1. Cancer Genetic Counseling
Deena Wahba
Genetic Counselor, MMSc
Annual Virginia Cancer Registrars Association Conference
October 21, 2016

2. Objectives Understand role of genetic counselors in patient care
Review the process of cancer development
Define sporadic versus hereditary cancer
Understand how having a hereditary cancer syndrome impacts an individual’s medical management

3. What is Genetic Counseling?
Process of helping people understand and adapt to
the medical, psychological and familial implications of
genetic contributions to disease.
                         
Integrates:
Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence.
Education about inheritance, testing, management, prevention, resources and research.
Counseling to promote informed choices and adaptation to the risk or condition.   
National Society of Genetic Counselors, 2005

4. Education and Training
Enter the field from a variety of backgrounds
Consecutive 2 year training program consisting of didactic coursework, clinical rotations, and research project (thesis/manuscript/capstone)
Graduate with MS in genetic counseling and human genetics
Board exam
: biology, genetics, animal science, psychology, public health, women’s studies.
31 U.S. programs; 3 Canadian programs
Accepting between students/year
Emory – class of 10, Predominantly female , Out class – 1 male

5. What do we do? Gather information
family/medical/pregnancy histories
Assess risk for genetic condition/genetic predisposition to disease
Provide information to patient, family, doctor
Psychosocial assessment & counseling
Facilitate decision-making
Provide ongoing support
Serve as patient advocates
Serve as educators and resource people for other health care professionals and for the general public
Engage in research activities related to the field of medical genetics and genetic counseling
Give presentations at professional meetings
Develop patient/family educational materials and resources
Write scientific articles for publication
Serve as the interface between clinicians and genetic laboratories
Promote health insurance and health policy practices which support individuals impacted by genetic conditions

6. What do we do?
Help person as they consider genetic testing, when they receive the test results, and in the weeks/months afterward.
What are the genetic testing options?
How accurate is the testing?
What will a positive, negative, or uncertain result mean for patient and family?
What medical management and support options are available?
Important I know what services are offered at the hospital
Patient navigator roles
Connecting with “look good feel good”
Support groups
Outreach, etc
By far, extremely important to be acutely aware of patient responses to content of our conversation – remember, it’s a 2-way communication which we both learn from – know 2 patients are the same or have the same needs – culture, personality, family dynamics… ensuring safety (mental/physical) is something I consider and also communicate with patient about
- EMR may not history of depression… anxiety… If I feel it is necessary I will discuss with patients

7. Many Career Paths Laboratory Clinical Public Health Research
Laboratory: Act as a liaison between labs, referring physicians, and patients
Genetic testing companies/ diagnostic laboratories – some of you may have ordered genetic testing and have seen variants – lab counselors are responsible for researching and reclassification of variants (alongside PhDs) – also communicate with institutions/individuals who have ordered testing if there is an issue (wrong test chosen, better candidate for testing, etc)
Research laboratories –huntington’s or dystonia
Public Health departments – Carrier screening or Newborn Screening initiatives
Universities/colleges
Private practice – Cali doing Psych genetics
Web-based testing/consulting firms
Professional associations -NSGC
Healthcare organizations
Government agencies
Public Health: Raise awareness of genetics, Improve access to services, Outreach services, Determine public policy
Research: Design, conduct, obtain funding for clinical genetics research projects

8. Back to the Basics

10. CHROMOSOMES

11. What is Cancer? Cancer is a disease of cells.
Cells are controlled by genetic instructions present in every cell of the body that control cell growth, reproduction and death.
If the instructions not correct, cell behavior and reproduction may become uncontrolled, which leads to cancer.

12. How a cell becomes cancerous
All cancers start from a single cell that undergoes many changes.
If the changes are permanent alterations to the DNA mutations.
The body has a host of defensive strategies to make sure damaged or mutated cells don’t reproduce.
Cancer development can take years (even decades) to make it past our natural defenses. If it does, and starts multiplying without control tumor.
Not all tumors are dangerous. Those that arise and then go quiet are benign. Malignant or cancerous tumors can spread into surrounding tissues, damaging nearby cells or organs.
OVER TIME GATHER MUTATIONS… EXPOSURES… LIFESTYLE… ENVIRONMENT… AGE
HEREDITARY… CELLS ALREADY AT DISADVANTAGE and DNA MORE SUSPECTIBLE TO MUTATIONS

13. Hallmarks of Cancer
Hanahan and Weinberg (2011)

14. In fact, only 5-10% of cancer is hereditary
All Cancer is Genetic
But, not all cancer is hereditary
So… what do I mean by that???
In fact, only 5-10% of cancer is hereditary

15. Cancer Risk in Men (US) Ever 1 in 2 To age 39 1 in 70 60-69 1 in 6
Top 5 Cancers in Men
Prostate 1 in 6
Lung 1 in 13
Colorectal 1 in 19
Urinary bladder 1 in 26
Melanoma 1 in 37 (white)
Lifetime rates exclude non-melanoma skin ca

16. Cancer Risk in Women (US)
Ever 1 in 3
To age 39 1 in 50
in 9
Top 5 Cancers in Women
Breast 1 in 8
Lung 1 in 16
Colorectal 1 in 20
Uterine 1 in 40
Thyroid 1 in 60

17. Breast Cancer Risk by Age
Risk that a woman will be diagnosed with breast cancer during the next 10 years:
Birth to 49……1.9% (or 1 in 53)
Birth to death……12.3% (1 in 8)
Age (years)
Incidence 30
1/277 40
1/68 50
1/42 60
1/28 70
1/26
Starting at following ages;
Siegel, R. et al. Cancer Statistics, CA Cancer J Clin 2014;64:9-29.

18. BRCA Associated Breast Cancer Risk
By age 40
By age 50
Lifetime
Slide 10: BRCA1-2 Mutations Increase the Risk of Early-Onset Breast Cancer and contralateral breast cancer
Without intervention, the majority of women with inherited mutations in BRCA1 and BRCA2 will develop breast and/or ovarian cancer. The range of risks of breast and ovarian cancer associated with mutations in these genes has been characterized through numerous studies. The lower estimates of risk are derived from analysis of mutations in an unselected general population of individuals, whereas higher estimates of mutation-associated cancer risk are believed to be more appropriate for individuals with a strong family history of cancer.
Generally, mutations in BRCA1 and BRCA2 are associated with a 56% to 87% risk of breast cancer by age 701,2. Most importantly, hereditary breast cancer occurs at a far earlier age than the nonhereditary (sporadic) form. Women in the general population have only a 2% chance of developing breast cancer before age 50. As shown in the middle panel, however, a woman with a mutation in BRCA1 or BRCA2 has a 33% to 50% likelihood of developing breast cancer before reaching 50 years of age2,3.
References:
1. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE, Breast Cancer Linkage Consortium: Risks of cancer in BRCA1-mutation carriers. Lancet 1994;343:
2. Struewing JP, Hartge P, Wacholder S, et al: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. New England Journal of Medicine 1997;336:
3. Easton DF, Ford D, Bishop DT, Breast Cancer Linkage Consortium: Breast and ovarian cancer incidence in BRCA1-mutation carriers. American Journal of Human Genetics 1995;56:
Core slide for a health care professional presentation
Core slide for a community presentation
Population Risk
0.5% 2%
12%
51-85% (BRCA1)*
33-54% (BRCA2)*
Hereditary Risk
10%-20%
33%-50%

19. Question:
What is the largest risk factor for development of cancer?
AGE
Of the firm opinion that Mr. Clooney continues becomes better looking with age ☺

20. What Causes Cancer? Genetics Environment
What are some examples of environmental exposures?
Why Age – Sporadic changes and mutations accumulate in our DNA over time → development of cancer
Machinery in charge of fixing our cells not as ____ as it once was
EXAMPLE: cancer cells FULL of mutations – they are out of control; growing and dividing without adhering to rules and regulations guiding these processes. Mind of their own. By definition, this is cancer
PRENATAL:
Example: women have a higher chance of giving birth to children with DS and chromosome problems… WHY??? Because women areborn with ALL of their eggs, and as eggs age, their machinery is less able to work correctly

21. Causes of Hereditary Breast Cancer
CHEK2, PALB2, ATM
TP53, STK11
REMEMBER: This is the 5-10% of breast cancer cases
The main genes are BRCA1 and BRCA 2 (50% of cases).. The are number in the order they found them in. There are rare genes that we know about and have management conditions for, but then there are other genes that we don’t know as much about. These may not have been discovered or they haven’t been researched enough to know management recommendations.
TEST BRCA genes it is not 100% because it could still be in these other genes category that we do not know much about right now.
WE WILL TALK ABOUT DIFFERENT TESTING OPTIONS LATER
Rarer known: tp53, PTEN
Other: NBN, RAD51

22. Sporadic: occurs by chance or related to environmental factors
Ovarian: 25% hereditary cause….
BRCA1/2 Increased risk for: Breast cancer (females & males), prostate & pancreatic cancers (50% of individuals with hereditary form of BC)
Lynch: Increased risk for: Colon cancer/polyps, uterine cancer, stomach cancer
-STK11 (Peutz-Jeghers syndrome), RAD51C, RAD51D

23. The Cancer Pedigree Minimum of 3 generations
Include information about affected AND unaffected relatives
Ask about possible environmental exposures
Ethnicity
AGE
Ages and Causes of deceased
Surgeries such as TAHBSOs
Ethnicities… triple negs more frequent, middle eastern melanoma more common
UV, alcohol, smoking (lung and pancreatic)

24. Hereditary Breast and Ovarian Cancer Syndrome (HBOC)
Genes: BRCA1 and BRCA2- Tumor Suppressors
Incidence of mutation:
BRCA1: 1/974
BRCA2: 1/734
Ashkenazi Jewish: 1/40

25. Referral Indications for HBOC
Individual Risk Factors
Bilateral, multifocal tumors, multiple primaries
Atypical age/gender/site
Breast cancer ≤45
Male Breast any age
Ovarian any age
Triple negative hormone status ≤60
Ashkenazi Jewish ancestry
Family Risk Factors
1st degree relative with any of the individual risk factors above
2-1st degree relatives with breast/pancreatic/prostate Cx
****Triple negative = 15-20% of BCX, 80-90% BRCA1
***CONSIDER LIMITED FAMILY HISTORY or MALE HEAVY FAMILIES
Family hx only – LIMITED – testing for affected most informative

26. Cancer Risks- HBOC

27. Hereditary Non-Polyposis Colon Cancer Risk Factors (AKA Lynch)
Accounts for ~5% of colorectal cancers
Risk Factors:
Colorectal or endometrial cancer less than age 50
Multiple Lynch associated cancers in same individual (ex. colon and endometrial cancer)
Three family members affected with Lynch associated cancers
MLH1, MSH2, MSH6, or PMS2 mutation identified in family
ABNORMAL IHC SCREEN – lack of proteins in tumor
*Colorectal, endometrial, stomach, ovary, small bowel, pancreas, and urinary tract
3-5% of ccx cases

28. Mismatch Repair Mechanism

29. Immunohistochemistry
Identify MMR proteins
Normally present
If protein is absent, gene is not being expressed (mutation or methylation)
Helps direct gene testing by predicting likely involved gene
If abnormal IHC (absent), MSI+
MLH1
MSH2
PMS2
MSH6 32

30. Immunohistochemical testing (IHC)
Sensitivity 83%
Specificity 88.8%
Pinpoints suspicious MMR gene
MLH1/PMS2 absence
MSH2 absence
MSH6 absence
PMS2 absence

31. 1. Normal – All 4 Stains Present
80% of the time you will get this result
CRC is probably not MSI+
Prognosis worse than if MSI+
Refer to Genetics ONLY if you suspect polyposis, patient dx <45, patient has had multiple CRC primaries, or the patient has an FDR with CRC at any age 34

32. 2. Abnormal – MLH1 AND PMS2 Absent
15% of the time
CRC is MSI+
Better prognosis
80% acquired methylation of MLH1
20% will be LS
Can order BRAF & methylation
MLH1
MSH2
MSH6
PMS2 35

33. 3. Abnormal – MSH2 AND MSH6 Absent
3% of the time
CRC is MSI+
Better prognosis
Most likely LS due to either MSH2 or MSH6 gene mutation
Always refer to Genetics
MLH1
MSH2
PMS2
MSH6 36

34. MSH2 AND MSH6 Absent Order MSH2 genetic testing (including EPCAM)
Consider MSH6 genetic testing if negative

35. 4. Abnormal – MSH6 OR PMS2 Absent
MLH1
MSH2
MSH6
PMS2
2% of the time
CRC is MSI+
Better prognosis
Most likely LS due to an MSH6 or PMS2 gene mutation
Always refer to Genetics 38

37. Lynch Syndrome- MLH1, MSH2, MSH6, and PMS2 Genes (Mismatch repair genes)
*Risk of second colon cancer is 20%-50% for individuals with Lynch syndrome

38. Let’s walk through a case:
Patient Mary
50 year-old recently dx with ovarian cancer
Treatment: TAH-BSO
Referred for Genetic Counseling

39. During the Appointment….
Contracting
Collect medical and family hx
Talk about cancer genetics
Review hereditary breast and ovarian cancer (HBOC)
Inheritance
Cancer Risks
NCCN Management Guidelines
Review testing options including risks and benefits
Discuss GINA, health insurance, and life insurance

40. I. Contracting Build rapport
What does the patient know about his/her referral to genetic counseling?
Review what will be discussed at the visit and make an agenda
Patient goals and questions
Psychosocial check in, where is she in her treatment? Family support?
**** prognosis poor – keep in mind

41. II. Collect a Family History
What I look for in family hx…. Young ages, rare, cancer, generation to generation, certain combinations of cancer
Ask crowd what they notice right away – limited maternal side, small family, young ages of dx of BC, rare OC
- Incorporate psychosocial – imagine how patient is feeling while collect this

42. IV. Inheritance BRCA2 BRCA1
Checking in with patient throughout… how much detail is too much? Education level, where they are at with treatment/anxiety/etc, personality
The BRCA genes are suppose to protect us from getting cancer. When we do genetic testing we are not looking for the gene. Everyone has 2 genes located on each chromosome. We received one chromosome from mom and one chromosome from dad for a total of 23 pairs of chromosomes. The first 22 pairs are the same in males and females and the last pair determines gender. If one of our copies of these genes has a change or a mutation the gene is not as protective from cancer, increase cancer susceptibility.
BRCA2
BRCA1

43. IV. Autosomal Dominant Inheritance

44. III. Sporadic Cancer vs Hereditary Cancer
Cancer Development
Sporadic Cancer
Hereditary Cancer
Two acquired mutations
One inherited and one acquired mutation
Why we see younger ages… hereditary cancer = 2 more hit because already have one non-working copy of BRCA

45. IV. HBOC Cancer Risks Cancer Type General Population BRCA1 Carrier
Breast
12%
47-66%
40-57%
Ovarian
1-2%
35-46%
13-23%
Male Breast
0.1%
5-10%
Prostate
15-18%
30%
39%
Pancreatic
0.50%
1-3%
2-7%
Always stress: does not mean you will get cancer!!! Increased lifetime risk
*Melanoma risk also increased

46. V. NCCN Management Guidelines
Monthly breast self-examinations, beginning at age 18
Annual breast MRIs from years of age
Yearly breast MRI alternating every 6 months with mammograms, beginning at age 30
Pelvic examination, trans-vaginal ultrasound with color doppler, and CA-125 blood test every 6 months, beginning at age 30
Recommended BSO by 35 or once child-bearing is complete (screening for ovarian cancer not yet able to identify the majority of early cancers)
*Mutation carriers have a 50% chance of developing BC by age 50, compared to gen. population 2%
* What makes us suspicious: young ages, multiple females generation to generation, combination of certain cancers (ovarian, breast), triple negative (er/pr/her2 = 18%), bilateral, rare (male breast)
* Limitations of family hx: male heavy, paternal contribution, small family size, limited info/adoption/no contact/etc *Homozygous mutations in BRCA2 → Fanconi anemia type D

47. V. NCCN Management Guidelines
Monthly BSEs beginning at age 35
Annual clinical breast examinations starting at age 35
Annual prostate cancer screening with digital rectal exam and PSA blood test beginning at age 45 for BRCA2 mutation carriers (consider for BRCA1 mutation carriers)
*Mutation carriers have a 50% chance of developing BC by age 50, compared to gen. population 2%
* What makes us suspicious: young ages, multiple females generation to generation, combination of certain cancers (ovarian, breast), triple negative (er/pr/her2 = 18%), bilateral, rare (male breast)
* Limitations of family hx: male heavy, paternal contribution, small family size, limited info/adoption/no contact/etc *Homozygous mutations in BRCA2 → Fanconi anemia type D

48. To test or not to test?

49. VI. Genetic Testing Options
Targeted Testing
Panel Testing
Outside scope of this presentation…

50. VI. Possible Test Results
Gene mutation found
POSITIVE
No gene mutation found
NEGATIVE
Gene change found, but potential link to cancer risk is unknown; occurs in:
~3-4% BRCA tests
~30% panel tests
VARIANT OF UNCERTAIN SIGNIFICANCE
The dreaded VUS
Ps… negative result does not mean no hereditary form of cancer in family…
ASK- why????

51. VI. Benefits of Genetic Testing
Management- personalized screening recommendations
Assist with decision making
Finally have explanation for diagnosis
More accurate picture of cancer risk
Could reduce anxiety
Help other family members
KNOWLEDGE IS POWER!
- Super clear…. RESULTS DO NOT TELL US PROGNOSIS OF CURRENT Cx OR how Aggressive cancer is…
- DO TELL US RISKS FOR SECONDARY CANCER AND HAVE IMPLICATIONS FOR FUTURE MANAGEMENT OF PATIENT AND AT RISK RELATIVES

52. VI. Risks of Genetic Testing
Emotional reactions
Not the answer the patient expected
Can increase anxiety
Survivor’s Guilt
Concern for children and family members
Fear of genetic discrimination

53. VI. Limitations of Genetic Testing
Positive results- Cannot predict when, where, or if cancer will occur
Negative result does NOT mean cancer is not hereditary
Patient’s family members may test positive
Mutation not detectable
Unknown gene that contributes to risk
Cancer risks and management for moderately penetrant or newly discovered genes not clear
Variants of uncertain significance may be found
Pseudogene or very repetitive sequences right next to each other… PMS2
Variants… not medically actionable… stressful… patient left with no answers (potentially)

54. VII. GINA, confidentiality, and insurance
GINA I: illegal for health insurance companies to discriminate against applicants or subscribers based on genetic info
GINA II: Genetic Information Nondiscrimination Act (2008)
Illegal to discriminate against, harass, demote employees or applicants because of genetic information
Confidentiality:
Unlawful to disclose genetic information about employees or applicants – genetic info must be kept in separate medical file
Long term disability and Life Insurance…
Although insurance companies can not discriminate, long term disability and life insurance companies can. ALWAYS talk to patient’s about this. Some companies will not even ask about genetic predisposition to disease, other’s will. To ensure patient’s can make an informed decision about whether or not to pursue testing at a given time, must respect autonomy.

55. After the Appointment
Document session and send to appropriate providers
Evaluate patient’s insurance coverage for testing, obtain authorization (can be done before or after)
Connect with HBOC support group and resources
Refer to specialists for follow-up care
Provide information to patient and sometimes aid them with drafting letters to family members
Follow-up calls/appointments to determine adjustment to results
Martha, elizabeth carter
Calling

56. Psychosocial Content Genetic counseling is a two way discussion
Validate the patient and his/her feelings and decisions
Non-directive decision making and support of patient autonomy
Guilt… Patients often worry more about their family members than themselves and feel that they are “giving” the mutation to their children
Individuals have a variety of reasons for not wanting to pursue testing
TRY TO TRULY CARE FOR OTHERS AS THOSE I LOVE
HEAR MY PATIENTS… what do they hope to gain????
JK –MUTYH carrier, MAP syndrome son
This patient… has daughter and son…
Patient has rough family hx… listen to her, don’t slash lines across a page in cases of death, be more subtle – saying I am sorry for your loss… noting that as patients approach age of dx of family member’s cancer can be scary
Don’t want: guilt, fear, hopelessness of inevitable – ensure that does not mean pt will get testing
Touched base with her 2 weeks later – described her outlook (day at a time), her son’s out look
Ovarian cancer patient – 31; she and her husband present – dx beginning of august
Why me?
Freezing eggs since no children of own - tahbso one week – supplied reproductive clinic info knowing not enough time
Offer martha services – WE ARE A TEAM
Touched base 2 wks later

57. Look good feel better – wigs, make-up (empowers women, makes them feel better, like a woman… human… not their disease)

58. Let’s work through some cases!!!

59. Case Example 1 39 year old recently diagnosed with ovarian cancer
Family history may be the key to identifying an inherited risk

60. Case Example 1 HBOC Lynch Li-Fraumeni
39 year old recently diagnosed with ovarian cancer
HBOC
Lynch
Li-Fraumeni

61. Case Example 2 71 year old dx with colon cancer
Significant family hx of colon cancer
What are some red flags?
Mention daughter and niece with breast at young ages too…
Mention hysterectomies….

62. Conundrum: Did the mutation come from mother or father?
Case Example 2
Conundrum: Did the mutation come from mother or father?
71 year old dx with colon cancer
Significant family hx of colon cancer
Lynch Syndrome: MSH6 mutation
MSH6 carrier – later onset of colon cancers
Surgery pending- Complete colectomy
+MSH6

64. Genetics and Your Family Tree
“To care for others as we would care for those we love”
Genetics and Your Family Tree
Comprehensive Care is an absolute – working with one another to promote individualized care, to truly understand AND RESPECT a patient’s needs and wishes, to want to enhance their health, or even ease their passing – TO DO THIS, we must work together

65. We are entering the Genomics Era

66. Questions?

67. References
"American Cancer Society | Information and Resources for ..." American Cancer Society. 1 Aug Web. 1 June <
Arvold ND, Taghian AG, Niemierko A, et al. Age, breast cancer subtype approximation, and local recurrence after breast- conserving therapy. J Clin Oncol. 29(29): , 2011.
Couch FJ, et. al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer Feb 1;33(4): doi: /JCO Epub Dec 1. PMID:
Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast cancer Study. JAMA. 295(21): , html#sthash.oVxOArt2.dpuf
"Hereditary Cancer." Hereditary Breast and Ovarian Cancer Information and Advocacy. 1 Aug Web. 23 Aug
"Learn About Molecular Subtypes of Breast Cancer at Susan G. Komen®." Molecular Subtypes of Breast Cancer. 1 Aug Web. 23 Aug
Metzger-Filho O, Sun Z, Viale G, et al. Patterns of recurrence and outcome according to breast cancer subtypes in lymph node-negative disease: results from international breast cancer study group trials VIII and IX. J Clin Oncol. 31(25): ,
"NCCN - Evidence-Based Cancer Guidelines, Oncology Drug ..." National Comprehensive Cancer Network. 1 Aug Web. 1 June (
Sharma et al. Spectrum of Mutations Identified in a 24-gene Hereditary Cancer Panel for Patients with Breast Cancer
Voduc KD, Cheang MC, Tyldesley S, Gelmon K, Nielsen TO, Kennecke H. Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol. 28(10): , 2010 .

68. Acknowledgements Riverside Health System’s Tumor Registry
Patient and families I’ve worked with
National Comprehensive Cancer Network
Greenwood Genetics Center
Fox Chase Cancer Center
Memorial Sloan Kettering Cancer Center
National Society of Genetic Counselors

69. THANK YOU!
Deena Wahba, MMSc
(P):