmental exposures (carcinogens), and most commonly the normal aging process of cells.
The chances of both copies of an important tumor suppressor gene being independently knocked out in the same cell are extremely small.
Individuals with hereditary cancer have inherited one nonfunctional copy of a specific tumor suppressor gene in every cell of their body. Therefore these individuals require only one additional mutation to knock out the functional copy of the gene, making cancer development much more likely.
Tumor
develops
1 damaged gene
1 normal gene
2 damaged genes
Myriad Genetics, Inc.
© 2006 Myriad Genetic Laboratories, Inc.

25. 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?

26. We start to accumulate damage This damage can lead to disease
Time
We start off at our genetic best from day one, and then the aging begins
Time passes
We start to accumulate damage
This damage can lead to disease
You end up with 23 pairs of chromosomes holding all of our genetic material.
You get one of each pair from mom and one of each pair from dad.

27. Gene mutations increasing risk for ovarian cancer
BARD1
BRIP1
CDH1
CHEK2
MRE11A
MUTYH
NBN
PALB2
RAD50
RAD51C
RAD51D
STK11
TP53
Hereditary breast and ovarian cancer syndrome
BRCA1, BRCA2
Lynch syndrome
MLH1, MSH2, MSH6, PMS2, EPCAM

28. 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
Slide 13:
BRCA1 and BRCA2
What happens when their function is compromised?
Both BRCA1 and BRCA2 genes are tumour suppressor genes.
BRCA1 and BRCA2 are also important in the cell cycle; they have a regulatory role in the rate of cell death.
When the function of tumour suppressor genes, like BRCA1 and BRCA2, is compromised, it leads to uncontrolled cell growth, and the accumulation of mutations leading to tumour development.
BRCA1 and BRCA2 protein products likely function as ‘caretaker’ genes by maintaining genomic integrity with some role in DNA synthesis and DNA repair. The role of the BRCA1 and BRCA2 genes is likely to prevent the accumulation of harmful mutations which could lead to cancer.

29. 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

30. Hereditary Ovarian Cancer
BRCA 1 Germline Mutations
65-74% Breast Cancer risk
39-46% Ovarian Cancer risk
BRCA2 Germline Mutations
12-20% Ovarian Cancer risk
ACOG Practice Bulletin #103, 2009.

31. Screening Guidelines for BRCA Patients
Begin at age or 5-10 years before earliest diagnosed cancer in family
annual CA125
annual TVS
NO evidence improved overall survival

32. 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

33. Risk Reduction
Oral Contraceptive Pills
Breast Feeding
Tubal ligation
Risk reducing salpingo-oophorectomy

34. 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

35. Lynch syndrome cancer risks
General Population Risk
Lynch syndrome
Colorectal
5.5%
40-80%
Uterine
2.7%
25-60%
Stomach
<1%
1-13%
Ovarian
1.6%
1-24%
Also at increased risk: Small intestine, biliary system (pancreas, liver, bile duct), brain, skin, and urinary tract (kidneys, ureters, bladder, urethra)

36. Screening guidelines for HNPCC patients
Start at age 25 or 10 years before earliest diagnosed cancer in family
annual EMB
annual TVS
annual Colonoscopy

37. RRSO for Lynch Syndrome
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 carcinoma
Women with HNPCC mutations should be offered hysterectomy/RRSO by age or when child bearing is complete

38. All patients with a diagnosis of ovarian cancer
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
Standard of care to refer all women with breast cancer over the age of 45 and their mutation risk is 4.7% while a single case of ovarian cancer has a risk of 7.7% (at any age, regardless of family history)

39. 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

40. 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

41. Misconceptions about genetic testing
Testing is not covered by insurance. In most instances insurance covers the cost of testing like any other medical expense.
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.
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

42. 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

43. Psychological Aspects to Consider
Motivation for genetic testing:
Reduce uncertainty
Learn about risk for children
Childbearing/marital decisions
Explore further surveillance/treatment options
Slide 20:
Psychological Aspects to Consider
Assessing the patient’s thoughts about breast cancer. Personal experiences affect how patients may feel about testing, treatment and survival from cancer.

44. Results from Genetic Testing
Positive
Deleterious mutation identified
Negative
Interpretation differs if a mutation has previously been identified in the family
Mutation known – true negative
Mutation unknown – uninformative
Variant of unknown significance
Significance will depend on how variant tracks through family - i.e. is variant present in people with disease?
Can use software to predict functional significance
Check with lab to see if reported previously
Slide 23:
Results of Genetic Testing
POSITIVE: a deleterious mutation has been identified. Follow high risk screening recommendations for breast and ovarian cancer.
In some provinces expedited testing is available in 6 to 8 weeks. Consider expedited testing in cases of newly diagnosed cancer – a positive result may alter management. Patient may consider surgery instead of radiation treatment.
Consider referral to psychologist to help patient adjust to the diagnosis.
If they have (or had) cancer, then they are at risk for a second primary (contralateral breast or ovarian cancers).
NEGATIVE: interpretation depends on whether or not a deleterious mutation has been previously identified in the family.
If a deleterious mutation has been previously identified in the family, then this is the best result - a true negative - and your patient should follow population screening recommendations for breast cancer as they are still at risk for sporadic cancer.
If no deleterious mutation has been previously identified and your patient has cancer then the results are uninformative. This may mean:
There is a mutation in BRCA genes that is not detectable by the current technology.
The family history of cancer is caused by a yet to be discovered gene.
The family history of cancer is due to chance or common environmental factors.
The family has a rare genetic syndrome that has an associated increased risk for cancer.
VARIANT OF UNKNOWN SIGNIFICANCE:
It is not known if the changes identified in your patient’s DNA are harmful or benign.
A patient may carry a variation in their BRCA genes which may be a harmless polymorphism – a change in genetic code that will not alter the function of the BRCA proteins and therefore not cause an increased risk for cancer but;
The patient is still has an increased risk for cancer based on family history.
The family history of cancer may be caused by a yet to be discovered gene.
The family history of cancer may be due to chance or common environmental factors.
The variant may be a harmful mutation causing a predisposition to cancer. Studying other family members with cancer to see whether or not the variant is tracking with cancer in the family may provide clarification for this family.
Patient should still follow high risk management recommendations.
The clinical significance of these variants may be clarified with further research. Genetics referral is recommended in these circumstances.

45. 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
Slide 24:
Risk/Benefits/Limitations of Genetic Testing 1
Positive Result: Benefits
Explains the pattern of cancer in the family and provides clinical information.
Clinical intervention may improve outcome (specific guidelines will be listed later)
Family members at risk can be identified and offered testing
May benefit from more intensive screening or clinical intervention if mutation positive
Positive health behaviour can be reinforced
Decreases uncertainty – can move forward acceptance of the disease and consider options for management
Positive Result: Risks
Adverse psychological reaction
Anxiety, depression, grief, isolation, loss of control
Guilt or shame for passing it on to their children
Fear of disfigurement, of becoming a burden, of dying
Fatalistic attitude toward health
Family issues – some members may not want this information
Uncertainty - incomplete penetrance- some mutation carriers will never develop cancer
Unnecessary anxiety, interventions etc.
Possible discrimination: insurance, employment
Confidentiality issues
Surgical intervention (if taken) carries risk

46. 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
Slide 25:
Risk/Benefits/Limitations of Genetic Testing 2
Negative Result: Benefits
Avoidance of unnecessary clinical interventions i.e. no need to consider risk reducing surgery.
Emotional - relief
Importance of positive health behaviour can be reinforced
Children can be reassured
Theoretically may avoid higher insurance premiums
Negative Result: Risks
If a mutation was previously identified in the family and the patient’s result is negative this is the best possible outcome. However the patient may still have adverse psychological reactions (uncommon):
Survivor guilt, isolation
Family dynamics – the patient may not feel accepted by or that they “belong” to the disease group – may include other family members who are at high risk for cancer and are acting as support for the other high risk family members.
Patients may feel that their risk to develop cancer is zero and are reluctant to participate in general population screening. – become complacent

47. Goals of genetic testing
Understand cause of cancer in family
Surveillance and prevention of other cancers
Allow unaffected family members to test
Surveillance
Prevention options
Family planning

48. Possible risk of another, new cancer Risks to your children
Why?
Possible risk of another, new cancer
Risks to your children
Risks to other family members
Screening and prevention are often available and may save a life
We're trying to predict the future so we can maybe change the future

49. Gene Panels Cancer risks may not be very high
How high does risk need to be before we pursue surgery or medications?
Cancer risks may be unclear
How do we make medical decisions when we don’t know the risks?
We’re still learning
The recommendations you get today may be different in 5 years