+Screening for Genetic Disease

Douglas Riegert-Johnson, MDAssistant Professor of Medicine and Medical GeneticsMayo Clinic Florida

Amelia Island

Mayo Clinic Review Course

Douglas Riegert- Johnson, MDRiegertjohnson.douglas@mayo.eduMayo Clinic Florida - JacksonvilleAssistant Professor of Medicine and Medical Genetics

+Conflicts of Interest and off Label Drug Use

None.

+Objectives

What questions do I need to ask as a primary care provider to screen for genetic disease?

How do I refer a patient for a genetic evaluation?

What genetic tests can I order as a non geneticist?

+What questions do I need to ask to screen for genetic disease? Does anyone in your family

have cancer? Breast, ovarian, or colon cancer?

At what age were the cancers diagnosed?

Breast cancer 80

Breast cancer 65

+What questions do I need to ask to screen for genetic disease? Does anyone in your family

have cancer? Breast, ovarian, or colon cancer?

At what age were the cancers diagnosed?

Compliance with cancer family history in oncology practices

77% of medical records reviewed documented presence or absence of CFH in first-degree relatives. Of patients with increased risk for hereditary cancer, 52% of patients with Breast CA and 26% of those with Colorectal CA were referred for GC/GT.Quality of Cancer Family History and Referral for Genetic Counseling and Testing Among Oncology Practices: A Pilot Test of Quality Measures As Part of the American Society of Clinical Oncology Quality Oncology Practice Initiative J Clinical Oncology 2014

Breast cancer 80 41

Breast cancer 65 50

+ Age of diagnosis and presence of an affected family member changes the odds of a hereditary cancer syndrome diagnosisMyraid Genetics BRCA mutation prevalence tablesPersonal history

No family history of breast or ovarian cancer

Family history of first degree relative with breast cancer dx < 50 yo

Breast CA > 50yo

2.2% 8.0%

Breast CA < 50 yo

4.7% 21.2%

Male breast CA 6.9% 36.6%

Ovarian CA 7.7% 27.4%* Not applicable to Ashkenzai Jewish populations.

+ Age of diagnosis and presence of an affected family member changes the odds of a hereditary cancer syndrome diagnosisMyraid Genetics BRCA mutation prevalence tablesPersonal history

No family history of breast or ovarian cancer

Family history of first degree relative with breast cancer dx < 50 yo

Breast CA > 50yo

2.2% 8.0%

Breast CA < 50 yo

4.7% 21.2%

Male breast CA 6.9% 36.6%

Ovarian CA 7.7% 27.4%* Not applicable to Ashkenazi Jewish populations.

+ Treatment is different for BRCA1/2 patients:Bilateral mastectomy prolongs survival in patients with BRCA1/2 mutations.

Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations. BMJ 2013.

390 women with stage 1 or stage 2

breast cancer. All

with a mutation in the BRCA ½

genes.

181 bilateral mastectomy 88% survival

209 unilateral

mastectomy66% survival

* Survival at 20 years. Reduction in risk hazard ratio 0.52, 95% confidence interval 0.29 to 0.93; P=0.03.

+

Hereditary cancer syndrome patients are not rare!Location by Zip Code

139 patients (out of 280)MCF 6.2014

+ Selected criteria for referral of the Breast Cancer patient for genetic evaluationRefer if patient has any of the following

Early-age-onset breast cancer (less the 50 yo)

Breast cancer at any age if, Triple negative (ER-, PR-, HER2-) breast cancer Two breast primaries at any age Personal history of breast cancer and family history of close

blood relative with breast cancer dx <50yo

Ovarian/fallopian tube/primary peritoneal cancer

Male breast cancer

NCCN 1.2014

+ Selected criteria for referral of the Breast Cancer patient for genetic evaluation In unaffected patient if, family history of

2 breast primaries in single individual close relative 2 individuals with breast primaries on the same side of

family (maternal or paternal) 1 ovarian and breast primary from the same side of family

(maternal or paternal) First- or second-degree relative with breast cancer 45 y 1 family member on same side of family with a 1 of the following

(especially if early onset): pancreatic cancer, aggressive prostate cancer (Gleason score 7) sarcoma, adrenocortical carcinoma, brain tumors, endometrial cancer, leukemia/lymphoma; features of Cowden syndrome.

From a population at increased risk (Ashkenazi Jewish)

NCCN 1.2014

+Simplified criteria for referring Colon Cancer patients for genetic evaluation.(Lynch syndrome)

NCCN 2.2014

All patients with colon cancer or endometrial cancer under the age of 50.

All patients with metachronous or synchronous colon cancer.

Any patient with colon cancer who has a family member with colon or endometrial cancer.*

Any patient with a specific colon cancer pathology tumor-infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern

Any patient with >10 cumulative colon adenomas* Revised Bethesda criteria in supplemental slides.

+ Lynch Syndrome: Frequent colonoscopy is protective for a colon cancer diagnosis (but does not prevent all cases)

Järvinen HJ, Gastroenterology 2000.

90 Lynch syndrome patients

44 Colonoscopy (every 3 years)

46 No colonoscopy

15 years

Outcome Colonoscopy No colonoscopy

Colon cancer dx 8 (18%) 19 (41%)

Colon cancer deaths 0 4

Total deaths 4 (9%) 12(26%)

+ Lynch syndrome polyps are often flat and difficult to detect. Indigo carmine chromoendoscopy 45 year old female Lynch syndrome patient (MLH1): Ascending colon

polyp before injection with saline.

+ Overlooked polyps. Indigo carmine chromoendoscopy 45 year old female Lynch syndrome patient (MLH1): Ascending

colon polyp after injection with saline.

+2014 NCCN recommends all patients with colon cancer be screened for Lynch syndrome by tumor testing.

Protocol screen testing on tumors

Immunohistochemistry (4 Lynch syndrome genes)

Genetic testing on blood (germline)

Colon cancer patients

NEWSFLASH

MCF

154

22

4

1014 LS ptsIdentify family

members

+

How do I refer a patient for genetic evaluation?

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+ www.nsgc.org

+

Genetic Counseling as a medical speciality

Under Graduate 4 years + Post Graduate 2 years

Specialty n

Internists 189,587

Family medicine specialists 114,000

GI 12,398

Genetic counselors 2,573

Medical geneticists 1,509 (all time)

+ NEXT GENeration Sequencing

Name for numerous technologies used for high through put relatively low cost DNA sequencing Illumina – HiSeq Ion torrent

Conceivable to sequence 1 DNA base, but usually used for panels of genes

Ion torrent

+

BRCA1

BRCA2

ATM

BARD1MSH2MSH6 MLH1

Some of the genes included on Next Generation panels for breast cancer

PALB2

NF1

CHEK2

CDH1TP53

RAD50

PMS2

+ Case presentation: Family with breast cancer, but no BRCA1/2 mutation

30

62 40

NEWSFLASHNEXT GENERATION SEQUENCING RESULTS:

PALB2 MUTATION

22 2

Changes to medical care:Consider prophylactic mastectomy of femalesPancreas cancer screening

22

+

What genetic tests I can perform as a non geneticist?

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+Genetic tests commonly ordered. Would not recommend ordering any Next Gen

testing: Billing and interpretation too complex.

Hemochromatosis HFE gene test Indication: Elevated ferritin

Factor V Leiden in PTE 16% One copy: Recurrence risk VTE OR 1.56 ?1-2% Two copies: Recurrence risk VTE OR 2.56 At this time no convincing evidence testing changes

should change duration of therapy. No randomized controlled trials have shown any

benefit to testing.

Testing for Inherited Thrombophilia.Thrombosis and Hemostasis 2014.

+ The new standard for genetic testing: Randomized double blind controlled trials.

Discovery Medicine 2013.

51 patients with depression

26 Treatment guided bypharmacogenetics

25 Treatment as usual

+Summary Cancer Family History should include cancer diagnosis

and age of diagnosis.

Which patients should be referred for genetic counseling? All breast, colon and endometrial cancer patients diagnosed

under the age of 50. All ovarian and male breast cancer patients regardless of

age. Newsflash: Screening of all colon cancers for Lynch

syndrome is recommended and being implemented.

How to refer: Directory of genetic counselors at www.nsgc.org.

Genetic testing is maturing. The efficacy of genetic tests are being evaluated by DB RCTs. DRJ: I predict with further development of Next Generation sequencing DB RCTs will show utility in genetic testing in common diseases.

+ The End

+

Supplemental slides

Douglas Riegert-Johnson, MD

+Revised Bethesda Criteria

1.Colorectal cancer diagnosed under the age of 50 years of age.

2. Presence of synchronous, metachron ous colorectal, or other HNPCC- associated tumors * , regardless of age.

3. Colorectal cancer with the MSI-H † histology € diagnosed in a patient who is less than 60 years of age.

4. Colorectal cancer diagnosed with one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed under age 50 years.

5. Colorectal cancer diagnosed in two or more first or second degree relatives with HNPCC-related tumor, regardless of age.

Used to identify colorectal cancers for Lynch syndrome tumor testing.

+Revised Bethesda Critieria

* Hereditary Nonpolyposis Colorectal Cancer (HNPCC)-related tumors include colorectal, endometrial, stomach, ovarian, pancreas, bladder, ureter and renal pelvis, biliary tract, brain (usually glioblastoma as seen in Turcot Syndrome), sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome, and carcinoma of the small bowel.

† MSI-H = high microsatellite in stability in tumors refers to

changes in two or more of the five NCI-recommended panels of microsatellite markers. MSI-L = low microsatellite instability in tumors refers to changes in only one of the five NCI-recommended panels of microsatellite markers.

€ Presence of tumor infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet ring differentiation, or medullary growth pattern. There was no consensus on whether to include the age criteria

in point (3) above; participants voted to keep age 60 years in the guidelines.

Continued

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