© coc 2011—content cannot be reproduced or repurposed without written permission of the coc....

© CoC 2011—Content cannot be reproduced or repurposed without written permission of the CoC.

EGAPP Recommendations for Lynch Syndrome Genetic Testing: Impact on Colorectal Cancer Care

Heather Hampel, MS, CGCProfessor, Division of Human Genetics

The Ohio State UniversityDepartment of Internal Medicine

Columbus, OH


Outline

• Why determine which cases of CRC have defective mismatch repair?

• Screening for Lynch syndrome among newly diagnosed CRC patients

• EGAPP recommendations

• OSU clinical experience doing IHC on all newly diagnosed CRC patients


13%<1% 85%

FAP Sporadic

MIN (MSI+)(Microsatellite Instability)

CIN (Chromosome Instability)

Lynch Syn Sporadic MSI(+)

Germline Mutation MMR genes

MLH1, MSH2, MSH6 & PMS2

15%

2-3%

•Epigenetic silencing of MLH1 by hypermethylation of its promoter region

85%

Colorectal Cancer

Acquired APC, p53, DCC, kras, LOH,...

Germline Mutation APC


Why Determine which CRC Cases are MSI+ and which have LS?

• All MSI+ CRC patients have a better prognosis

• MSI+ CRC patients MAY need different treatment in future

• LS patients at high risk for second primary cancers (CRC and others)

• LS patients have at-risk relatives who could benefit from genetic testing


Prognostic Implications

• Pooled data analysis of 32 studies with 7,642 cases found:– HR for Overall Survival with MSI = 0.65– Restricting analysis to clinical trial patients

(HR=0.69) did not alter benefit– Restricting to those with locally advanced

disease (HR=0.67) did not alter benefit

Popat S, et al. JCO. 2005;23:609-618.


Treatment Implications

• MSI-H stage II and III patients did not have a significant difference in RFS whether or not they received 5-FU (HR, 0.96; 95% CI, 0.62 to 1.49; P=.86)

• MSI-H patients did not have a significant difference in OS whether or not they were treated with 5-FU (HR, 0.70; 95% CI, 0.44 to 1.09; P=.12)

• MSS patients do benefit from 5-FU (HR, 0.77; 95% CI 0.68 to 0.87; P<.001)

Des Guetz G, et al. Euro J Cancer 45:1890-6,2009.


Patient & Family Implications: Lynch Syndrome

MLH1

MSH2

MSH6

PMS2


Carrier Parent Non-carrier Parent

Autosomal Dominant Inheritance

Aa aa

Aa Aa aa aa

Carrier Carrier Non-carrier Non-carrier

1/2 1/2


Lynch Syndrome: Lifetime Risks for Cancer

Cancer Lynch syndrome

General Public

Colon cancer 56% 22%

Endometrial cancer 35% 26%

Gastric cancer 13% 1%

Ovarian cancer 12% 1.5%

Small bowel, bladder, ureter, renal pelvis, brain

<4% each <1% each


Lynch Syndrome Surveillance Options

Lindor N et al. JAMA 2006;296:1507-17. & Vasen HFA et al. J Med Genet 2007;44:353-62.

Intervention Recommendation

Colonoscopy Every 1-2 y beginning at age 20 (MLH1), 25 (MSH2), or 30 (MSH6 & PMS2)

Endometrial sampling

Every 1 y beginning at age 30-35

Transvaginal U/S Every 1 y beginning at age 30-35

Urinalysis with cytology

Every 1-2 y beginning at age 25-35

History & Exam w/ review of systems

Every 1 y beginning at age 21


15-year prophylactic colonoscopic screening

Järvinen et al. 1995 and 2000

Screened Not screened

n=133 n=119

Colorectal cancer 8 19 n=0.014

Death from colorectal cancer 0 9 p<0.001

Overall deaths 10 26 p<0.001


Lynch Syndrome Prophylactic Surgery Options

• Options include subtotal colectomy, hysterectomy, and oophorectomy

• Subtotal colectomy does not eliminate cancer risk

• Hysterectomy eliminates risk of endometrial and ovarian cancer

• Expert panels made no recommendation for or against surgery due to unproven efficacy

Schmeler et al. NEJM 2006;354:261-9.


Lynch Syndrome Implications for Patient

• 16-30% chance of second primary CRC in the 10 years after their first diagnosis

• NCCN guidelines differ for CRC patients with LS and without LS– With LS, colonoscopy every 1-2 years for life– Without LS, colonoscopy 1 yr after dx, repeat

in 2-3 yrs, then every 3-5 years based on findings

• Management also changes due to the risk for other cancers


Lynch Syndrome Implications for Family

• 6 relatives tested on average per proband identified with LS

• 50% with LS need increased cancer surveillance– High Compliance (96% CRC & 97% Gyn)– Cancer risk ratio of relatives with LS compared

to relatives without LS is 5.8– No significant difference in cancer mortality

(RR, 2.28) or overall death rates (RR, 1.26)• 50% without LS follow the ACS guidelines

Jarvinen HJ et al. J Clin Oncol 2009;27:4793-7.


Tumor Tests to Screen for Lynch Syndrome• Microsatellite Instability (MSI) testing

– Performed on DNA extracted from tumor and normal tissue – requires laboratory

– Test is positive in 15% of CRC cases– Test is positive in 77-89% of LS cases

• Immunohistochemistry staining– Performed on thin slide of tumor – can be done in

pathology department– 1-2 proteins are absent in 20% of CRC cases– 1-2 proteins are absent in 83% of LS cases


MSI testing on Genotyper


Five Possible IHC Results: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 first degree relative (FDR) with CRC at any age


2. Abnormal – MLH1 & PMS2 Absent

• 15% of the time

• CRC is MSI+

• Better prognosis

• 80% acquired methylation of MLH1

• 20% will be LS

MLH1 MSH2

MSH6PMS2


2. Abnormal – MLH1 & PMS2 Absent

• Either refer all cases to Genetics OR

• Refer those diagnosed under age 60, those with multiple primary LS cancers, and those with an first or second degree relative (SDR) with a LS cancer at any ageOR

• Reflex to BRAF or MLH1 methylation testing & refer those without BRAF mutation or without methylation


BRAF and CRC

• V600E (1799T>A) mutation strongly associated with MSI+ and CpG island methylator phenotype (CIMP)

• Not yet reported in a patient with a germline MLH1 gene mutation

• MLH1 promoter methylation– MLH1 absent on IHC, no MMR gene

mutation; 68% with V600E in BRAF


3. Abnormal – MSH2 & 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

PMS2MSH6


4. Abnormal – MSH6 Absent


to an MSH6 gene mutation


MLH-1MSH-2

MSH-6 PMS-2


5. Abnormal – PMS2 Absent


to an PMS2 gene mutation


MLH1 MSH2

MSH6 PMS2


The Family History Is Key to Diagnosing LS – or is it?

CRCdx 50s

CRCdx 45

CRCdx 61

CRCdx 75

OvarianCa, dx

64

CRCdx 48

CRCdx 52

EndometrialCa, dx 59

CRCdx 42

45


Amsterdam II criteria

• 3 or more relatives with verified Lynch-associated cancer in family

• Two or more generations• One case a first-degree relative of the

other two• One CRC dx <50• FAP excluded

Vasen HFA et al. Gastroenterology. 116:1453, 1999

Does not include ovarian, gastric, brain,

biliary tract or pancreatic cancer


Bethesda Guidelines

• Individual with CRC dx <50

• Individual with synchronous or metachronous CRC, or other Lynch-associated tumors regardless of age

• Individual with CRC with MSI-H histology dx <60

• Individual with CRC with >1 FDR with an Lynch-associated tumor, with one cancer dx <50

• Individual with CRC with >2 FDRs or SDRs with an Lynch-associated tumor, regardless of age

Umar A, et al. JNCI. 2004;96(4):261-268.


Warning: Family Histories can be Deceiving

• Family size is getting smaller

• Wider use of colonoscopy likely to prevent many colon cancers

• MSH6 & PMS2 may have lower cancer risks


• Can predict who is more likely to have LS using family history criteria (Amsterdam & Bethesda)

• Can predict the likelihood of a MMR gene mutation using three new programs– PREMM1,2,6

http://www.dana-farber.org/pat/cancer/gastrointestinal/crc-calculator/

– MMRpro http://www4.utsouthwestern.edu/breasthealth/cagene/

– MMRpredict http://www1.hgu.mrc.ac.uk/Softdata/MMRpredict.php

• Can order MSI and/or IHC on tumor to screen for LS• Can diagnose Lynch syndrome with genetic testing

Identification of Lynch syndrome in the Genetics Clinic


Identification of Lynch syndrome among all Newly Diagnosed CRC Patients

• Unlikely to have good family history

• High volume

• Must rely on screening tests for LS (MSI/IHC)

• Pathologists will know age at dx, synchronous primaries, but not likely to know all metachronous primary or family history of patients


Columbus-area HNPCC study (1999-2005)

Hampel et al. New Engl J Med 2005; 352:1851-60Hampel et al. J Clin Oncol 2008; 26:5783-88

MSI positive (high & low)n=307 (19.6%)

Deleterious mutationn=44* (2.8%)

*2 had MSI- tumors

Variant of uncertain significancen=55 (3.5%)

SequenceImmunohistochemistry

Methylation of MLH1 promoter

Polymorphism or no mutationn=209 (13.4%)

Colorectal cancer Total accrued (n=1600)

Testing completed (n=1566)

MSI negativen=1259 (80.4%)


CRC probands with deleterious mutations (n=44)

• Age at diagnosis – 51.4 (range 23-87)• 50% diagnosed over age 50• 25% did not meet either Amsterdam or

Bethesda criteria• Mutations

– 20.5% MLH1 – 52.3% MSH2– 13.6% MSH6– 13.6% PMS2

Hampel et al. New Engl J Med 2005; 352:1851-60Hampel et al. J Clin Oncol 2008; 26:5783-88


35 CRC probands have had genetic counseling

Family Studies of 35/44 CRC Probands

Hampel et al. NEJM 2005;352:1851-60.; Hampel et al. JCO 2008.

Degree of Kinship Tested Positive

First 99 52

Second 64 28

> Second 86 29

Total 249 109


11/2/2006

59 Melanoma 53

Prostate Cancer 55Skin Cancer, NOS 56

SCC on back and nose

Colon Cancer 57

14

+64 Colon Cancer 45

Prostate Cancer 61

86

+64 Colon Cancer

Colon Cancer

2-3 Colon Cancer

1-2

+89 Prostate Cancer

+54 Stomach Cancer

Liver

Amsterdam: YesLynch: Yes

942+3 a>t MSH2 mutation


11/2/2006

+85 Colon Cancer 82Prostate Cancer 82

85

+54 Uterine Cancer 51

+82

85 Uterine Cancer 52

67

65

58 Endometrial Cancer 50

56

55

57

52

62

+50's CaSU

+elderly

+40's

+20's

+birth

Amsterdam: NoLynch: Yes

3155delAG MSH6 mutation


11/2/2006

37 Colon Cancer 37

62

+57 Colon Cancer 57

+60s

82

+35

+30 Colon Cancer 29

14

21 months

11

10

4

+60's

+60's

57

+40's Brain Cancer 40's

60

Amsterdam: YesLynch: No

Tumors MSI- with intact IHC


EGAPP Recommendations

• Evaluation of Genomic Applications in Practice and Prevention

• Established in 2005 to assess evidence regarding the validity & utility of rapidly emerging genetic tests for clinical practice

• Independent, multidisciplinary panel prioritizes and selects tests, reviews CDC-commissioned evidence reports, finds gaps, and provides guidance


Steps in the EGAPP Working Group Review Process


Seven Evidence Reports Available to Date

1. October 2006 - Genomic Tests for Ovarian Cancer Detection and Management

2. January 2007 – Testing for CYP450 Polymorphisms in adults with depression before trtmnt with SSRIs

3. May 2007 – Lynch diagnostic strategies

4. January 2008 – Gene Expression Profiling and Breast Cancer Outcomes

5. January 2009 – DNA strategies aimed at reducing morbidity and mortality from Lynch syndrome

6. January 2009 – Can UGT1A1 genotyping reduce M&M in pts with metastatic CRC treated w/Irinotecan

7. June 2009 – Outcomes of genetic testing in adults with a history of venous thromboembolism


Four EGAPP Working Group Recommendations

Insufficient Evidence to recommend for or against

1. Tumor profiling to improve outcomes in patients with breast cancer

2. UGT1A1 genotyping to reduce morbidity and mortality in patients with metastatic CRC treated with Irinotecan

3. Use of CYP450 testing to predict response to SSRis in adults with depression

Sufficient Evidence to recommend for

4. Screening newly diagnosed CRC patients for LS with either MSI or IHC


EGAPP Recommendations• Moderate certainty that testing patients with CRC for LS and then

testing their relatives would provide moderate population benefit.• Adequate evidence to conclude that the analytic sensitivity and

specificity of the preliminary and diagnostic tests were high.• Adequate evidence to describe the clinical sensitivity and

specificity of three preliminary tests and four testing strategies.• Adequate evidence for testing uptake, compliance with

surveillance, relatives approachable, harms associated with f/u and effectiveness of routine c-scope supporting the use of genetic testing strategies to reduce morbidity and mortality in relatives with LS.

• No one test strategy was clearly superior.• Inadequate evidence that screening for LS will reduce EC

morbidity or mortality

EGAPP Genet Med 2009;11:35-41; Palomaki G, Genet Med 2010;11:42-65.


Potential Impact

• 146,970 new cases of CRC in the US in 2009

• 4,115 have Lynch syndrome (2.8%)

• 12,345 of their relatives have LS (~3 per proband)

• Total of 16,460 individuals who could be diagnosed with LS this year with universal screening

American Cancer Society Facts & Figures


Choosing the Screening Test: MSI vs. IHC

• IHC is available in virtually all hospitals • MSI requires molecular diagnostics and

normal for comparison• IHC with 4 antibodies is similar in cost to MSI

with 5 markers• IHC directs gene testing saving money • Ethical issues surrounding IHC • IHC and MSI have limitations


Cost-effectiveness Study

• Follow-up to EGAPP evidence review

• Modeling used the statistics from the EGAPP review

• My role on the project was to:– Explain the various strategies one might use

to screen for LS– Provide Medicare reimbursement rates & list

prices for various tests


Strategies Compared


Cost-effectiveness Results


Incremental Cost-Effectiveness Ratios per LYS compared to no testing at all

Strategy Medicare rates

List prices from labs

12 relatives

IHC, BRAF testing & sequencing

$22,552 $30,331 $12,332

IHC testing & sequencing

$23,321 $30,740 $12,663

MSI testing & sequencing

$41,511 $49,272 $20,470

Genetic sequencing for 4 genes

$142,289 $200,037 $63,773


Cost-Effectiveness Evaluation

• Universal screening detects nearly twice as many cases of LS as targeting younger patients

• Strategy 1 is the most cost effective strategy• Cost-effectiveness ratio of universal screening is

< $25,000 per life-year saved relative to no testing

• ICER comparable with other preventive services (colonoscopy every 10 years has ICER of $25,000)


Universal IHC screening for CRC: OSU experience

• Genetics notified by pathology of all abnormal CRC results

• Permission from ordering physician to contact patient• Patient contacted

– Take limited family history– Make recommendation for genetic consultation

• Letter sent• If contact cannot be made, letter is sent explaining

results with our contact information• Gyn/Onc’s notify their own patients regarding their

IHC results


Universal IHC screening for CRC: OSU experience

• Began March 1, 2006• 270 cases of CRC in first 2 years

– 57 (21.1%) absent for one or two MMR proteins– 54 contacted by genetics with physician consent

• 5 deceased, reported to next of kin• 7 prisoners

– 34 appropriate for consultation– 18 scheduled appointment – 9 completed appointment– 7 tested– 2 confirmed Lynch, 3 with MLH1 methylation

South et al, Genet Med 2009; 11:812-817


All proteins present(80%)

MSH2 and/or MSH6 absent;

PMS2 only absent (5%)

How to Follow-up on IHC Results

MLH1 and PMS2 absent(15%)

STOP

Sequence and large

rearrangements for absent one(s)

No germline mutation in MLH1, MSH2, MSH6, PMS2Consider family history, MSI analysis

BRAF mutation analysis

BRAF mutation present (10-12%)

BRAF mutation absent (3-5%)

Sequence and large

rearrangements for MLH1


Universal IHC - Challenges

• These patients are not as motivated to seek genetic counseling and testing– Many who likely have Lynch syndrome declined

further counseling/testing– Prisoners??

• Many do NOT have Lynch syndrome but we cannot rule these out without further testing - not easy to order and cost– BRAF testing has helped with this tremendously


OSU Successes and Pitfalls• Successes

– Proven need for tumor testing rather than family history reliance

– Proven equivalence of MSI vs IHC– Institutional buy-in for universal screening– IHC plus BRAF to optimize efforts

• Pitfalls– Need for multi-provider communication of tumor results to

increase patient follow through– IHC only routine on primary CRC resections

• Uninformative on many polyps• IHC should be done on initial biopsy for rectal cancers since

neoadjuvant radiation reduces available cancer cells• Can be ordered on any specimen

– Each institution requires adherence to pathology standards to assure equivalence of results


Conclusions

• 1 out of every 35 CRC patients has LS• Family history criteria will miss 25% of CRC

patients with LS • Lives can be saved by diagnosing LS early• Universal Screening for LS among all newly

diagnosed CRC patients– Is feasible– Is recommended– Is cost-effective


Acknowledgements

Albert de la Chapelle Jenny Panescu

Judith Westman Jan Lockman

Ilene Comeras Jennifer LaJeunesse

Wendy Frankel Dan Fix

Julie Stephens Leigha Senter

Thomas Prior Mark Clendenning

Jeffrey Fowler Kaisa Sotamaa

David Cohn Yange Zhang

Edward Martin Hidewaki Nakagawa

Mark Arnold Martha Yearsley

© coc 2011—content cannot be reproduced or repurposed without written permission of the coc....

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