By Rob Pilarski, MS, MSW

1. Genetics Implications for
Survivorship Programs
The Ohio State University
Clinical Cancer Genetics Program
Comprehensive Cancer Center

2. Learning Objectives
The presentation will enable the participant to:
 Recognize patients appropriate for genetic testing.
 Understand the value of panel testing for patients who
previously had normal testing.
 Identify the management implications for hereditary
cancers.
 Understand the psychosocial issues for patients with
hereditary cancer.

3. Who is appropriate for testing
(and might have been missed!)

4. Genetic Testing
 Ideally, everyone who is appropriate for genetic
testing would have been identified and tested as
some point during their journey through
diagnosis and treatment.
 However some people are missed by their
treatment team.
 Some people may have been overwhelmed at
the time of diagnosis and declined testing for the
time being.
 Survivorship programs can help identify these
missed patients and refer them for testing.

5. 5
Most cancers are not inherited
5-10% hereditary10-15% familial
75-85% sporadic

6. 6
Who is at high risk for cancer?
History is the key…

7. CLUES:
 Cancer in 2 or more close relatives
(on same side of family)
 Early age at diagnosis
 Bilateral/multiple cancers
 Multiple rare cancers
 Multiple primary tumors (breast and ovary;
colon and uterus)
 Evidence of autosomal dominant transmission

8. Family History Issues
 Many patients do not know the details of their
family history (site of primary tumor and age of
diagnosis).
 Some reported diagnoses may need to be
confirmed through medical records.
 Family histories changes over time but providers
often fail to update it regularly.

9. Who should be retested
if prior testing was normal?
(In the era of “panel” testing)

10. 10
Breast Cancer

11. 11
Causes of Hereditary Breast Cancer
Gene
BRCA1
BRCA2
TP53
PTEN
Other genes
Contribution to
Hereditary Breast Cancer
20%–40%
10%–30%
<1%
<1%
30%–70%

12. 12
Causes of Hereditary Breast Cancer
Gene
BARD1, BRIP1,
MRE11A, MUTYH,
NBN, NF1
RAD50, RAD51C,
RAD51D
Contribution to
Hereditary Breast Cancer
?

13.  ATM Breast, Pancreatic CHEK1 RAD51
 ATR Oropharyngeal CHEK2 Breast RAD51B
 BABAM1 FAM175A Breast RAD51C Ovarian, Breast
 BAP1 Uveal melanoma, breast MLH1 Colon, Endometrial RAD51D Ovarian, Breast
 BARD1 Breast, Ovarian MRE11A Breast RBBP8
 NBN Breast STK11 Breast UIMC1 Breast
 BRCC3 TP53BP1 XRCC2 Breast
 BRIP1 Breast, Ovarian TP53 Breast, Ovary XRCC3
 CDH1 Breast, Gastric PALB2 Breast, Pancreatic
 CDK4 Melanoma PTEN Breast
 CDKN2A Pancreatic, Melanoma RAD50 Breast
Panel Testing (6 - >45 breast ca genes at once)

15. Patients with significant personal
and/or family histories of cancer who
previously had normal genetic testing
for only one or a few genes may be
appropriate candidates for re-testing for
a broader panel of genes.

16. Management Implications of
Hereditary Cancers

17. Hereditary Breast Cancer

18. 18
BRCA-Associated Cancers:
Risk by age 70
Increased risk of prostate,
laryngeal, melanoma and
pancreatic cancers
breast cancer
(50-85%)
ovarian cancer
(10-45%)
male breast cancer
(1-6%)

19. BRCA Management
 Screening:
 Monthly BSE beginning at age 18
 CBE every 6 - 12 months starting at age 25*
 Annual breast MRI starting at age 25*
 Annual mammographystarting at age 25*
 Chemoprevention:
 Tamoxifen
 Oral contraceptives
 Prophylactic surgery:
 Oophorectomy strongly recommended (35-45 yo)
 Mastectomy is an option but not pushed.
*or 5-10y before the earliest age at which breast cancer
was diagnosed in the family

20. Li-Fraumeni syndrome – TP53 gene
 Rare hereditary cancer syndrome causing high
lifetime risk for cancer.
 Early onset breast cancer, bone/soft tissue
sarcomas, brain tumors, leukemia, adrenocortical
tumors and others.
 Multiple cancers often seen in same individual.
 Caused by mutations in the TP53 gene, and perhaps
others.

21. Villani Screening Protocol (Lancet Oncology 2011:12:559-567)
ADULTS:
 Breast cancer:
 BSE monthly starting 18 yo
 CBE q 6 mos starting at 20-25 yo
 MRI and mammo annually starting 20-25 yo
 Consider prophylactic mastecomy
 Brain tumors – annual brain MRI
 Sarcoma – annual total body MRI; abd U/S q 6 mos
 Leukemia/lymphoma – blood work q 4 mos (CBC, sed
rate, lactate dehydrogenase)
 Colon cancer: Colonoscopy q 2 yrs starting 40 yo
 Melanoma– annual dermatology exam
21

22. 22
 AD multiple hamartoma/cancer syndrome
 Prevalence of ~1/200,000-1/250,000
 “80% of patients have PTEN mutations” =
 ~30% have PTEN mutation
 KILLIN mutations? – No clinical testing available
 SDH mutations? – Not likely to be associated.
 Diagnostic criteria are based on presence of major
and minor criteria.
COWDEN SYNDROME (CS)

23. Cancer RisksCowden Syndrome
Thyroid Cancer (5-10%)
-follicular or papillary
Breast Cancer (25-50%)
Uterine Cancer (5-10%)
Also observed:
-Colon Cancer
-Lhermitte-Duclos disease (Cerebellar
dysplastic gangliocytoma)
-Renal Cell Carcinoma (Kidney)
-Melanoma?

24. Benign FeaturesCowden Syndrome
Large head size (>80%)
Skin lesions (up to 99%)
- trichilemommas (hair follicle)
- papillomatous papules(mouth/face)
- lipomas, vascular malformations
Thyroid disease (50-65%)
-thyroid adenoma, goiter
Hands and feet
- wart-like papules,
- acral keratoses
Intestinal polyps (mixed path; >80%)

25. 25
Women:
 Clinical breast exam q. 6-12 months starting age 25
 Annual mammogram and breast MRI from age 30-35
 Consider annual endometrial biopsy +/- ultrasound
 Discuss option of prophylactic mastectomy, hysterectomy
Men and Women:
 Annual thyroid ultrasound from age 18
 Colonoscopy every 5 years from age 35
 Consider renal U/S every 1-2 years from age 40
NCCN PHTS Management

26. 26
Causes of Hereditary Breast Cancer
Gene
BARD1, BRIP1,
MRE11A, MUTYH,
NBN, NF1
RAD50, RAD51C,
RAD51D
Breast Cancer risk
And management?
?

27. 27
 7500 BRCA-negative cases in Poland: 3% had one of four
truncating founder mutations vs. 0.8% of 4300 controls.
 Odds ratios were higher with stronger family history
 Estimated lifetime breast cancer risks for carriers (vs 6%):
 20% with no affected relatives (OR 3.3)
 28% with one second degree relative (OR 4.7)
 34% with one first degree relative (OR 5.7 vs. ~1.8 fam hx alone)
 44% with a first and second degree relative (OR 7.3)
 Accounts for 3% of all breast cancer cases.
 “Women with mutation and a positive family history are
candidates for breast MRI and Tamoxifen” (like BRCA).
CHEK2 and Breast Cancer
(Cybulski, J Clin Oncol 2011;29:3747-52)

28. 28
PALB2 Breast Cancer Risk
Antoniou NEJM 2014;371:497-506

29. 29
For some genes it appears that no single
estimate of cancer risk applies to all
mutation carriers, and management may
need to individualized base on family history.

30. 30
Colon Cancer

31. 31
Causes of Colon Cancer
Adapted from Burt RW Prevention and Early Detection of CRC, 1996
Familial
(10%–30%)
Sporadic
(65%–85%)
Lynch Syndrome
(Hereditary
nonpolyposis colorectal
cancer; HNPCC) (5%)
Familial adenomatous
polyposis (FAP) (1%)
Rare CRC
syndromes
(<0.1%)

32. 32
Lynch Syndrome: Cancer risks
Aarnio Int J Cancer 64:430, 1995
% with
cancer
100
80
60
40
20
0
20 40 60 800
Age (years)
Colorectal 78%
Endometrial 43%
Stomach 19%
Biliary tract 18%
Urinary tract 10%
Ovarian 9%
ASCO

33. Lynch Syndrome: Management
 Colon
 Colonoscopy q 1-2 years starting at age 20-25*
 Age 30 yrs for MSH6 or PMS2 carriers
 Total abdominal colectomy for colon cancer
 Uterus and Ovary cancer surveillance (annual)
 Uterine (endometrial) biopsy:
 Transvaginal ultrasound and;
 CA-125 blood test, all beginning at age 30
 Gastric and small intestine cancer screening
 Consider upper endoscopy starting at age 30-35, repeating
every 2-3 years depending on findings
 Urinary tract cancer surveillance
 Consider urinalysis with cytology annually at age 25 – 30 y.
Lindor, et al JAMA 296 (12), 1507-1517, 2006
* Or 2-5 years prior to youngest age at which colon cancer was diagnosed in the family.

34. Lynch Syndrome: Management
 Uterus and Ovary cancer surveillance (annual)
 Uterine (endometrial) biopsy:
 Transvaginal ultrasound and;
 CA-125 blood test, all beginning at age 30
 Gastric and small intestine cancer screening
 Consider upper endoscopy starting at age 30-35, repeating
every 2-3 years depending on findings
 Urinary tract cancer surveillance
 Consider urinalysis with cytology annually at age 25 – 30 y.
Lindor, et al JAMA 296 (12), 1507-1517, 2006
* Or 2-5 years prior to youngest age at which colon cancer was diagnosed
in the family.

35. Familial Polyposis
 Caused by mutations in the APC gene
 Affects ~1/5000 people
 Causes 100s to 1000s of colon polyps
 Risk of colon cancer is nearly 100%
 Risks for hepatoblastoma, duodenal, thyroid cancers also
increased.

36. Familial Polyposis: Management
 Colon
 Colonoscopy q 1-2 years starting at age 10-12*
 Colectomy or proctocolectomy for colon cancer or
when polyp number is too great to manage.
 Continued surveillance for rectal or pouch cancer
 Other sites:
 Upper GI: Upper endoscopy starting at 20-25 yo.
 Thyroid: annual exam and consider annual U/S
 Hepatoblastoma: No recommendations have been made;
however, the following have been considered: Liver
palpation, abdominal ultrasound, and measurement of
AFP, every 3–6 mo, during the first 5 y of life.

37. 37
Beggs AD et al. Gut 2010;59:975-986
Van Lier MGF et al. Am J Gastroent 2010;105:1258-1264

38. NCCN Colon Cancer Guidelines 2.2014: PJS

38
Site Lifetime
Risk
Screening Initiation
Breast 45-50% Mammogram and Breast MRI annually
Clinical breast exam q 6 mos
~25 yo
Colon 39% Colonoscopy every2-3 y ~late teens
Stomach 29% Upper endoscopy every 2-3 y ~late teens
Small Intestine 13% CT or MRI baseline at 8-10 yo with f/up based on findings,
but at least by age 18, then q 2-3 y
~8-10 yo
Pancreas 11-36% MR cholangiopancreatography or endoscopic U/S q 1-2 y ~30-35 yo
Ovary
Cervix
Uterus
18-21%
10%
9%
Pelvic exam and Pap smear annually.
Consider transvaginal ultrasound.
~18-20 yo
Testes ? Annual testicular exam and observe for feminizing changes ~10 yo
Lung 15-17% Educate about symptoms and smoking cessation.
“The surveillance guidelines… are provisional, but may be considered in view of
the cancer risks in PJS and the known utility of the tests. There are limited data
regarding efficacy of various screening modalities in PJS.”

39. 39

40. CDH1 (e-cadherin) NCCN Management
 Gastric cancer:
 Upper endoscopy w/ multiple bxs q 6-12 mos
 Prophylactic gastrectomy between 18-40 yo
 Breast cancer –
 40% risk for lobular breast cancer (average dx 53 yo)
 Follow BRCA screening guidelines:
 Clinical exam q 6-12 months from age 25
 Annual breast MRI >25 yo and mammograms >30 yo.
 Consideration of prophylactic mastectomy

41. Psychosocial and Family
Implications

42.  Patients may feel overwhelmed and want additional
information, advice or referrals to help them navigate
the medical system for their cancer screening need.
 Patients may need guidance in making difficult
decisions regarding prophylactic surgeries.
 Patients may need updated information on correct
screening and management practices months or
years after their genetic diagnosis.
Patient Needs

43.  Patients may feel guilt for (possibly) having passed
on the risk to their children
 For some people this is so great that they refuse to do
genetic testing.
 For others they may decide not to tell relatives that
they are at risk!
 Some may hesitate to tell their children or other
relatives about their risk in an attempt to “protect
them” from the information.
Testing Implications

44.  More often, people who test positive do want to
share the information but may need guidance on
how to tell family members about their risk.
 Who is appropriate to tell?
 How to bring it up?
 When is the best time?
 What is the best way?
Testing Implications

45.  In some families conflict can arise through
disagreement over whether testing should be done.
 Some may feel anger or resentment against
relatives who refuse to test.
 Issues arise over what to tell the at-risk children of
relatives who refuse to test or share the information.
 Some relatives without the gene may have “survivor
guilt” or face resentment from those with the gene.
Testing Implications

46. Genetic counseling can help individuals
and families deal with all of these
issues.
Refer patients back for an additional
visit if unresolved issues exist.

47. Summary
Genetic issues relevant to Survivorship programs include:
 Identifying patients appropriate for genetic testing who
were “missed” early in their journey.
 Identifying patients who previously had normal testing
who may be appropriate for panel re-testing.
 Helping patients understand and navigate the
management implications of their hereditary risk.
 Recognizing and understanding the psychosocial issues
for patients with hereditary cancer.