Immunotherapy Suggestion: Add MSI/MSS Status to Your Signature Line (Explained)

[bitchslapped]

I suggested to put your MSI-status in your signature line as an easy reminder to find out the data if you don’t know the answer yet…

Once again, great info, great suggestion!

BS

[Nik Colon]

Thank u guys

[jortego128]

Ive been doing some research on MSI/MSS status and thought it would be helpful to have a checklist of histologic features commonly associated with MSI-high status. This can be really helpful if someone does not know their status or it wasnt tested for-- if that is the case and you have some of the histologic features listed below, it may be prudent to get the test done because as DK has informed, MSI-high cancers are more responsive to some of the newer immunotherapy drugs than MSI-low or MSS cancers. I came across some really good info at the Stanford University Pathology webpage, which is has been copied and pasted below:

"The following features are suggestive of microsatellite instability and/or hereditary non-polyposis colorectal carcinoma syndrome (HNPCC) but may also be seen in a subset of sporadic adenocarcinomas.

Intraepithelial lymphocytes, ≥3 per HPF
Crohn-like response at edge of carcinoma
Lymphoid aggregates / follicles with or without germinal centers not associated with a lymph node
Mucinous or signet ring carcinoma component
Medullary carcinoma

Less specific criteria:
Right side location
High grade histology (poorly differentiated)
Lack of dirty necrosis

Sporadic carcinomas with these features are frequently MSI high. Such carcinomas share essentially all histologic features with HNPCC tumors. May be present in 15% of colorectal adenocarcinomas.

Familial and sporadic cases share some other clinical features:
Better prognosis than non-MSI carcinomas
Decreased response to 5-FU therapy
Right sided predominance"

DK-- perhaps it would be helpful to update your first post of this thread with this info.

[jortego128]

The above list has really got me to thinking theres a good chance my mom is either MSI-high or HNPCC (or both), because I have her pathology report in front of me and it has the following:

Right Side Location
Histologic Grade: High Grade (Poorly Differentiated)
Histologic Type: Adenocarcinoma with Prominent Signet Ring Component (~50%)

Before, I wasnt aware that a signet ring component was associated with MSI-high status. Thats now a 3rd histologic feature she shares with MSI-high patients. We are definitely getting the test done now, and if they claim its been done already and she is MSS, I will demand to see it myself. Maybe Im wrong and the Onc is way ahead of me on this, but Im really starting to doubt that. If it turns out the test wasnt done, and she is found to be MSI-high after we do have the test done, I will be thankful (to DK for educating me on this), hopeful/excited (for the possibility of a better treatment), and very angry (that if I hadnt brought it up, it may never have been even thought about).

I dont want to get ahead of myself though, as all this may just be wishful thinking on my part. Im praying that its more than that though.

[DK37]

DK-- perhaps it would be helpful to update your first post of this thread with this info.

Will do - thanks Jortego!
-DK

[Nik Colon]

Thanks again for the info DK

Also, where would I find that info for me, I never noticed it or missed it

If it isn't in your path report Nik, ask your doctor if he/she has the info somewhere else in your files. If not, ask about having the test done (it can be done off of archived samples in your pathology dept if they exist). Here is a journal article abstract to print out and bring with you to the Onc appt: http://www.nejm.org/doi/full/10.1056/NEJMoa1500596

-DK

I will have to look more, but info I got from current place said I would have to get records from previous. Info I got was (my notes of what she said)

KRAS positive
Mismatch repair protein Normal (no lynch)
All 4 expressed
MSI not tested (will test if lynch)?

She was just reading the notes as she wasn't sure what I meant when I called, I told her microsatalite instability and this is some of what she read to me, I may be misquoting, but from what she said o got that they didn't test MSI because my genetic consult showed most likely no lynch so they didn't do the extra testing. All I remember is them saying they did some tests right away and had me see the genetic counselor after which she said I didn't have much history so didn't do more testing. I am still going to see if I can find the original tho for all info and tests that were done.

Does this sound right?

And what does KRAS positive mean? I have heard wild but not sure what just saying positive means

[DK37]

I will have to look more, but info I got from current place said I would have to get records from previous. Info I got was (my notes of what she said)

KRAS positive
Mismatch repair protein Normal (no lynch)
All 4 expressed
MSI not tested (will test if lynch)?

And what does KRAS positive mean? I have heard wild but not sure what just saying positive means

Hi Nik,
I think you need a follow-up in person discussion with your MD to discuss/make more clear. I hate hearing docs say "KRAS positive" because no scientists would ever say that - it is ambiguous. They have the info, just confirm if they meant "KRAS-wild type" or "KRAS-mutated" - for completeness sake, if mutated, you can ask for what the mutation was (should be a number/letter mix like "G12D" or similar).

Re: MSI - I would ask for more clear confirmation explanation of what exactly they have done, with a 1 page copy of this paper in your hand: http://www.nejm.org/doi/full/10.1056/NEJMoa1500596 showing why you consider finding out if you are MSI-high such important info.

-DK

[Nik Colon]

I will have to look more, but info I got from current place said I would have to get records from previous. Info I got was (my notes of what she said)

KRAS positive
Mismatch repair protein Normal (no lynch)
All 4 expressed
MSI not tested (will test if lynch)?

And what does KRAS positive mean? I have heard wild but not sure what just saying positive means

Hi Nik,
I think you need a follow-up in person discussion with your MD to discuss/make more clear. I hate hearing docs say "KRAS positive" because no scientists would ever say that - it is ambiguous. They have the info, just confirm if they meant "KRAS-wild type" or "KRAS-mutated" - for completeness sake, if mutated, you can ask for what the mutation was (should be a number/letter mix like "G12D" or similar).

Re: MSI - I would ask for more clear confirmation explanation of what exactly they have done, with a 1 page copy of this paper in your hand: http://www.nejm.org/doi/full/10.1056/NEJMoa1500596 showing why you consider finding out if you are MSI-high such important info.

-DK

Thanks DK, will get info

[DH2Sleen]

So Tom, can you confirm one of the things in the paper you linked for Niki.

In our discussion with one of the research fellows at NIH, he said that since Sleen only has 62 mutations, she would be MSS (even though they didn't specifically test for MMR). He said that MSI tumors typically have hundreds of mutations and that makes them easier targets for immunotherapy. The paper noted that the MSI cohort had over 1700 mutations and the MSS cohort had less than 100.

So for those who do not have their MMR/MSI status, but do have genome mutation results, would you say that the number of mutations would be a good guide?

[DK37]

So Tom, can you confirm one of the things in the paper you linked for Niki.

In our discussion with one of the research fellows at NIH, he said that since Sleen only has 62 mutations, she would be MSS (even though they didn't specifically test for MMR). He said that MSI tumors typically have hundreds of mutations and that makes them easier targets for immunotherapy. The paper noted that the MSI cohort had over 1700 mutations and the MSS cohort had less than 100.

So for those who do not have their MMR/MSI status, but do have genome mutation results, would you say that the number of mutations would be a good guide?

Good question - I think it could be a rough guide indeed. On a practical level however you would need Whole Exome Sequencing (WES) of the tumor ( https://en.wikipedia.org/wiki/Exome_sequencing ) to get the number of mutations - and that test is both harder to get & more expensive than the MSI test - so on a practical level, MSI testing should normally be an "easier" way to go for most patients...

Great question!

-DK

[jortego128]

Well, after I had my mom suggest to the oncs a couple rounds ago, they had the path lab run the test. Much to my dismay, the test came back:

"DNA mismatch repair enzymes intact (normal protein expression), Microsatellite Stable (MSS) by PCR"

"NO NRAS or BRAF mutation was detected"

"KRAS G12D and TP53 C242fs mutations were detected"

She has 3 markers and a family history of cancer, just not in the colon, so I had legitimate reason to be hopeful I think. The news was crushing to me. Opposite of good, from what I gather, prominent signet ring component, if NOT MSI-high, is actually bad and indicates a more aggressive cancer/worse prognosis.

Her CEA also went up from the 30s to the 40s from last round. The round before that it had decreased from the 40s to the 30s. CT scan done prior to 4th round (about a month ago) showed significant tumor growth compared to original June scan. She did have to wait about a month and a half to start chemo after the first scan due to the primary resection, Im hoping most of the growth can be attributed to that.

Does anyone have any info on the KRAS and TP53 mutations detected? The report indicated there may be investigational therapies to target these. I understand the KRAS is associated with decreased response to EFGR targetting mabs. I guess this means cetuximab is out? Does this also mean decreased response to Avastin?

-Josh

[GrouseMan]

No - This doesn't mean that Avastin is off the table. It's an anti-angiogenesis MAB. It prevents tumors from recruiting a blood supply and starts to starve them of nutrients, puts them into more stress, and hopefully push them into apoptosis. In combo with FOLFOX or simply 5-FU it seems to be holding my wife's met's at bay.

I hope you manage to find a successful plan of attack.

GrouseMan

[DK37]

Sorry to hear the MSS news Josh - I know you had (histologically appropriate) hopes up...

Maybe one less arrow in the quiver (PD-1 monotherapy) but after the news settles, try to keep up the fighting spirit you've been showing!

-DK

[Steph20021]

DK, I hope there is more for us MSS folk down the line! Thanks for all the great current research and your blog.

[jortego128]

Thanks Grouseman & DK. I knew Avastin was an angiogenesis inhibitor, but for some reason I was thinking the way it worked was related to EFGR. Good to hear its not.