MSI status strangeness

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boddob
Posts: 3
Joined: Sat Jun 05, 2021 2:28 am

MSI status strangeness

Postby boddob » Sat Jun 05, 2021 4:42 am

Hi all,

I firstly wanted to thank the community here. I'm posting for the first time, but I visit frequently to read about your experiences. It's been really helpful to gain knowledge and get some highly needed solidarity.

My dad's a metastatic rectal cancer patient. Chemo was pretty effective in the beginning, but the disease relapsed pretty soon after. Once we had exhausted the standard chemo lines of treatment (FOLFOX/FOLFIRI), we tried Regorafenib/Stivarga, but that hasn't helped stop the progression. Immunotherapy is the obvious next option, for which we need to be certain about his MSI status. We've had conflicting lab results, and we've not been able to get tissue for more testing, so I wanted some help to make help sense of this.

- A MSI test using the IHC technique was done on the tissue collected at the time of the original diagnosis. It reported MSI-H/dMMR, with MLH1, MSH2 and PMS2 markers not expressed, and only MSH6 expressed.
- Since this was a rare result, we sent the same tissue again for a MSI test using PCR. Both tissue and a blood sample were collected here. This reported MSS, with the markers BAT25, BAT26, NR21, NR22 and NR24 detected as stable.
- After this, we exhausted the primary tumor tissue as it seems to have grown inwards (extraluminary regions). The lung (and liver) mets were small and inaccessible, so we couldn't get tissue from those either.
- We'd done a ctDNA blood test, and that also reported MSS. However, I don't know how accurate the ctDNA tests are for assessing MSI status (the variant allele frequency in the blood sample was between 0.5 to 1%)

I had some queries:
- I wanted to know if someone has had a similar experience, i.e, conflicting MSI results?
- From what I've read, IHC looks for the proteins (the phenotype), and PCR/NGS would look at mutations in the gene sequence (genotype). Is it possible that one can be MMR deficient, but have the standard PCR markers stable?
- Any opinion about the case in general?

Our docs say that if we can't get new tissue, we should go by the PCR result as that's more accurate, but I didn't want us to rule out a potential line of treatment without being certain.

Thank you!
Son of (DX 12/19) Male, age 62
Rectal cancer, T3N1M1, 2 liver and ~8 Lung mets
MSI-H (IHC), MSS (PCR), KRAS G12D
12/19 - 04/20: 9 rounds FOLFOX+Avastin : tumor shrinks, no liver/lung mets
05/20 - Radio on rectum tumor + xeloda
07/20 - Reappearance of lung mets, rectum tumor increasing again
07/20 - 6 rounds FOLFIRI+Avastin
11/20 - lung mets and rectum higher activity
12/20 - Regorafenib
06/21 - liver reappearance, lung and rectum higher activity
CEA: 1.5 ~ 3.0 ng/mL
ctDNA shows MSS, KRAS, TP53 and APC

catstaff
Posts: 85
Joined: Wed Mar 03, 2021 11:37 am

Re: MSI status strangeness

Postby catstaff » Sat Jun 05, 2021 7:59 pm

I am not a biochemist but I would go with the PCR also. IHC attempts to detect proteins by using antibodies. But if the antibody is not completely specific to the variant, there could be errors. If they get a good genome sample, however, that should be definitive.

Am I to understand that both folfox and folfiri have failed? Have you looked into clinical trials? There are several trying to apply immunotherapy with something else to make it work for "cold" tumors (which most CRC is).
D/H Dx 10/2019 RC age 61
Clinical T4bN2M1a (common iliac and para-aortic lymph nodes)
MSS KRAS G12D
CRT 11/19-1/20 FOLFOX 3/20-7/20
Pelvic exenteration w/LAR 8/20
ypT4bN0Mx G3 0/14 nodes LVI not seen PNI-
CEA 10/19:20, 1/20-11/20:1.6, 4.3, 3.4, 2.7, 2/21:9.0 3/21:18,40 4/21:28,19, 5/21:13.3,8.6
PET 3/21 recurrence in distal nodes, L5 vertebra, pelvis
FOLFIRI+bev 3/21-

boddob
Posts: 3
Joined: Sat Jun 05, 2021 2:28 am

Re: MSI status strangeness

Postby boddob » Sun Jun 06, 2021 1:44 am

Thanks for the reply catstaff!

I am not a biochemist but I would go with the PCR also. IHC attempts to detect proteins by using antibodies. But if the antibody is not completely specific to the variant, there could be errors. If they get a good genome sample, however, that should be definitive.


Thanks for the details. We've been told to get a tissue from a distant site at some point anyway to do an exhaustive NGS test, so that should more give a more definitive answer. I've read that the TMB result that comes along with the test is helpful to decide if you're a immunotherapy candidate despite being MSS.

Am I to understand that both folfox and folfiri have failed? Have you looked into clinical trials? There are several trying to apply immunotherapy with something else to make it work for "cold" tumors (which most CRC is).


FOLFOX was originally planned for 12 sessions. After a very positive response after the first 9, the docs thought it was a good window to attempt a radiochemotherapy on the primary tumor, followed by surgery. Unfortunately, after the radiochemotherapy, some of the lung mets reappeared, so had to resort back to chemo. FOLFIRI was chosen (6 sessions) because my Dad developed peripheral neuropathy due to Oxaliplatin. That didn't help very much other than probably slowing the rate of progression. We're still collecting opinions, but the rough plan seems to be to attempt a chemo re-challenge (6 sittings). We're going to start considering clinical trials soon. I've read about the trials that combine TKIs with immunotherapy, will consider those. Do you by any chance happen to know whether the upcoming drug by boehringer ingelheim (BI 1701963) is effective? It claims to be a pan-KRAS inhibitor. They have a trial going on, but haven't posted any prelimiary results yet.
Son of (DX 12/19) Male, age 62
Rectal cancer, T3N1M1, 2 liver and ~8 Lung mets
MSI-H (IHC), MSS (PCR), KRAS G12D
12/19 - 04/20: 9 rounds FOLFOX+Avastin : tumor shrinks, no liver/lung mets
05/20 - Radio on rectum tumor + xeloda
07/20 - Reappearance of lung mets, rectum tumor increasing again
07/20 - 6 rounds FOLFIRI+Avastin
11/20 - lung mets and rectum higher activity
12/20 - Regorafenib
06/21 - liver reappearance, lung and rectum higher activity
CEA: 1.5 ~ 3.0 ng/mL
ctDNA shows MSS, KRAS, TP53 and APC

catstaff
Posts: 85
Joined: Wed Mar 03, 2021 11:37 am

Re: MSI status strangeness

Postby catstaff » Sun Jun 06, 2021 6:09 pm

I don't think anything has come out for preliminary results of these pan-KRAS inhibitors. Supposedly they also have specific KRAS inhibitors, as does Mirati, but those are all currently for G12C which is mainly seen in lung cancer, and is fairly rare in colorectal. Mirati supposedly has a G12D one ready to start in trials soon but only at MD Anderson. (My DH is G12D.)
I am also extremely interested in a CXCR2 (chemokine receptor 2) inhibitor+checkpoint inhibitor. Chemokines are known to play a major role in KRAS-mutated cancers in particular.

There is at least one other trial attempting to block two parts of the MAPK signaling pathway (the one KRAS in involved in) -- two paths will have to be blocked with KRAS mutations, one alone won't work. EGFR is part of this signaling pathway but KRAS mutations let it work around EGFR blockade (which is why that category of drugs doesn't work for KRAS mutations).

There are also several vaccine+immunotherapy trials. Cancer vaccines are always five years away from working but we may have more accumulated knowledge now. Both Pfizer and Moderna are working on or have mRNA vaccines for KRAS. There are some virus-based vaccines as well.

KRAS is usually associated with a lower TMB overall for MSS.
D/H Dx 10/2019 RC age 61
Clinical T4bN2M1a (common iliac and para-aortic lymph nodes)
MSS KRAS G12D
CRT 11/19-1/20 FOLFOX 3/20-7/20
Pelvic exenteration w/LAR 8/20
ypT4bN0Mx G3 0/14 nodes LVI not seen PNI-
CEA 10/19:20, 1/20-11/20:1.6, 4.3, 3.4, 2.7, 2/21:9.0 3/21:18,40 4/21:28,19, 5/21:13.3,8.6
PET 3/21 recurrence in distal nodes, L5 vertebra, pelvis
FOLFIRI+bev 3/21-

catstaff
Posts: 85
Joined: Wed Mar 03, 2021 11:37 am

Re: MSI status strangeness

Postby catstaff » Mon Jun 07, 2021 6:44 am

Preliminary results did come out for the Mirati G12C inhibitor. It was pretty effective for NSCLC but not very effective at all on its own for CRC. The company said this was "expected" because CRC is "more biologically complex" than lung cancer. I don't know why that is the case but it's an issue. Maybe more complex immune involvement, perhaps a different cascade of mutations. Also the same mutation can have different effects in different cancers/tissues. Pancreatic is usually adenocarcinoma and is nearly always KRAS mutated (something like 90%) with G12D the most common, but it's still more aggressive than CRC with KRAS G12D.
D/H Dx 10/2019 RC age 61
Clinical T4bN2M1a (common iliac and para-aortic lymph nodes)
MSS KRAS G12D
CRT 11/19-1/20 FOLFOX 3/20-7/20
Pelvic exenteration w/LAR 8/20
ypT4bN0Mx G3 0/14 nodes LVI not seen PNI-
CEA 10/19:20, 1/20-11/20:1.6, 4.3, 3.4, 2.7, 2/21:9.0 3/21:18,40 4/21:28,19, 5/21:13.3,8.6
PET 3/21 recurrence in distal nodes, L5 vertebra, pelvis
FOLFIRI+bev 3/21-

boddob
Posts: 3
Joined: Sat Jun 05, 2021 2:28 am

Re: MSI status strangeness

Postby boddob » Mon Jun 07, 2021 7:50 am

I don't think anything has come out for preliminary results of these pan-KRAS inhibitors. Supposedly they also have specific KRAS inhibitors, as does Mirati, but those are all currently for G12C which is mainly seen in lung cancer, and is fairly rare in colorectal. Mirati supposedly has a G12D one ready to start in trials soon but only at MD Anderson. (My DH is G12D.)
I am also extremely interested in a CXCR2 (chemokine receptor 2) inhibitor+checkpoint inhibitor. Chemokines are known to play a major role in KRAS-mutated cancers in particular.


My dad has the G12D kind too. I wasn't aware of the CXCR2 inhibitor, thanks for sharing that.

There are also several vaccine+immunotherapy trials. Cancer vaccines are always five years away from working but we may have more accumulated knowledge now. Both Pfizer and Moderna are working on or have mRNA vaccines for KRAS. There are some virus-based vaccines as well.

KRAS is usually associated with a lower TMB overall for MSS.


I'd read about the cancer mRNA vaccines. They've been there for a while, but still haven't seen them in use. Maybe the learnings from mRNA vaccines from pandemic would help accelerate their development. I didn't know about KRAS/MSS generally points to a TMB. I suppose getting a NGS test done is still worth it. It might point to some actionable mutation for which there are trials.

Preliminary results did come out for the Mirati G12C inhibitor. It was pretty effective for NSCLC but not very effective at all on its own for CRC. The company said this was "expected" because CRC is "more biologically complex" than lung cancer. I don't know why that is the case but it's an issue. Maybe more complex immune involvement, perhaps a different cascade of mutations. Also the same mutation can have different effects in different cancers/tissues. Pancreatic is usually adenocarcinoma and is nearly always KRAS mutated (something like 90%) with G12D the most common, but it's still more aggressive than CRC with KRAS G12D.


The BI 1701963 (SOS1 + MEK inhibitor) trial page says the primary result comes out later this month. Hope it sheds some light on how effective such drugs could be.
https://clinicaltrials.gov/ct2/show/NCT04111458
Son of (DX 12/19) Male, age 62
Rectal cancer, T3N1M1, 2 liver and ~8 Lung mets
MSI-H (IHC), MSS (PCR), KRAS G12D
12/19 - 04/20: 9 rounds FOLFOX+Avastin : tumor shrinks, no liver/lung mets
05/20 - Radio on rectum tumor + xeloda
07/20 - Reappearance of lung mets, rectum tumor increasing again
07/20 - 6 rounds FOLFIRI+Avastin
11/20 - lung mets and rectum higher activity
12/20 - Regorafenib
06/21 - liver reappearance, lung and rectum higher activity
CEA: 1.5 ~ 3.0 ng/mL
ctDNA shows MSS, KRAS, TP53 and APC


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