Not Valid After March 13, 2020 · M M R and M SI Test i ng i n Pat i ent s B ei ng C onsi dered f...

MMR and MSI Testing in Patients Being Considered for Checkpoint Inhibitor Therapy: DRAFT

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65.03% 106

3.68% 6

16.56% 27

3.07% 5

0.00% 0

4.91% 8

8.59% 14

2.45% 4

9.82% 16

Q1 What is your occupation/role? (select all that apply)Answered: 163 Skipped: 0

Total Respondents: 163

Pathologist

Physician(non-patholo...

MedicalDirector

Technologist/Technician

QA/QCCoordinator

LaboratoryManager

Industry

PatientAdvocate

Other (pleasespecify)

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ANSWER CHOICES RESPONSES

Pathologist

Physician (non-pathologist)

Medical Director

Technologist/Technician

QA/QC Coordinator

Laboratory Manager

Industry

Patient Advocate

Other (please specify)Not

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DisclaimerThe information, data, and draft recommendations provided by the College of American Pathologists are presented for informational and public feedback purposes only. The draft recommendations and supporting documents will be removed on March 20, 2020.The draft recommendations along with the public comments received and completed evidence review will be reassessed by the expert panel in order to formulate the final recommendations. These draft materials should not be stored, adapted, or redistributed in any manner.


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# OTHER (PLEASE SPECIFY) DATE

1 Laboratory Director, Clinical Molecular Geneticist 3/2/2020 10:30 AM

2 Genetic Counselor 3/2/2020 9:12 AM

3 Clinical Reference Laboratory Director 2/28/2020 12:43 PM

4 Med 2/26/2020 11:55 PM

5 Genetic Counselor 2/26/2020 8:56 AM

6 xxx 2/24/2020 6:32 AM

7 s 2/21/2020 7:33 AM

8 Staff Scientist 2/20/2020 2:47 PM

9 ABMG molecular geneticist 2/20/2020 2:18 PM

10 Laboratory scientist 2/20/2020 1:58 PM

11 a 2/20/2020 12:43 PM

12 . 2/20/2020 12:04 PM

13 PhD laboratory director 2/20/2020 8:03 AM

14 Geneticist 2/20/2020 2:37 AM

15 Laboratory Director 2/19/2020 6:59 PM

16 Computational biologist 2/19/2020 4:19 PM

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Q2 Which of the following best describes your practice setting? (selectone)

Answered: 163 Skipped: 0

Universityhospital/aca...

Voluntary,non-profit...

Proprietaryhospital

City/County/State hospital

Veteranshospital

Army/AirForce/Navy...

National/corporate laboratory

Regional/localindependent...

Public Health,non-hospital

Clinic, group,or doctor...

Industry orvendor

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47.85% 78

8.59% 14

1.23% 2

4.91% 8

0.61% 1

0.00% 0

6.75% 11

5.52% 9

0.00% 0

4.29% 7

14.72% 24

1.23% 2

4.29% 7

TOTAL 163


1 National Institute of Health?National Cancer Institute 2/21/2020 11:12 AM

2 s 2/21/2020 7:33 AM

3 Reference lab for healthcare system (non-profit) 2/21/2020 7:31 AM

4 a 2/20/2020 12:43 PM

5 Health System 2/19/2020 6:59 PM

6 independent pathologist owned lab 2/19/2020 6:58 PM

7 Public health academic university affiliated community hospital 2/19/2020 2:42 PM


University hospital/academic medical center

Voluntary, non-profit hospital

Proprietary hospital

City/County/State hospital

Veterans hospital

Army/Air Force/Navy hospital

National/corporate laboratory

Regional/local independent laboratory (except clinic or group practice and not owned by a national corporation(s))

Public Health, non-hospital

Clinic, group, or doctor office laboratory

Industry or vendor

Patient Advocacy Organization

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71.95% 59

12.20% 10

10.98% 9

3.66% 3

Q3 Draft Recommendation Statement 1In CRC patients being consideredfor checkpoint blockade therapy, pathologists should use MMR IHC and/orMSI by PCR for the detection of DNA mismatch repair defects. Although

MMR IHC or MSI by PCR are preferred, pathologists may use a validatedMSI by NGS assay for the detection of DNA mismatch repair defects.

Note: MSI by NGS assay must be validated against MMR IHC or MSI byPCR and must show equivalency.(Quality of Evidence: Moderate;

Strength of Recommendation: Strong)Answered: 82 Skipped: 81

TOTAL 82

Agree aswritten

Agree withsuggested...

Disagree(please incl...

Neutral

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Agree as written

Agree with suggested modifications (please include comments)

Disagree (please include comments)

Neutral

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# COMMENTS DATE

1 In CRC patients being considered for checkpoint blockade therapy, pathologists should useMMR IHC, MSI by PCR and/or validated MSI by NGS assayfor the detection of DNA mismatchrepair defects. Note: MSI by NGS assay must be validated against MMR IHC or MSI by PCRand must show equivalency.

3/2/2020 10:47 AM

2 Should offer PD-L1 testing as an alternative and bypass MMR MSI testing. 2/29/2020 12:54 AM

3 MSI-NSG is depended on the availability of the NGS platform for each lab. MMR-IHC and MSI-PCR should sufficient for diagnostic purposes for regular labs.

2/28/2020 1:13 PM

4 NGS assay might need a common standard, such as a set of markers and set the cut off. 2/28/2020 12:48 PM

5 Should follow EU recommendations and read MMR IHC and MSI by PCR. The assays measuretwo different aspects of the same biological phenomenon and have a~10% differential detectionrate. Also MSI by NGS has not been clinically proven to be equivalent. Only real correlativedata is Foundation Medicine PMA submission. Assay need a high level of validation as TMB isnot equivalent clinically!

2/24/2020 10:25 AM

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2/24/2020 10:16 AM

7 Validation of MMR IHC using the CAP Guidelines can be very challenging. Will this beaddressed in the final manuscript?.

2/22/2020 9:32 AM

8 There is robust data supporting the performance of validated NGS testing for detection of MSIin CRC and other tumor types (27863258, 29955144, 30211344, 29596542, 29277635,30389464, 31530574, and more) and it should be considered an equal of IHC and PCR. In theabsence of seeing the data used to assemble this recommendation, it is difficult to know if thetwo tiered recommendation is an artifact of the way GRADE criteria are applied or if the timingof the literature review meant that much of the supporting literature was missing.

2/22/2020 8:01 AM

9 CT guided biopsies performed for these assessments have limited tumoral tissue and MMR isthe most appropriate study in these siturations. MSI and NGS require substantially more tissueand are more appropriate for resection specimens. This should be incorporated into therecommendation.

2/21/2020 11:22 AM

10 I believe the data supports that MSI detection in a validated NGS assay is equivalent to MMRby IHC and MSI by PCR. By stating that MMR by IHC and MSI by PCR are preferred you areimplying that they are superior. According to our labs validation of MSI detection by NGS theyare equivalent.

2/21/2020 9:05 AM

11 In CRC patients being considered for checkpoint blockade therapy, pathologists should useMMR IHC and/or MSI by PCR or a validated NGS MSI technique for the detection of DNAmismatch repair defects.

2/21/2020 7:05 AM

12 I completely disagree with this recommendation, for the following reasons. 1) MSI detection byNGS is more sensitive than the traditional 5-7 marker PCR panel. Our lab has been using NGSfor MSI for the past 2 years and we have seen several examples where it has identified MSI-high tumors that were missed by PCR (and in one case missed by MMR IHC). 2) NGS panelsnot only can provide MSI coverage, but can simultaneously provide broad coverage forclinically informative mutations in KRAS, NRAS, BRAF and the MMR genes. Why run othertests when NGS is a single solution? 3) Several NGS tests on the market, including the oneoffered by our (non-profit) academic laboratory, now have approval for coverage by Medicare,so insurance coverage is no longer a good reason to bias testing recommendations againstNGS-based assays. I strongly urge you to consider changing the recommendation to put NGSassays on equal footing with MMR IHC and MSI PCR. There is no good reason to prefer thesetests over NGS.

2/20/2020 3:29 PM

13 MSI is change in nucleotide hence has to be a sequencing technology to detect accurately.With 11 steps of cumulative errors NGS is not accurate MSI by PCR is subjective read smallpeaks and not accurate. MMR IHC is non verifiable.

2/20/2020 2:35 PM

14 To suggest that PCR MMR is superior to NGS MSI is misleading. The fact that PCR MMR hasbeen around longer does not make it the superior test.There are many advantages of NGS.There is the ability to know the quality of material that is being sequenced. NGS assess 100s-1000s of microsatelittes compared to <6. If NGS preceded PCR we would never consider usingit in clinical practice. I don't think guidelines should enshrine technology that is on its way out.

2/20/2020 2:11 PM

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15 'cancer' is a broad term and includes e.g. lymphoma. Here and throughout the document,specify adenocarcinoma or other specific cancer types.

2/20/2020 10:54 AM

16 This suggestion applies to other tumor types as well. While MMR by IHC or NGS can be donewith tumor tissue only, MSI by PCR requires submitting normal tissue, which causesinconvenience and delay, especially when dealing with small biopsy specimens. I suggest MMRshould be first line. When equivocal, NGS or PCR may be attempted.

2/20/2020 8:16 AM

17 As many laboratories are moving to next generation sequencing for mutation detection,expanded panels are more often including the MMR genes. We now have the capability ofidentifying the specific mutation in the MMR gene, something we used to use IHC for. I believeit would be fraudulent to bill for MMR IHC and NGS when the NGS panel includes these genes.It would also allow for better tissue stewardship if we did not need to do MMR IHC.

2/20/2020 8:10 AM

18 We use the Idylla of Biocartis and is a very robust method 2/20/2020 7:49 AM

19 MMR IHC AND MSI BY PCR, PERFORMED SIMULTANEOUSLY ARE MORE LIKELY TOIDENTIFY PATIENTS ELIGIBLE FOR CHECKPONT INHIBITOR THERAPY

2/20/2020 12:25 AM

20 Testing is being recommended for patients being considered for target therapy. ? Testing shouldbe done on all patients to investigate for Lynch syndrome, irrespective of check point therapy?

2/19/2020 11:49 PM

21 Consider spelling out abbreviations in the final document, at least when first mentioned. 2/19/2020 11:23 PM

22 I have no way of actually knowing how these NGS labs have validated their MSI by NGS assay.Getting detailed validation studies out of these commercial laboratories can be challenging. It isalso impractical for community pathologists to be able to assess the robustness of an NGSvalidation. I would recommend rephrasing this so that the impetus for assessing validationdocuments is not placed upon community pathologists who will be providing this service as asend out test.

2/19/2020 2:42 PM

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59.26% 48

11.11% 9

14.81% 12

14.81% 12

Q4 Draft Recommendation Statement 2In gastroesophageal and smallbowel cancer patients being considered for checkpoint blockade therapy,pathologists should use MMR IHC and/or MSI by PCR over MSI by NGS

for the detection of DNA mismatch repair defects.Note: Thisrecommendation does not include esophageal squamous cell carcinoma.

(Quality of Evidence: Low; Strength of Recommendation: Strong)Answered: 81 Skipped: 82

TOTAL 81

Agree aswritten



Neutral

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%


Agree as written



Neutral

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# COMMENTS DATE

1 Not sure I understand why this should be different to the recommendations for CRC. Is thereevidence that MSI by NGS is less accurate for GE/SI tumours than for CRC? A priori thisdoesnt make a lot of sense. Is this due to a lack of published evidence in non-CRCmalignancies for MSI by NGS?

3/3/2020 9:40 PM

2 In gastroesophageal and small bowel cancerpatients being considered for checkpoint blockadetherapy, pathologists should use MMR IHC, MSI by PCR and/or validated MSI by NGS assayforthe detection of DNA mismatch repair defects. Note: MSI by NGS assay must be validatedagainst MMR IHC or MSI by PCR and must show equivalency.

3/2/2020 10:47 AM

3 Please remove phrase: being considered for checkpoint blockade therapy. We need these testsalso to evaluate for LS, not just therapy evaluation. Should offer PD-L1 testing as an alternativeand bypass MMR MSI testing.

2/29/2020 12:54 AM

4 MSI-PCR should be used when MMR-IHC display heteromerous staining due to the htergeinityof tissue.

2/28/2020 1:13 PM

5 Should follow EU recommendations and read MMR IHC and MSI by PCR. The assays measuretwo different aspects of the same biological phenomenon and have an ~10% differentialdetection rate

2/24/2020 10:25 AM

6 For patients undergoing NGS for clinical care, NGS can serve as a screen test for MMR/MSI.The provider should consider the sensitivity and specificity for MSI detection of any NGS assaywhen used for patient care.

2/22/2020 10:05 AM

7 Again, there is data to support use of NGS in this context, albeit less than for CRC (31028081;30211344; 31048490) but there is evolving data to suggest that the additional data provided byNGS (TMB, relative number of indels) stratifies response rates to immunotherapy among MSI-Hpatients; this is data that is not apparent from MMR or MSI testing.

2/22/2020 8:01 AM

8 If there is adequate validation of MSI by NGS against IHC or PCR for GE & Small bowelcancers, NGS should be an equal option to IHC & PCR.

2/21/2020 2:21 PM

9 CT guided biopsies performed for these assessments have limited tumoral tissue and MMR isthe most appropriate study in these siturations. MSI and NGS require substantially more tissueand are more appropriate for resection specimens. This should be incorporated into therecommendation.

2/21/2020 11:22 AM

10 I believe the data supports that MSI detection in a validated NGS assay is equivalent to MMRby IHC and MSI by PCR. By stating that MMR by IHC and MSI by PCR are preferred you areimplying that they are superior. According to our labs validation of MSI detection by NGS theyare equivalent.

2/21/2020 9:05 AM

11 Why not also use the potential of a validated NGS assay? Why have different wording toabove? Good and ambitious labs will have the capacity to deliver NGS MSI and MSI by PCR.

2/21/2020 7:05 AM

12 NGS statement should reflect that of CRC. 2/20/2020 9:30 PM

13 The recommendation is for "patients being considered for checkpoint blockade therapy". Thatinformation is generally not available to the pathologists. The clinicians often demand reflexMMR testing for all cases, which is not a cost-effective approach. Please further elaborate andguide the pathologists to identify "patients being considered for checkpoint blockade therapy".

2/20/2020 6:38 PM

14 Please see comments under Statement 1. 2/20/2020 3:29 PM

15 See statement 1 2/20/2020 2:35 PM

16 same as above 2/20/2020 2:11 PM

17 1. In GEA, MLH1 methylation is very closely associated with MSI status, and Lynch syndromeis rare and is unrelated to the IO therapy goal of this guideline. Especially in low resource areasbut even generally, discuss if it is reasonable to do MLH1 IHC alone (skipping the IHCs forother rarely-lost MMR proteins) or MLH1 methylation test? 2. It is unseemly to recommend anon-FDA approved commercial product, but if you insist on doing so then use the specific kitname that you recommend, e.g. 'Microsatellite Instability Analysis System, v1.2'. Explain whyyou do not recommend alternative commercial products such as the kit at

2/20/2020 10:54 AMNot

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https://www.thermofisher.com named 'TrueMark MSI Assay for Microsatellite InstabilityAnalysis'

18 Labs should not be discouraged from using technology available to them if adequately validatedfor purpose. Include Note: MSI by NGS assay must be validated against MMR IHC or MSI byPCR and must show equivalency.

2/20/2020 10:35 AM

19 Newer MSI assays like the one from Biocartis use a SNP based system and requires only onesection of tumor tissue. This is much easier, cheaper, faster and better tissue stewardship.

2/20/2020 8:10 AM

20 Should be written as for CRC. If MSI by NGS is compared with IHC or MSI-PCR then it can besubstituted

2/20/2020 2:42 AM

21 MMR IHC AND MSI BY PCR, PERFORMED SIMULTANEOUSLY ARE MORE LIKELY TOIDENTIFY PATIENTS ELIGIBLE FOR CHECKPONT INHIBITOR THERAPY

2/20/2020 12:25 AM


2/19/2020 11:49 PM

23 I think I have an issue with the phrase “patients being considered for checkpoint therapy”because pathologists are not the physicians considering the checkpoint therapy. How is acommunity pathologist suppose to know what the oncologist is considering? I think theseshould be revised to state best practices for determining MMR/MSI status regardless of theindication.

2/19/2020 2:42 PM

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53.75% 43

11.25% 9

15.00% 12

18.75% 15

Q5 Draft Recommendation Statement 3In endometrial cancer patientsbeing considered for checkpoint blockade therapy, pathologists should

use MMR IHC over MSI by PCR or NGS for the detection of DNAmismatch repair defects. (Quality of Evidence: Low; Strength of

Recommendation: Strong)Answered: 80 Skipped: 83

TOTAL 80

Agree aswritten



Neutral

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Agree as written



Neutral

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# COMMENTS DATE

1 MSI PCR changes are more subtle in endometrial cancers with MMR-D, but may still be reliablydetectable by an NGS approach interrogating multiple loci e.g Foundation's publishedevidence.

3/3/2020 9:40 PM

2 It is not clear why MSI testing should be considered less informative in endometrial cancercompared to CRCA or EGJ cancers.

3/2/2020 9:11 PM

3 Please remove phrase: being considered for checkpoint blockade therapy. We need these testsalso to evaluate for LS, not just therapy evaluation. Also, MMR IHC and/or MSI by PCR and/orNGS testing. Should offer PD-L1 testing as an alternative and bypass MMR MSI testing.

2/29/2020 12:54 AM

4 MSI-PCR should be used when MMR-IHC display heteromerous staining due to the htergeinityof tissue.

2/28/2020 1:13 PM

5 MSI by PCR could be used with MMR IHC. 2/28/2020 12:48 PM

6 Rationale for this? Is this saying MMRd hypermethylated MLH1 patients should be consideredfor checkpoint blockade therapy or that the IHC should be used as initial screening? Veryunclear, needs clarification.

2/28/2020 9:38 AM

7 Pathologists should use both MMR IHC and MSI by PCR to increase sensitivity of detection ofdMMR

2/24/2020 1:21 PM

8 Should follow EU recommendations and read MMR IHC and MSI by PCR. Again assayvalidation criteria NGS assays needs to be spelled out in detail - see Foundation Medicine PMAsubmission

2/24/2020 10:25 AM

9 For patients undergoing NGS for clinical care, NGS can serve as a screen test for MMR/MSI.The provider should consider the sensitivity and specificity for MSI detection of any NGS assaywhen used for patient care.

2/22/2020 10:05 AM

10 Use of the word "over" in the two above recommendations seems awkward to me. 2/22/2020 9:32 AM

11 Same issues as above. 2/22/2020 8:01 AM

12 certain MSI by PCR kits have included (and are starting to include) LTR's that are moresensitive to endometrial tumor types and maintain the high level of sensitivity over IHC.

2/22/2020 12:20 AM

13 Is this due to MMR/MSI heterogeneity in endometrial cancers, more subtle changes inmicrosatellite lengths in endometrial cancers, larger proportion of MSH6 -> MSI-Low cases?

2/21/2020 2:21 PM

14 I believe the data supports that MSI detection in a validated NGS assay is equivalent to MMRby IHC and MSI by PCR. By stating that MMR by IHC and MSI by PCR are preferred you areimplying that they are superior. According to our labs extensive validation of MSI detection byNGS they are equivalent.

2/21/2020 9:05 AM

15 MSI by PCR should be used over MMR IHC or NGS for the detection of DNA mismatch repairdefects with simple, fast turn around and reliable results.

2/21/2020 7:39 AM

16 From personal experience, the Promega MSI assay has lower sensitivity for MMR as comparedto the IHC analysis in endometrial cancers

2/21/2020 7:35 AM

17 NGS statement should reflect that of CRC. 2/20/2020 9:30 PM

18 See comments on above statement 2/20/2020 2:35 PM

19 same as above This pattern of Quality of Evidence: Low; Strength of Recommendation: Strongis concerning to me. And I strongly disagree with every one so far.

2/20/2020 2:11 PM

20 Use MMR IHC and/or MSI by PCR 2/20/2020 2:11 PM

21 Evidence quality being low, is it reasonable to do both IHC and MSI PCR or NGS? 2/20/2020 10:54 AM

22 Labs should not be discouraged from using technology available to them if adequately validatedfor purpose. Level of evidence to choose MMR over MSI is low and this recommendation isconsidered premature. Would also add the Note: MSI by NGS assay must be validated againstMMR IHC or MSI by PCR and must show equivalency.

2/20/2020 10:35 AM

23 Newer SNP based MSI assays perform better in endometrial ca. 2/20/2020 8:10 AM

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24 We do not apply this test for Endometrial Cancer 2/20/2020 7:49 AM

25 Should be written as for CRC. 2/20/2020 2:42 AM


2/19/2020 11:49 PM

27 See other comments. 2/19/2020 2:42 PM

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60.26% 47

11.54% 9

12.82% 10

15.38% 12

Q6 Draft Recommendation Statement 4In patients with cancer types otherthan CRC, GEA, small bowel, and endometrial being considered for

checkpoint blockade therapy, pathologists should test for DNA mismatchrepair, although the optimal approach for the detection of MMR defects

has not been established. Note: Assays must be adequately validated forthe specific cancer type being tested with careful consideration ofperformance characteristics of MMR IHC and MSI by NGS for the

detection of DNA mismatch repair defects.(Quality of Evidence: Very Low;Strength of Recommendation: Conditional)


TOTAL 78

Agree aswritten



Neutral

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# COMMENTS DATE

1 I do not think we should recommend such blanket testing without better evidence of how wellMMR IHC performs in other tumors. I also disagree with issuing a statement recommendingtesting but not giving some guidance as to testing methodology.

3/2/2020 9:11 PM

2 1. Please remove phrase: being considered for checkpoint blockade therapy. We need thesetests also to evaluate for LS, not just therapy evaluation. 2. Cannot validate for all tumor types.Tests are tumor agnostic. 3. Should offer PD-L1 testing as an alternative and bypass MMR MSItesting.

2/29/2020 12:54 AM

3 NGS assay might need a common standard, such as a set of markers and set the cut off. 2/28/2020 12:48 PM

4 this statement ommitts MSI by PCR - effectively the gold standard. Again I have concernsabout Laboratories submitting TMB results for MSI while using NGS as the detectiontechnology. Validation requirements should be specificfied.

2/24/2020 10:25 AM

5 There is insufficient evidence evaluating clinical validity of IHC vs. PCR vs. NGS to supportStatements 1-4. The performance characteristics of NGS assays vary depending on size ofpanel, informatics tool used, etc.; therefore, clinical decisions should be made depending on thevalidated performance of the individual assay.

2/22/2020 10:05 AM

6 Might be worth modifying this to indicate that certain tumor types have other primarybiomarkers for selection of immunotherapy responders (e.g. PD-L1) in the first line setting. thismay render MMR/MSI testing less relevant- and indeed may lead to an additional unnecessarytesting expense if this recommendation is interpreted to mean that all patients should getreflexive MMR testing (because, to be honest, nearly all cancer patients are now beingconsidered for immunotherapy).

2/22/2020 8:01 AM

7 Individual labs will not have adequate numbers of cases to perform their own validations.Published large validation studies of specific cancer types should be used.

2/21/2020 2:21 PM

8 For non CRC/nonendometrial carcinomas the Promega MSI kit includes 5 markers that wereoptimized for analyzing microsatellite instability in CRCs. The sensitivity for detection of MSI-high is lower in endometrial cancers than CRC and lower than MMR IHC. In addition, there isnot sufficient data to recommend MSI over MMR IHC in these other types of tumors.

2/21/2020 11:22 AM

9 I do not think the data favors MMR IHC or MSI testing. The promega MSI in particular seemsoptimized for CRC and its performance is less characterized for these other cancer types.

2/21/2020 7:35 AM

10 The recommendation is for "patients being considered for checkpoint blockade therapy". Thatinformation is generally not available to the pathologists. The clinicians often demand reflexMMR testing for all cases, which is not a cost-effective approach. Please further elaborate andguide the pathologists to identify "patients being considered for checkpoint blockade therapy".

2/20/2020 6:38 PM

11 This recommendation should endorse NGS-based testing rather than leave open the questionof method. NGS panels can provide not only excellent coverage for MSI detection, but will turnup other (more common) alterations that may inform treatment, such as mutations in the DNAdamage repair genes (BRCA1/2, etc.). There is not reason to isolate MSI has a stand-alonetesting target when there are well-validated NGS-based assays that provide more all-aroundinformative coverage.

2/20/2020 3:29 PM

12 as above 2/20/2020 2:35 PM

13 Make it clear that if the patient qualified for therapy by another means, such as PDL1 status,then the pathologist should not be required to also test for mismatch repair status.

2/20/2020 10:54 AM

14 In this instance when "MMR" is being used as a specific IHC strategy, would clarify that MMR,MSI by PCR or MSI by other methods including NGS may be pursued providing appropriatevalidation studies.

2/20/2020 10:35 AM

15 Must include SNP based MSI assays as these may soon be FDA approved. 2/20/2020 8:10 AM

16 Validation in every tumor type is difficult if not impossible. I believe the assays are tumoragnostic. PCR may be preferable since it evaluates the end result of MMR.

2/20/2020 7:59 AM


2/19/2020 11:49 PM

18 It is impractical to validate for each cancer type being tested. 2/19/2020 7:03 PM

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19 How can we validate if there is no evidence for the optimal approach? Need guidance on whata validation for uncommon or less common cancer types.

2/19/2020 3:19 PM

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70.89% 56

6.33% 5

6.33% 5

15.19% 12

Q7 Draft Recommendation Statement 5For all cancer patients beingconsidered for checkpoint blockade therapy based upon defective

mismatch repair, pathologists should not use TMB as a surrogate for thedetection of DNA mismatch repair defects. If a tumor is identified as TMB-

high, pathologists may perform IHC and/or MSI by PCR to determine ifhigh TMB is secondary to mismatch repair deficiency. Note: In patients

being considered for checkpoint blockade therapy, pathologists should notuse TMB as a surrogate based on DNA mismatch repair defects.(Quality

of Evidence: Low; Strength of Recommendation: Strong)Answered: 79 Skipped: 84

TOTAL 79

Agree aswritten



Neutral

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# COMMENTS DATE

1 Can MSI be performed by a panel other than the NIH 7-microsatellite panel? Some studiessuggest for prostate cancer that a larger number of microsatellites is better. the UW MSINGSMSI NGS is also more comprehensive.

3/2/2020 9:19 AM

2 1. Please remove phrase: being considered for checkpoint blockade therapy. We need thesetests also to evaluate for LS, not just therapy evaluation.

2/29/2020 12:54 AM

3 should read IHC and PCR as you have no published data either way! 2/24/2020 10:25 AM

4 Although MSI and TMB are correlated, high TMB can result from multiple mechanisms ofmutagenesis and should not be used as a surrogate for MSI. These are different biomarkers.

2/22/2020 10:05 AM

5 Or may use data from a validated NGS panel to inform likelihood of MSI-G status 2/22/2020 8:01 AM

6 Very low evidence and often high inconsistency with cutoff being considered for positive ornegative results.

2/21/2020 7:39 AM

7 Please spell out "TMB": what does that stand for? How to determine TMB? 2/20/2020 6:38 PM

8 The phrase 'based upon defective mismatch repair' implies that there are many ways to qualifyfor IO therapy, and indeed there are. If the goal of this guideline is to remain focused on use ofMMR tests to qualify pts for IO Rx, then you can skip discussion of TMB or merely state thatTMB status is not a test for MMR deficiency and thus is outside the scope of this guideline.Likewise PDL1 IHC and EBV status and other predictors of IO Rx response are outside thescope of this guideline.

2/20/2020 10:54 AM

9 "TMB-high" may be used to guide additional testing by MMR-IHC or MSI-PCR/NGS but shouldnot be used as a definitive guide to I/O therapy recommendations.

2/20/2020 10:35 AM

10 There is insignificant clinical data to support TMB testing at this time. 2/20/2020 8:10 AM

11 "TMB" is an abbreviation and requires a explanation in the text 2/20/2020 7:57 AM

12 Depends on the PCR and the laboratory should have a external control to check its testingpreformance. The sensitivity should be validated and the testing very well standarized in tissueselection and procedure

2/20/2020 7:49 AM

13 Not always required 2/20/2020 5:06 AM

14 Consider spelling out "Tumor Mutational Burden" before using the abbreviation. 2/19/2020 11:23 PM

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68.42% 52

22.37% 17

2.63% 2

6.58% 5

Q8 Draft Recommendation Statement 6For cancer patients beingconsidered for checkpoint blockade therapy, if a MMR deficiency is

identified, pathologists should recommend follow-up evaluation for LynchSyndrome(Quality of Evidence: Low; Strength of Recommendation:

Strong) Answered: 76 Skipped: 87

TOTAL 76

Agree aswritten



Neutral

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%


Agree as written



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# COMMENTS DATE

1 1. Please remove phrase: being considered for checkpoint blockade therapy. We need thesetests also to evaluate for LS, not just therapy evaluation. 2. Need to recommend MLH1 reflex toBRAF testing. If Neg, then perform genetic testing.

2/29/2020 12:54 AM

2 by ordering additional tests such as MLH1 hypermethylation or BRAF mutation testing. 2/28/2020 1:16 PM

3 In endometrial cancer testing should be done for hypermethylation if this was detected on IHC 2/28/2020 9:38 AM

4 If the tumor type has been associated with Lynch syndrome and if there are no other features tosuggest a somatic etiology, eg. MLH1 promoter methylation

2/22/2020 4:51 PM

5 In the Cancer Care Ontario guidelines MLH1/PMS2 deficient tumour patients are only referredfor genetic counselling assessment after negative methylation/BRAF testing.

2/22/2020 9:32 AM

6 Pathologists should take some initiative to rule out sporadic forms of MSI-H in particular MLH-1promoter methylation in endometrial and CRC patients with MLH1 loss. perhaps this needs toreworded as "should follow existing recommendations regarding exclusion of sporadic casesand followup for LS"

2/22/2020 8:01 AM

7 Need to do BRAF testing snd mlh1 methylation testing first 2/22/2020 2:33 AM

8 This recommendation needs some caveats. I think its fairly standard that in the case of PMS2and MLH1 loss that BRAF and MLH1 testing will be performed as most of the tumors with thisstaining pattern are sporadic tumors and likely do not require further workup for Lynchsyndrome.

2/21/2020 9:05 AM

9 Specific recommendations should be made as to the type of follow up, i.e. in CRC vs. other. 2/20/2020 9:30 PM

10 Follow-up evaluation of Lynch syndrome appears to be outside of a pathologist's power. Thisshould be done by medical geneticist or oncologist. In addition, this recommendation should notbe limited to "cancer patients being considered for checkpoint blockade therapy".

2/20/2020 6:38 PM

11 Why does this say MMR deficiency? It should be MMR deficiency or micro-satellite instabilityhigh.

2/20/2020 2:11 PM

12 depending on age 2/20/2020 12:03 PM

13 This recommendation should be considered in the context of all clinicopathological informationavailable.

2/20/2020 10:35 AM

14 My understanding (which is probably outdated) is that the cost-benefit of diagnosing LynchSyndrome has not been well established, particularly outside the colon. I wonder whether thestrength of this recommendation should be downgraded to "conditional" or "moderate."Alternatively, the suggestion could be for pathologists to "discuss" (rather than "recommend")evaluation for Lynch Syndrome.

2/19/2020 11:23 PM

15 Follow - up is ideal but comment should state "when such services are available" 2/19/2020 10:34 PM

16 Genetic counseling referral should be offered on these cases 2/19/2020 7:04 PM

17 Lynch Syndrome follow up testing recommendations should be specific and stronglyrecommended.

2/19/2020 7:03 PM

18 This is highly dependent on tumor type. Colon and endometrial have well established algorithmis place that help identified sporadic versus lynch associated MMR deficiency. Other tumortypes we really don’t have a good adjunct test to help make that distinction so I feel making thisrecommendation may lead to over reliance of MLH1 promoter methylation assays outside ofcolon and endometrial cancers. I have recently looked into the performance of MLH1 promotermethylation assays outside of these common lynch related cancers and there doesn’t seem tobe enough evidence to understand what those results may mean. If you are going to make thisrecommendation then I would contest that the statement must include something on the adjunctworkup for sporadic versus lynch associated.

2/19/2020 2:42 PM

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64.94% 50

5.19% 4

16.88% 13

12.99% 10

Q9 Good Practice Statement 1Discordant results:In the event ofdiscordant results, pathologists should interpret any evidence of MMR

deficiency by IHC, MSI by NGS or PCR as a positive result for patients tobe eligible for checkpoint blockade therapy.


TOTAL 77

Agree aswritten



Neutral

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Agree as written



Neutral

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# COMMENTS DATE

1 I'm not sure about "any evidence". What if it is a difficult to interpret 'patchy' IHC result, reflexedto MSI, which is normal? Do you go with the uncertain IHC? Perhaps "any clear evidence ofMMR deficiency" or "any analytically valid evidence of MMR deficiency" could substitute for"any evidence"

3/3/2020 9:44 PM

2 We should recommend that testing be repeated either on a different sample of the tumor (incase of resections) or possibly at a different lab.

3/2/2020 9:12 PM

3 Need to also include PD-L1 IHC testing for therapy, not just dMMR. 2/29/2020 1:01 AM

4 Is there evidence that normal staining for MMR proteins by IHC is trumped by MSI by NGS?? 2/28/2020 1:17 PM

5 Should read MSI by PCR or NGS. Again NGS assay must be appropriately validated - seeFoundation Medicine PMA subumission

2/24/2020 10:27 AM

6 Pathologist should evaluate the performance characteristics of each assay and assess allevidence in total to make an accurate interpretation of MMR/MSI based on IHC, MSI, and NGS.If the pathologist concludes there is a false positive result in one of the assays, which can bedue to multiple factors, the patient should not receive immunotherapy.

2/22/2020 10:09 AM

7 Not sure about this. IHC is known to suffer from false positive results due to technical issues.PCR can be difficult to interpret. NGS across tumor types that are not well characterized in theMSI spectrum may also be difficult to interpret. These isolated positive results should bereported with a caveat so as not to give cinicians and patients a false hope of possibility ofresponse When NGS data is available, they should be interpreted in the context of othergenomic data such as TMB.

2/22/2020 8:06 AM

8 Has this question really been answered? Any evidence is extremely loose wording. Clinicalinput is needed. Essentially a cinicopathological decision not a definition on paper,

2/21/2020 7:07 AM

9 It seems to be a biased recommendation that every effort be made to get a positive result. 2/20/2020 6:44 PM

10 Poorly worded. "Discordant" should be clarified. 2/20/2020 3:31 PM

11 Reason for discordance must be, at least plausibly, determined. The discordance must bedisclosed to the treating oncologist who can then act accordingly.

2/20/2020 2:27 PM

12 This statement should explain the recommendation further. It is acknowledged that both MMRIHC and MSI testing have limitations that will lead to false negative results. ~

2/20/2020 2:14 PM

13 There should be no discrepancy, in results . Existing guidelines must be followed 2/20/2020 5:08 AM

14 Technical limitations sometimes preclude unequivocal results. If so, am additional biopsy orrepeat testing should be done

2/19/2020 7:07 PM

15 If results appear valid - don’t you want to do sone double check? 2/19/2020 3:20 PM

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81.82% 63

15.58% 12

0.00% 0

2.60% 2

Q10 Good Practice Statement 2Indeterminate:In the event ofindeterminate result in any method, pathologists should perform an

orthogonal technique or repeat on a different tumor block. Laboratoriesshould have a robust peer review process for indeterminate cases.


TOTAL 77

Agree aswritten



Neutral

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Agree as written



Neutral

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# COMMENTS DATE

1 This probably addresses my concern above 3/3/2020 9:44 PM

2 In the event of indeterminate result in any method in GI cancer pateint samples, pathologistsshould perform an orthogonal technique or repeat on a different tumor block. Laboratoriesshould have a robust peer review process for indeterminate cases.

3/2/2020 10:49 AM

3 Define orthogonal. Also, if repeat is again indeterminate, then what? Need to be more precisein statement.

2/29/2020 1:01 AM

4 ideally this a default or reflex process rather than asking for a new order to be placed by theclinician, which tends to occur only after clinician asks about results and is informed that it wasQNS or indeterminate. This is not timely for patient care

2/28/2020 9:10 AM

5 Sometimes different tests are perfumed in different labs without each lab receiving the otherresults or knowing the test is being carried out. Unfair burden of responsibility on thepathologist. Should be the responsibility of whoever is requesting and coordinating the testing.

2/24/2020 11:38 PM

6 I agree with orthogonal testing, but not necessarily with different tumor block; unless it is thesame tumor in separate blocks.

2/22/2020 12:23 AM

7 Please specify what "orthogonal technique" means. 2/20/2020 6:44 PM

8 Careful not to call actual discordant results as indeterminate... 2/20/2020 2:27 PM

9 Explain what you mean by peer review in the text that will accompany this guideline 2/20/2020 10:54 AM

10 We need to acknowledge there are borderline (indeterminate) cases present. 2/20/2020 8:22 AM

11 I am not sure the term "orthogonal technique" is apt. First of all, many readers will notunderstand it. Secondly, the various tests that can be used are not entirely orthogonal -- theyhave some interdependence. Perhaps the term "alternative technique" or "alternative method"would be a better choice.

2/19/2020 11:25 PM

12 Or additional biopsy obtained. Proper FFPE fixation often overcomes technical problems. 2/19/2020 7:07 PM

13 Please define robust and give examples of acceptable peer review process. 2/19/2020 2:45 PM

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61.04% 47

6.49% 5

15.58% 12

16.88% 13

Q11 Good Practice Statement 3Clonal loss:In the event of a clonal loss byMMR IHC, pathologists should perform MSI by PCR specifically in a

dissected area of tumor that has IHC loss of MMR deficiency.Clonal lossis defined as a complete loss of MMR protein in tumor cells with adjacentnormal cells having intact expression. Adjacent areas of tumor have intact

expression of MMR protein.Answered: 77 Skipped: 86

TOTAL 77

Agree aswritten



Neutral

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Agree as written



Neutral

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# COMMENTS DATE

1 Ridiculous recommendation. Poor fixation frequently results in loss of MMR IHC staining. Also,it is totally impractical to microdissect these areas for MSI.

2/29/2020 1:01 AM

2 Once again, is assuming all platforms for testing are in the same lab. Not so in some centres 2/24/2020 11:38 PM

3 shouldn't this read "subclonal loss"? there is no great data to suggest that a subclonal patternwill predict response. Why is PCR necessary in this setting?

2/22/2020 8:06 AM

4 MSI by PCR in dissected area IF FEASIBLE. 2/21/2020 2:23 PM

5 MSI by PCR or by NGS validated assay 2/21/2020 7:07 AM

6 There is no evidence on how cancers with clonal loss will respond to ICI treatment. 2/20/2020 9:32 PM

7 I am not whether this is necessary. If IHC is negative, that is considered a positive result. Thisrecommendation appears contradictory to Statement 1. In addition, the phrase "adjacentnormal cells" appear to indicate "adjacent tumor cells".

2/20/2020 6:44 PM

8 Would include MSI by NGS as an equally good approach to determining whether clonal loss isclinically relevant.

2/20/2020 3:31 PM

9 Seems like a dumb recommendation. Has anyone showed that this is valid or has ever beenvalid, just in one case?

2/20/2020 2:14 PM

10 MSI can already be detected by PCR if normal tissue is also present. 2/20/2020 2:10 PM

11 why do you use the word clonal, do you mean subclonal or focal? What is the evidence that ptsw focal loss of a MMR protein benefit from IO Rx?

2/20/2020 10:54 AM

12 Consider alternative approach for those cases with insufficient tumor tissue for further testing. 2/20/2020 10:36 AM

13 When there is no normal tissue present, performing PCR is a problem 2/20/2020 8:22 AM

14 i don't know if this is practical, especially with the variable sensitivity of some of the MMRantibodies.

2/20/2020 8:04 AM

15 Difficult to perform in all labs 2/20/2020 2:43 AM

16 What are the implications of clonal loss? Generally not Lynch and perhaps not eligibility forimmune drugs. More details and support needed for this statement

2/19/2020 7:07 PM

17 This statement is unnecessary because according to good practice 1, a tumor is to beconsidered MMR deficient if either the IHC, PCR, or NGS are abnormal. In this specificscenario, the IHC is abnormal within the clonal area and thus should be considered MMR-deficient in the clone. I would suggest that clonal loss should be considered MMR-deficient forcheckpoint blockade purposes but should be considered somatic for Lynch Syndromescreening purposes.

2/19/2020 2:52 PM

18 We do not perform the MSI by PCR in house so the extent of any macro dissection is out of myhands. I can not assure that the reference labs will be doing this so I would Like that removefrom the statement. I have ordered MSI by PCR on these clinal loss cases and resulted a MSIhigh based on bulk tumor.

2/19/2020 2:45 PM

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60.00% 45

38.67% 29

1.33% 1

Q12 How feasible is it to implement this guideline?Answered: 75 Skipped: 88

TOTAL 75

# COMMENTS ABOUT THE FEASIBILITY OF IMPLEMENTING THE GUIDELINE: DATE

1 It gives options regarding choice of test; seems feasible to me 3/3/2020 9:46 PM

2 As this becomes essentially SOC, most if not all labs will have the capability to test via IHC andPCR at the very least

2/28/2020 1:18 PM

3 It should be feasible. There will likely remain hindrance to the clinician of noncolorectal/GE/endometrial patients who need this testing done more routinely

2/28/2020 9:11 AM

4 Availability and funding of testing beyond MMR IHC will be problematic in some systems, I amsure.

2/22/2020 9:36 AM

5 Most laboratories have no problem in performing IHC. PCR or NGS based testing can be aproblem - it is costly, not widely available, and has a longer turnaround time. Therecommendations puts all burdens on pathologists. The biggest challenge for a pathologist ishow to identify "patients being considered for checkpoint blockade therapy". This is notaddressed in the recommendation.

2/20/2020 6:52 PM

6 In a discordant there should be a Reference Laboratory, to confirm the results. It is preferablyone per country that could do this test to solve difficult cases. That remains to be defined byeach country. It is necessary to have external quality evaluation surveys and peer comparisonfor this relative new testing

2/20/2020 9:24 AM

7 Depends on easy access to this testing specially in countries like ours( India) 2/20/2020 5:11 AM

8 I do not think that good practice #3 is necessary 2/19/2020 2:53 PM

All of it isfeasible to...

Parts of itare feasible...

None of it isfeasible to...

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%


All of it is feasible to implement.

Parts of it are feasible to implement.

None of it is feasible to implement.

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36.51% 23

12.70% 8

22.22% 14

9.52% 6

15.87% 10

9.52% 6

28.57% 18

7.94% 5

22.22% 14

Q13 What barriers might impede adoption of the final guideline? (Chooseall that apply.)



Disagreementwith the dra...

Disagreementwith how the...

Too burdensome

Lack ofsupport from...



Lack ofresources...

Do not wish togive up...


0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%


Disagreement with the draft recommendations

Disagreement with how the guideline was developed

Too burdensome

Lack of support from administration

Lack of support from other members of the medical team

Lack of support from the community (others outside your institution e.g., patients, industry)

Lack of resources (funding)

Do not wish to give up personal autonomy to follow the guideline


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1 Insufficient tumor amounts in what will likely be a population made up predominantly ofbiopsies.

3/2/2020 9:13 PM

2 Recommendation by NCCN and/or ASCO. 2/25/2020 6:17 PM

3 Lack of resources for NGS based testing of MSI status because of increased cost and TAT 2/24/2020 1:23 PM

4 Insurance coverage policies need to be rewritten 2/24/2020 10:33 AM

5 Lack of literature evidence to support recommendations. 2/22/2020 10:10 AM

6 NA 2/21/2020 7:42 AM

7 Overall, I agree with the guidelines and think they should be implemented. I am not convincedMSI is better than MMR IHC for the non-CRC, endometrial, etc cancer types

2/21/2020 7:38 AM

8 Need clarification on the when and which sample (biopsy vs resection )needs testing 2/20/2020 7:55 PM

9 Insurance (incl. medicare) coverage can be a problem. 2/20/2020 6:52 PM

10 lack of available tissue is an issue 2/20/2020 10:54 AM

11 Standarization is an issue, and not all PCR are equal in preformance. Avalable Referencelaboratories in every region are necessary for some cases

2/20/2020 9:24 AM

12 As pathologists, we must embrace changes and replacement of methods for what we dosometimes.

2/20/2020 8:12 AM

13 Clinicians want MMR IHC performed on cell blocks from pancreatic fine needle aspirations.Evidence for this practice is scant and predominantly presented as abstracts from the 2019American Society of Cytopathology. This topic needs to be addressed.

2/20/2020 8:03 AM

14 The community pathology labs performing MMR IHC will have difficulty ensuring all of thesestatements CNA be enacted. Also, it is not our responsibility to know which patients are beingconsidered for immunotherapy. We really cannot be held responsible for an oncologist orderingan NGS test for a commercial lab and then being expected to work up results in our communitylabs. This burden should fall on the NGS and molecular labs performing the actual assays.

2/19/2020 2:50 PM

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49.32% 36

27.40% 20

24.66% 18

38.36% 28

53.42% 39

23.29% 17

8.22% 6

Q14 What facilitators might assist in your adoption of the final guideline?(Please select your top 3 facilitators.)



If leaders ofthe medical...

If there weretools to hel...

If we areforced to...

If we findthat peer...

If othertrusted...

If we know andtrust the...


0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%


If leaders of the medical staff discussed adoption/adaption of the guideline for our practice setting

If there were tools to help implement the guideline

If we are forced to comply with the guideline by administration or an accreditation body

If we find that peer institutions/practices adopt the guideline

If other trusted organizations endorse the guideline

If we know and trust the members of the panel members and/or organizations who developed the guideline


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1 Need Medicare approval, otherwise no traction in the market to implement therecommendations.

2/29/2020 1:02 AM

2 Need to get NCCN/ASCO to endorse guideline as improved testing (IHC and PCR according toEU guideline) is focussed on gaining access to life saving treatment for their pateints

2/24/2020 10:33 AM

3 If the panel can provide evidence for their recommendations, or if there is prospective clinicalevidence to show how different analytical methods ultimately impact patient care throughclinical trials.

2/22/2020 10:10 AM

4 Improved method to detect MSI 2/20/2020 2:37 PM

5 Due to clinician demand for MMR testing on cytology specimens, a comment from theAmerican Society of Cytopathology is needed.

2/20/2020 8:03 AM

6 Billable CPT codes for review of outside lab results or QA of outside molecular test results. 2/19/2020 2:50 PM

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Q15 Please provide any general comments or concerns in the spacebelow:


# RESPONSES DATE

1 I suspect that centers that already rely on a well-validated NGS assay for MSI detection will bereluctant to adopt the recommendations as written, as they feel like a step backwards,particularly for non-CRC indications. NGS should be generally given equal footing as IHC andPCR, with an emphasis that orthogonal testing is warranted in unusual or difficult to interpretcontexts.

2/22/2020 8:09 AM

2 I appreciate all of the time invested by the members in developing these guidelines and believethey will improve patient care. There is confusion currently regarding MMR IHC versus MSItesting for immune checkpoint inhibitors.

2/21/2020 7:38 AM

3 Not sure how the panel members are chosen. The recommendation is mostly for GI tumors, Idon't see many GI pathologists in the panel.

2/20/2020 6:52 PM

4 thank you for drafting this guidance 2/20/2020 10:54 AM

5 Its going to difficult to give IHC and PCR a primary role when the clinicians are clamoring forNGS and accept the results fairly uncritically.

2/20/2020 8:07 AM

6 Please address the use of cell blocks for MMR testing. 2/20/2020 8:03 AM

7 Nicely done! Very clear. 2/19/2020 11:26 PM

8 Nice work ! 2/19/2020 3:21 PM

9 Thanks for doing this 2/19/2020 2:50 PM

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