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

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DK37
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Immunotherapy Suggestion: Add MSI/MSS Status to Your Signature Line (Explained)

Postby DK37 » Tue Sep 08, 2015 1:24 pm

Hi Everyone,

I sometimes get asked by fellow Stage IV patients questions on the science of clinical trial possibilities. The very first question I always ask back is “Do you know if you are MSI-high or MSS?”.

I ask this because of the ASCO-2015 presentation and New England Journal of Medicine (NEJM) article (here: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1500596 ) which show a very significant effect of this “MSI biomarker” on response to the hottest current immunotherapy drug class, “PD-1 inhibitors”, in this case the drug “pembrolizumab (Keytruda)”. Scientifically it makes a lot of sense that MSI-high would be more likely to respond to this class of drugs. It was great to see this shown in preliminary trial data, I think there is a high chance that it will be confirmed in larger trials. There are multiple PD-1 (and closely related PD-L1) inhibitors in clinical trials. In other cancer types, the various inhibitors of this class have shown relatively similar efficacy profiles so far, although this remains to be seen in published MSI-CRC trials.

PD-1 inhibition in other cancer types has generated very long term remissions and stable disease (years!) in some patients. Although it remains to be seen if this will be the case in MSI-CRC, the very plausible scientific possibility of this happening makes exploring the possibility of a PD-1 inhibitor therapy a very important discussion to have with your MD if you are MSI-high. If you don’t know if you are… by the same sentiment, it makes finding out your MSI-status a key goal. I recommend printing out the above NEJM paper to discuss with your MD getting the test done. It is a test your MD can order if tissue sample is available.

If you are MSI-high, the strategic timing of when to switch to some sort of anti-PD-1 therapy is a decision you individually need to make with your MD. There is a chance that taking a PD-1 inhibitor now may preclude you from future combination clinical trials. There are currently multiple clinical trials open. I also personally know a MSI-CRC patient who was not able to travel to a trial but she is getting a PD-1 inhibitor right now from the drug company via “compassionate use”.

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… I'll update mine today :) As I posted in May – I personally believe this is the highest impact new therapy to hit CRC in many years. I personally know multiple MSI-high patients responding to it.

Cheers,
-DK
6/4/2012 Dx Stage 3C CRC @ 40 yo. MSS, KRAS-WT, BRAF-WT, p53-mut
7/12 FOLFOX/FOLFIRI
2/13 NED!
8/13 Enlarged lymphs - Stable
10/14 Stage IV. Lung & Lymph mets. 5-FU+bev
3/15 Cetuximab
11/15 FOLFIRI + bev
11/16 Signs of FOLFIRI resistance (Lymph mets)
1/17 Palliative radiation for resistant mets
2/17 FOLFIRI + bev + Maraviroc (off-label)
3/17 FOLFIRI + Erbitux + Maraviroc (off-label)
MSS-CRC Clinical Trial Finder: http://trialfinder.fightcrc.org/
2016 Colondar 2.0 Model
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DK37
Posts: 510
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Location: San Diego

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

Postby DK37 » Tue Sep 08, 2015 1:34 pm

Here is the exact definition from the New England Journal of Medicine article which published the study: "The size in bases was determined for each microsatellite locus and tumors were designated as MSI if two or more mononucleotide loci varied in length compared to the germline DNA"

That is the definition from the study you can ask your MD, or better yet a genetics counselor if you have one available at your care facility (they are common place at cancer centers and major hospitals now) about. "MSI" under the above definition is the group with a high response rate to Keytruda in the study.

-DK
6/4/2012 Dx Stage 3C CRC @ 40 yo. MSS, KRAS-WT, BRAF-WT, p53-mut
7/12 FOLFOX/FOLFIRI
2/13 NED!
8/13 Enlarged lymphs - Stable
10/14 Stage IV. Lung & Lymph mets. 5-FU+bev
3/15 Cetuximab
11/15 FOLFIRI + bev
11/16 Signs of FOLFIRI resistance (Lymph mets)
1/17 Palliative radiation for resistant mets
2/17 FOLFIRI + bev + Maraviroc (off-label)
3/17 FOLFIRI + Erbitux + Maraviroc (off-label)
MSS-CRC Clinical Trial Finder: http://trialfinder.fightcrc.org/
2016 Colondar 2.0 Model
DK37 Science Posts List

ieowi
Posts: 202
Joined: Mon Jul 27, 2015 1:27 am

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

Postby ieowi » Tue Sep 08, 2015 1:49 pm

Thank you DK37 . I wonder how MSI-low patient will respond to these new immunotherapy drugs. I Already have my father status in the signature :wink:
Father 58 yo , Colon cancer IV + 4 Lymph. 7/2015
K-ras Mutant,GNAS,FBXW7,PIK3CA, MSI-low
4 cycles irinotecan+FU5
developed abdominal met + lung met...Failed
4 cycle Oxaliplatin+folfox. peri met growing...Failed
unofficial trial !!!

stevieb
Posts: 401
Joined: Sat Feb 09, 2013 12:26 am

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

Postby stevieb » Tue Sep 08, 2015 2:37 pm

Anything for MSI- Low people?
Dx age 33
12/19/12 Stage IV liver/lung
1/14-2/28/13 Folfox
3/27/13 rectal/lung rst; temp ileo
7/11/13 liver res/ileo rev
9/30/13 - Folfox
11/13,2/21 NED
3/14 lung recur;6/16-VATS
7/14 5 bi lung mets
10&11/15 laser lung surg
2015 Colondar Model
12/15 5 lung met-folfiri
5/15 NED
11/15 2 lung mets; cryoablation
1/4/17 2 lung mets; cryoablation
NED as of 1/23/17

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DK37
Posts: 510
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Location: San Diego

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

Postby DK37 » Tue Sep 08, 2015 3:07 pm

stevieb wrote:Anything for MSI- Low people?


I am far from an expert on genetics, so with that being said... it isn't clear to me from the NEJM paper if they did any further analysis beyond the "2 bins of patient types" they present in the paper. That is a great question for a genetic counselor (ideally) or your MD. In terms of non-MSI-high patients, alternative immunotherapy agents and PD-1 combo clinical trials are in progress, crossing fingers that at least one of them finds the trick needed for non-MSI-high folks to see responses!

-DK
6/4/2012 Dx Stage 3C CRC @ 40 yo. MSS, KRAS-WT, BRAF-WT, p53-mut
7/12 FOLFOX/FOLFIRI
2/13 NED!
8/13 Enlarged lymphs - Stable
10/14 Stage IV. Lung & Lymph mets. 5-FU+bev
3/15 Cetuximab
11/15 FOLFIRI + bev
11/16 Signs of FOLFIRI resistance (Lymph mets)
1/17 Palliative radiation for resistant mets
2/17 FOLFIRI + bev + Maraviroc (off-label)
3/17 FOLFIRI + Erbitux + Maraviroc (off-label)
MSS-CRC Clinical Trial Finder: http://trialfinder.fightcrc.org/
2016 Colondar 2.0 Model
DK37 Science Posts List

jortego128
Posts: 286
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Re: Immunotherapy Suggestion: Add MSI/MSS Status to Your Signature Line (Explained)

Postby jortego128 » Tue Sep 08, 2015 4:06 pm

Thanks for the update and paper DK. We still dont know if my mom is MSI-high or MSS. I plan on taking a vacation day next week to go with my mom for her next infusion, and I will definitely take this paper with me. Even though the chances are low overall, she does share two markers commonly exhibited in MSI-high patients, so we will be testing for it, theres no way I could live with myself if we dont.

A question for you-- I read that MSI-high status is more common in low stage cancers (~20%) and less common in advanced or stage 4 cancers (5%)-- not sure I follow that line of thought-- does that mean that if left to its own devices an MSI-high stage 1 cancer likely will change to MSI-low or MSS over time? Or does it mean that metastases of MSI-high primary cancers are normally not MSI-high? Also, is there a difference between MSI-low and MSS status?

Also, it would be helpful if someone can post their personal experience in getting the test done, for example-- the time it takes, which tissue samples should be used (primary or metastases), the general cost of doing the test, and whether or not most insurances will cover getting it done. If I can get ours done soon, I will definitely share all the above info.
Last edited by jortego128 on Tue Sep 08, 2015 4:12 pm, edited 1 time in total.
DM 57 yrs old dx 6/8/15 T:4a N:1b M:1
KRAS G12D and TP53 C242fs mutations
Poorly Differentiated, Prominent Signet Ring Component(~50%)
Microsatellite Stable, 3 of (13)lymph nodes positive
15 Liver mets, largest 3.2 cm
Prim. Resection, Right Hemicolectomy 6/21/15
Start Chemo 7/20/15
2 rounds FOLFOX, 1 round FOLFOX +Avastin
CT 8/28/15, met growth, largest 4.5cm
4 rounds FOLFOX+Avastin
CT 11/06/15 mets stable, lungs clear
Begin FOLFIRI+Avastin 11/17/15, Stop chemo 1/26/16
Entered Paradise 3/11/2016

jortego128
Posts: 286
Joined: Sat Aug 15, 2015 7:47 am

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

Postby jortego128 » Tue Sep 08, 2015 4:11 pm

jortego128 wrote:...
DM 57 yrs old dx 6/8/15 T:4a N:1b M:1
KRAS G12D and TP53 C242fs mutations
Poorly Differentiated, Prominent Signet Ring Component(~50%)
Microsatellite Stable, 3 of (13)lymph nodes positive
15 Liver mets, largest 3.2 cm
Prim. Resection, Right Hemicolectomy 6/21/15
Start Chemo 7/20/15
2 rounds FOLFOX, 1 round FOLFOX +Avastin
CT 8/28/15, met growth, largest 4.5cm
4 rounds FOLFOX+Avastin
CT 11/06/15 mets stable, lungs clear
Begin FOLFIRI+Avastin 11/17/15, Stop chemo 1/26/16
Entered Paradise 3/11/2016

cathy123
Posts: 665
Joined: Sat Nov 08, 2014 3:36 pm

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

Postby cathy123 » Tue Sep 08, 2015 4:36 pm

They did msi testing on my colonoscopy biopsy sample. If it was high they were going to do a hysterectomy since it was possible I had lynch but mine was msi stable (which I think is the same as low?). Results took less than a week.
Cathy

Diagnosed 10/14 low rectal cancer age 43
Clinical T2NXMX
Radiation/xeloda 12/14-1/15
LAR with temp Ileo 3/15
pT2N0M0, lymphatic invasion 0/37 nodes
4 xelox, 1 xeloda only
Reversal 9/15
Mom to 9&11 year olds

cathy123
Posts: 665
Joined: Sat Nov 08, 2014 3:36 pm

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

Postby cathy123 » Tue Sep 08, 2015 4:38 pm

Also - I could be wrong but I think the reason msi high tend to be lower stages is that those cancers are less aggressive and less likely to spread.
Cathy

Diagnosed 10/14 low rectal cancer age 43
Clinical T2NXMX
Radiation/xeloda 12/14-1/15
LAR with temp Ileo 3/15
pT2N0M0, lymphatic invasion 0/37 nodes
4 xelox, 1 xeloda only
Reversal 9/15
Mom to 9&11 year olds

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DK37
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Location: San Diego

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

Postby DK37 » Tue Sep 08, 2015 5:30 pm

jortego128 wrote:
A question for you-- I read that MSI-high status is more common in low stage cancers (~20%) and less common in advanced or stage 4 cancers (5%)-- not sure I follow that line of thought-- does that mean that if left to its own devices an MSI-high stage 1 cancer likely will change to MSI-low or MSS over time? Or does it mean that metastases of MSI-high primary cancers are normally not MSI-high? Also, is there a difference between MSI-low and MSS status?
.


If someone knows the answer definitively - jump in (and I'll edit my response to correct if necessary) but my limited understanding:
- I have not heard of a cancer changing to MSI to MSS overtime, Scientifically that feels unlikely to me. Likewise, I assume that a MSI-high primary causes MSI-high mets. I think there is another explanation for the demographic differences in terms of stage of diagnosis.

- From my reading there are three classifications: "MSI-high" its opposite "MSS" and "MSI-low" is "in-between" these two groups (it is people with only 1 out of 5 markers of microsatellite) - hyperlink to reference & pasted section below.
In the NEJM article I did not see them discuss where MSI-low patients fit into their analysis.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1867601/

Pasted quote from the above ref: "In an attempt to standardize MSI analysis, a 1997 National Cancer Institute (NCI) workshop recommended a “reference panel” of five microsatellite markers for the detection of MSI and established MSI classification guidelines based on the results.14 The reference panel, referred to as the Bethesda panel, consists of two mononucleotide loci (Big Adenine Tract [BAT]-25and BAT-26) and three dinucleotide loci (D2S123, D5S346, and D17S250)... Using the Bethesda panel, cancers with instability at two or more of these loci were interpreted as MSI-high, and cancers with no instability at any of the five loci were considered MSS. Cancers showing instability at only one of the five recommended loci were interpreted as MSI-low, although it was unclear at the time whether MSI-low represented a biologically distinct category or whether this simply reflected the inherent limitations of faithfully replicating these repetitive sequences."

-DK
6/4/2012 Dx Stage 3C CRC @ 40 yo. MSS, KRAS-WT, BRAF-WT, p53-mut
7/12 FOLFOX/FOLFIRI
2/13 NED!
8/13 Enlarged lymphs - Stable
10/14 Stage IV. Lung & Lymph mets. 5-FU+bev
3/15 Cetuximab
11/15 FOLFIRI + bev
11/16 Signs of FOLFIRI resistance (Lymph mets)
1/17 Palliative radiation for resistant mets
2/17 FOLFIRI + bev + Maraviroc (off-label)
3/17 FOLFIRI + Erbitux + Maraviroc (off-label)
MSS-CRC Clinical Trial Finder: http://trialfinder.fightcrc.org/
2016 Colondar 2.0 Model
DK37 Science Posts List

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

Postby NateA » Wed Sep 09, 2015 8:50 pm

I read the article, and if I understand what I read, I'm liking this. Does this mean long chemo breaks? Also, did I read a stage 2 study? How many study stages does a drug go through, and how long, generally, is a stage of study? I'm going to ask my doctor to pull this marker sample at my 6 month CT.
7/15 dx CC stage 4 with lots of liver mets CEA 208
KRAS Mutant G12V, MSS.
9/23 from folfoxiri to folfox and Xeloda. CEA 25
11/11/15 all liver markers in the zone, CEA 4.0, moving to Avastin/xeloda for now..tumors shrinking
01/13/16 Avastin/xeloda CEA 3.5
03/11/16 clean PET CEA 4.4

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DK37
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Re: Immunotherapy Suggestion: Add MSI/MSS Status to Your Signature Line (Explained)

Postby DK37 » Thu Sep 10, 2015 12:15 am

NateA wrote:I read the article, and if I understand what I read, I'm liking this. Does this mean long chemo breaks? Also, did I read a stage 2 study? How many study stages does a drug go through, and how long, generally, is a stage of study? I'm going to ask my doctor to pull this marker sample at my 6 month CT.


The "goal" is to have these new immunotherapies replace chemo as much as possible. This class of drugs is already approved for lung cancer and melanoma - CRC trials are at the Phase 1 & 2 stage. Historically 3 phases of testing were required for drugs before FDA approval. In recent years, for cancer drugs the FDA has been approving drugs off of Phase 2 testing data if the data looked really strong. For lung cancer, the FDA approved this drug class *4 days* after the application was submitted it was such a groundbreaking advance. If the MSI-CRC data continues to look strong, I think there is a good chance it will also be approved quickly on Phase 2 data.

Trials aside, since already approved for other cancer types, if anyone is MSI-high and if it is hard for them to get to a trial site (e.g. due to geography), "compassionate use" may be possible to get the drug outside of a formal trial.

-DK
6/4/2012 Dx Stage 3C CRC @ 40 yo. MSS, KRAS-WT, BRAF-WT, p53-mut
7/12 FOLFOX/FOLFIRI
2/13 NED!
8/13 Enlarged lymphs - Stable
10/14 Stage IV. Lung & Lymph mets. 5-FU+bev
3/15 Cetuximab
11/15 FOLFIRI + bev
11/16 Signs of FOLFIRI resistance (Lymph mets)
1/17 Palliative radiation for resistant mets
2/17 FOLFIRI + bev + Maraviroc (off-label)
3/17 FOLFIRI + Erbitux + Maraviroc (off-label)
MSS-CRC Clinical Trial Finder: http://trialfinder.fightcrc.org/
2016 Colondar 2.0 Model
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Nik Colon
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Re: Immunotherapy Suggestion: Add MSI/MSS Status to Your Signature Line (Explained)

Postby Nik Colon » Thu Sep 10, 2015 12:51 am

Thanks again for the info DK

Also, where would I find that info for me, I never noticed it or missed it
KRAS-mut G12V,MSS
Stage IVa Sig CC 2 lvr mets 1/12 Ln
(3, =<3 lng spots at dx til 5/16)
=T3N1aM1a 4cmX4mm (lng not included)
dx 12/2014 at age 39
CEA 1/15-4.9, 12/16-4.9 again
neoadj FOLFOX 1/15-3/15 (4tx, 3w/1wo oxi)
Col/Lvr surg 4/23/15 NED
adj FOLFIRI start 6/15-9/15 (8tx, 5w/3wo iri)
1 sml lvr spot/cyst
12/6/16 multi lung spots/mets?
No longer NED :(
My tx ongoing-start 1/20/15
Adding your SIGNATURE, etc

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

Postby midlifemom » Thu Sep 10, 2015 5:50 am

ritz75 wrote:Thanks again for the info DK

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


Nik,
I searched through all my pathology reports and couldn't find it either. Saw my local onc yesterday so asked him. It seems (not sure), that MSKCC had requested this study BUTT we never heard the results. Trying to track them down now. Soo, if you can't find, try calling your onc office.
Stage 3 cc - dx Jan '14 age 53, cea 2.9
t2n2m0, KRAS mutant, MSS
Folfox Feb - Aug '14
Nov '14 cea 27.7 -2 liver masses
Dec '14 left lobectomy and HAI
Jan '15 FUDR and FOLFIRI
Aug '15 fudr done, liver clear, add avastin for lungs. Cea 4.3
Feb '16 CEA rising
May '16 2 wk break then drop Iri for 6 weeks.
Jul '16 cancer grew, constricted main bile duct. Stent inserted. On break till jaundice clears. CEA climbing. Doing reduced Folfox. Allergic to Oxali.
Sep'16 chemo failed. Trial or hospice?

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DK37
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Re: Immunotherapy Suggestion: Add MSI/MSS Status to Your Signature Line (Explained)

Postby DK37 » Thu Sep 10, 2015 8:12 am

ritz75 wrote: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
6/4/2012 Dx Stage 3C CRC @ 40 yo. MSS, KRAS-WT, BRAF-WT, p53-mut
7/12 FOLFOX/FOLFIRI
2/13 NED!
8/13 Enlarged lymphs - Stable
10/14 Stage IV. Lung & Lymph mets. 5-FU+bev
3/15 Cetuximab
11/15 FOLFIRI + bev
11/16 Signs of FOLFIRI resistance (Lymph mets)
1/17 Palliative radiation for resistant mets
2/17 FOLFIRI + bev + Maraviroc (off-label)
3/17 FOLFIRI + Erbitux + Maraviroc (off-label)
MSS-CRC Clinical Trial Finder: http://trialfinder.fightcrc.org/
2016 Colondar 2.0 Model
DK37 Science Posts List


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