Survivorship Issues Genetics 2016

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.

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

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.

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Most cancers are not inherited

5-10% hereditary 10-15% familial

75-85% sporadic

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Who is at high risk for cancer?

History is the key…

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.

Who should be retested

if prior testing was normal?

(In the era of “panel” testing)

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Breast Cancer

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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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Gene

BARD1, BRIP1,

MRE11A, MUTYH,

NBN, NF1

RAD50, RAD51C,

RAD51D

Contribution to


?

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.

Management Implications of Hereditary Cancers


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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

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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

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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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PALB2 Breast Cancer Risk

Antoniou NEJM 2014;371:497-506

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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.

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Colon Cancer

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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.

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Beggs AD et al. Gut 2010;59:975-986

Van Lier MGF et al. Am J Gastroent 2010;105:1258-1264

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.”

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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

Psychosocial and Family Implications

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?


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.


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.

Healthcare

Survivorship Issues Genetics 2016