survivorship issues genetics 2016
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Genetics Implications for Survivorship Programs
The Ohio State University Clinical Cancer Genetics Program Comprehensive Cancer Center
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.
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.
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
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.
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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%
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Causes of Hereditary Breast Cancer
Gene
BARD1, BRIP1,
MRE11A, MUTYH,
NBN, NF1
RAD50, RAD51C,
RAD51D
Contribution to
Hereditary Breast Cancer
?
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)
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.
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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%)
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
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.
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
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)
Cancer Risks Cowden 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?
Benign Features Cowden 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%)
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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
Causes of Hereditary Breast Cancer
Gene
BARD1, BRIP1,
MRE11A, MUTYH,
NBN, NF1
RAD50, RAD51C,
RAD51D
Breast Cancer risk
And management?
?
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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)
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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.
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%)
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Lynch Syndrome: Cancer risks
Aarnio Int J Cancer 64:430, 1995
% with
cancer
100
80
60
40
20
0
20 40 60 80 0
Age (years)
Colorectal 78%
Endometrial 43%
Stomach 19%
Biliary tract 18%
Urinary tract 10%
Ovarian 9%
ASCO
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.
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.
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.
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.
NCCN Colon Cancer Guidelines 2.2014: PJS
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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.”
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
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
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
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
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
Genetic counseling can help individuals and families deal with all of these
issues.
Refer patients back for an additional visit if unresolved issues exist.
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.
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