Tumor Mutations

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saltygirl
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Tumor Mutations

Postby saltygirl » Fri Jun 25, 2021 1:41 pm

How does cancer mutate? Can you have an original tumor with Kras. But metastases no mutations? Or reverse? Do most cancers eventually mutate? Just curios to learn more about mutations.
Stage 4, distant lymph nodes May 2020, braf/kras mutations
11 folfoxiri
Intense radiation 1 week on distant lymph nodes
Surgery, hysterectomy, colon resection, distant lymph nodes resection
Complete pathological response to chemo.
NED 2021
NED 2022
NED 2023

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O Stoma Mia
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Location: On vacation. Off-line for now.

Re: Tumor Mutations

Postby O Stoma Mia » Fri Jun 25, 2021 3:46 pm

saltygirl wrote:How does cancer mutate? Can you have an original tumor with Kras. But metastases no mutations? Or reverse? Do most cancers eventually mutate? Just curious to learn more about mutations.

I already asked some of these kinds of questions some 5 years ago. I think it might help to read through DK37's past posts to find what he had to say on these and other topics.

DK37 wrote:
In 2016, O Stoma Mia wrote:
Here are some of the types of questions that I have:

    MSI status – is it a property of patient or a property of a tumor? Some of the writings on the topic of MSI testing refer to “MSI patients” while other passages refer to “ MSI tumors”. So, is MSI status something that a patient has always had (like blood type), and if so can this be assessed at anytime during lifetime – for example could MSI status be assessed for a fetus by doing amniocentesis in the same way that Down’s Syndrome is assessed before childbirth, etc,?
    MSI status for tumors – Does MSI testing require a tumor? If so, does it make any difference whether it is the primary tumor or a metastatic tumor?
    MSI status for tumors – within-tumor variability - If MSI testing is done on tumors, then can the specimen from one part of the tumor turn out to be MSI-High while a specimen from a different part of the same tumor turns out to be MSI-Low?
    MSI status for tumors – tumor location - If MSI testing is done on metastatic tumors, and if the patient has several such tumors (eg., one in liver and one in lungs) then can one of these tumors test as MSI-High while the other tumor tests as MSI-Low? Can MSI testing on a primary tumor yield different results from MSI testing on a metastatic tumor?
    MSI status test-retest reliability - If MSI status is determined as MSI-Low on one testing, what is the likelihood that it will turn out to be MSI-High when a second test is done on the same sample? What if different labs give different results when they are doing tests on the same tumor?
    MSI testing sample requirements - What is minimally needed in order to do MSI testing? Can this be done on a blood sample or on a urine samle, or does it have to be done on a sample from a tumor? If it requires a tumor, then does it have to be a primary tumor, or a metastatic tumor, or does it make any difference? Can an MSI test be done on a pre-cancerous polyp, for example?
    MSI testing – specimen preservation requirements. If MSI testing requires a specimen taken from a tumor, does it make any difference how the specmen was preserved? What if it was not preserved in a paraffin block, but was preserved in a bottle of formaldehyde or in some non-standard manner? In other words, are there industry-wide standards on specimen preservation that must be met before MSI testing can take place? Prior to surgery, does the surgeon need to be informed that MSI testing will be needed so that he/she will be sure to preserve the specimen in the proper manner to allow subsequent MSI testing?
    MSI testing when tumor specimen is not available - What if the requirement is for a tumor sample, but the patient has been NED for 5 or 10 years, does not have any visible tumors any more, and the original resected/biopsied tumor is no longer available? Can MSI testing still be done, for example, by testing the Circulating Cancer Cells in the blood instead, or by using some other method?
    MSI testing for family members. If a patient has received his/her MSI testing results and now wants to have family members tested for MSI status, is this at all possible if the family members have never been diagnosed with cancer?
    MSI status stability - If a patient is tested for MSI now, in 2016, will these results still be valid 5 or 10 years from now, or could the patient’s current MSI status change after being subjected to 4 or 5 years of continuous chemo regimens of one type or another?



Absolutely fantastic questions O Stoma Mia! You are much better than some formally trained molecular biologists!! I'll try to gather answers for them

Cheers,
-DK

catstaff
Posts: 177
Joined: Wed Mar 03, 2021 11:37 am

Re: Tumor Mutations

Postby catstaff » Sun Jun 27, 2021 8:53 am

I'm not a molecular biochemist either but do have some background so..

MSI-H is a condition that increases the susceptibility to carcinogenic mutations. It may be itself the result of a mutation. But it's not the direct cause of the cancer.

However, all cancers start from a mutation. Cells that are dividing must copy their DNA. There is a cellular mechanism to keep this accurate, but it's not perfect and errors can happen. There are also error-correcting mechanisms but they aren't perfect either. (Mismatch repair aka MMR is a major part of the error correction process, and MSI-H is connected to deficient mismatch repair.) A change in DNA is the definition of a mutation. If it happens in a "regular" cell and not sperm or ovum it is called a somatic mutation. Some cell lines divide a lot, such as the lining of the gut and certain breast cells, so they are particularly prone to errors in DNA replication.

There is also an elaborate machinery for cells in multicellular organisms such as ourselves to behave properly. They should stay in their organ. They should do their jobs for the organ. They should politely kill themselves if they have errors in their DNA or other problems that cause them to malfunction. But mutations in certain genes enable them to get around those restrictions. They start to divide without restraint. They invade other parts of the organ where they are not supposed to be. They invade nearby organs. They break loose and travel through blood and/or lymph to other sites and establish colonies.

Usually a single mutation in an "oncogene" sets off a cascade. Most colon cancers are believed to start with a mutation in the APC gene. The job of the protein encoded by that gene is to prevent excessive growth. Once it is mutated, rapid cell division can lead to other mutations and it's off to the races. KRAS is part of a cellular signalling chain that tells the cell to divide (or not). If it mutates, as it frequently does in a lot of cancers, it's basically stuck on the "divide" setting. But KRAS certainly isn't the only gene whose mutation can result in cancer. Frequency of particular mutations varies by cancer location, age of the individual, and other factors.
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-

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GrouseMan
Posts: 888
Joined: Mon Aug 12, 2013 12:30 pm
Location: SE Michigan USA

Re: Tumor Mutations

Postby GrouseMan » Tue Jun 29, 2021 9:46 am

Well said Catstaff! I would go on to say that almost always the mix of mutations in a Met is different than it was in a primary. That's why its important to get biopsies of Mets if possible to help direct chemotherapy or Immunotherapies. Your primary could have been removed and gene tested, but that doesn't mean your Met's have the same set of mutations in its genes it could have a subset or new set of mutated genes. This is one of the main reasons we have such a difficult time treating advanced solid tumor cancers of any kind. A particular Met might be composed of many different mutated cancer cells even. A biopsy and tests on different parts of the met might yield different results. Outer parts of the tumor with a good blood supply might have one set where deep inside where it might not be as well vascularized could have another set.

This is why a lot of oncologists don't put a lot of faith in Genetic testing up front. Usually they have only the primary to test and its not a reliable indication of what the Met might be like. They stick pretty much with tried and true (ie Clinical trials) methods that appear to work for however long for a particular type of cancer. Everyone's Colon cancer is unique to that individual. They are as unique as each of us are to one another.

In preclinical testing of cancer chemotherapies and immunotherapies we use a lot of mouse models. They are at best crude approximations of a patient. They are often referred to as Xenographes. We might find a drug that works phenomenally in these models but only moderately well once in the clinic. I was involved in the discovery and development of one such drug. It was actually the first drug that our tumor biologists had ever seen where the mouse was cured and lived out its life to old age. That had never been seen in these Xenograph tests before. What is done is a tumor of a certain size is implanted in usually am immune compromised mouse species. These tumors are standard tumor types (ATCC Colon Types are Colo205, HCT-2998, HCT-116, HCT-15, HT29, KM12, and SW-620 all of human origin). The tumor is grown to a certain size for several days. Then treatment begins in the treated leg and usually drug vehicle is used on the control. Sort of matched pairs you might say. The size of the tumors are observed over several weeks and you end up with two curves, one showing growth in the controls verses the treated leg. Mind you this is done with many sets of mice at different doses and schedules to find the optimal one. In the tests of this particular drug - the optimal set of dose and schedule the test mice survived and tumors completely disappeared at least in terms of being able to find or locate them including biopsy! At that point dosing was stopped and they waited for the tumors to start to grow back. In the case of standard treatment methods using standard approved chemo drugs these tumors always came back. In the case of this particular drug treatment they never did. The treated mice lived out their natural lifespan. We thought we had a winner!

So what am I getting at. Well We went into human trials and this drug although useful and it had gotten approval, it didn't work nearly as well as we had hoped in people. The tumors in people mutated to become resistant to the drug over time. It was a much more complex situation than the mouse models suggested. Since then Anti-Cancer drug developers have learned a great deal more. And we constantly apply whats learned. We go after the mutated gene itself now rather than the one than the normal gene that controlled the proliferation of the tumor to begin with. So we now have 3rd generations of these drugs that do a better targeted job, but in people the tumor still finds a way to resist in some folks.

Unlike Bacterial, Viral and other diseases in cancer even for a particular cancer type we are attempting to treat thousands of really different tumors unique to each person.

Regards,
GrouseMan (Former Anti-cancer drug discovery chemist).
DW 53 dx Jun 2013
CT mets Liver Spleen lung. IVb CEA~110
Jul 2013 Sig Resct
8/13 FolFox,Avastin 12Tx mild sfx, Ongoing 5-FU Avastin every 3 wks.
CEA: good marker
7/7/14 CT Can't see the spleen Mets.
8/16/15 CEA Up, CT new abdominal mets. Iri, 5-FU, Avastin every 2 wks.
1/16 Iri, Erbitux and likely Avastin (Trial) CEA going >.
1/17 CEA up again dropped from Trial, Mets growth 4-6 mm in abdomen
5/2/17 Failed second trial, Hospitalized 15 days 5/11. Home Hospice 5/26, at peace 6/4/2017

roadrunner
Posts: 452
Joined: Sun Jan 12, 2020 8:46 pm

Re: Tumor Mutations

Postby roadrunner » Tue Jun 29, 2021 10:15 am

Grouseman: What is the old saying? “Mice lie and monkeys exaggerate.” Something like that . . ..

This is a super helpful post—thanks! I was just confronted by a conundrum around this. Two small lung nodules, 3mm and 5mm, question was “remove now vs. wait”? One of the factors that swayed me was the need for tissue to test for mutations in case they are mets. At that time, I did not understand that mets could look (genetically) and respond differently than primaries. Fortunately I have a great oncologist who explained this to me. Cancer is a difficult ocean to navigate, for certain.

P.S. Also a great point about individuality of disease, prognosis, and treatment. It’s good to keep considering one’s fight that way, I think. Helps guard against despair and potentially misleading signs from others’ experiences.
7/19: RC: Staged IIIA, T2N1M0
approx 4.25 cm, low/mid rectum, mod. well diff.; lung micronodule
8/19-10/19 4 rds.FOLFOX neoadjuvant, 3 w/Oxiplatin (reduced 70-75%)
neoadjuvant chemorad 11/19
4 rounds FOLFOX July-August 2020
ncCR 10/20; biopsies neg
TAE 11/20, tumor cells removed
Chest CT 3/30/21 growth in 2 nodules (3 and 5mm)
VATS 12/8/21 sub-pleural met 7mm.
SBRT nodule 1/22
6/20/22 TAE rectal polyp benign)
NED from 3/22 - 3/23
4 cycles FOLFIRI
LUL VATS lobectomy for radio resistant met 7/7/23

roadrunner
Posts: 452
Joined: Sun Jan 12, 2020 8:46 pm

Re: Tumor Mutations

Postby roadrunner » Tue Jun 29, 2021 2:51 pm

I ended up waiting for a new scan to see if they grow. In my case they’d been stable, but a contrast CT after 2 non-contrast CTs indicated suspicious growth. It was small (1mm and 2.3mm respectively over 4.5 months), but enough to create suspicion and right at the limits of variability if one subtracts the enlarging effect of contrast. I got varying views on whether to wait or operate, but mostly it was: “What do you want to do?” Because the nodules were small overall, removal might not have produced sufficient material to test, might have been tough because of their small size, and might have required removal of more healthy lung tissue than otherwise necessary. There is also a non-insignificant possibility that they are not metastases. It was a really tough call, though, because the growth rendered them—particularly the larger one—suspicious. I am now waiting for the results of the follow-up scan. I’m hoping for good news, of course, but need to be ready for the next battle if I don’t get it.

I wish you good luck and strength with your situation. This is a tough fight, requires a lot of tough calls, courage, goodwill, and good fortune.
7/19: RC: Staged IIIA, T2N1M0
approx 4.25 cm, low/mid rectum, mod. well diff.; lung micronodule
8/19-10/19 4 rds.FOLFOX neoadjuvant, 3 w/Oxiplatin (reduced 70-75%)
neoadjuvant chemorad 11/19
4 rounds FOLFOX July-August 2020
ncCR 10/20; biopsies neg
TAE 11/20, tumor cells removed
Chest CT 3/30/21 growth in 2 nodules (3 and 5mm)
VATS 12/8/21 sub-pleural met 7mm.
SBRT nodule 1/22
6/20/22 TAE rectal polyp benign)
NED from 3/22 - 3/23
4 cycles FOLFIRI
LUL VATS lobectomy for radio resistant met 7/7/23


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