Genome testing is back and looks really bad

[Spazzyjanet]

KRAS G12V
NRAS Wild type
MS-Stable
Tumor Mutational Burden 5 Muts (low)
APC R302
APC E1408
CCDN amplification
ERBB amplification
TP53 R273C
VEGFA amplification

Some of these are very rare.

The VEGFA amplification is present in only 3 percent of CRC cases and is associated with higher stage, tumor grade, vascular invasion and reduced overall survival.
(My note: Well, yes- but I've already experienced most of these, have I not?)

The CCDN3 amplification is present in only 1 percent of cases.

The only thing keeping me from falling apart right now is that my surgeon believes that the current metastasis in my liver is operable.

But what if that changes? Or the next metastasis is not operable? Am I just plain out of luck, or can traditional therapies still beat these?

I am seeing an oncologist who specializes in genetic research at OSU next Tuesday. Let's hope that he brings some hope.

Also, dumb question but does this confirm that my CRC was genetically based? Should I get my kids tested?

[cartech78]

So i also tested positive for the TP53 protien. My ONC wants me to see a geneticist to be tested for some disease called li-frameni disease. Also i am mss stable as well. Try not to fret to much as A lot of the studies they have done on some of these are controversial.

[hiker]

Hey Spazzy,

Don't forget that stats don't mean anything when it comes to treating an individual. Let the pros worry about all the details - you focus on getting better.

The overwhelming fear of knowing too much is exactly why I have never wanted to know all of my genetic info. There's absolutely nothing I can do about it and all I would do is look each thing up online and worry myself sick. Heck, I didn't even know I was KRAS wild until Dr. Kemeny told me as she was explaining a clinical trial she was doing for people who are KRAS wild - that was months after my original diagnosis. Every time I have a scan that shows something (like the CT I had 3 weeks ago that showed a 1.4 x 0.9 cm nodule in the area where my colon resection was done), Dr. K asks if I want to see the scan. I tell her absolutely not, she's the expert in this area, just tell me what the plan is. I wouldn't know what I was looking at anyway.

hiker

PS. This past Sunday I had a follow up MRI to see exactly what that nodule is. Dr. K called me yesterday to tell me it's a pocket of fluid and nothing to worry about.

[NHMike]

The vast majority of people that I've read about who know their mutation have only one mutation. I have seen some with a few mutations. I sent an email to my son to see if he has any comments on this sort of thing happening. That said, if this is contained to the tumor and they remove the tumor (or kill it with radiation or chemo), then it shouldn't be a problem. But I'm curious as to why there would be a large number of mutations.
I don't know that it would make the treatment different at this point.

[radnyc]

Ok, I would not freak out about genetic testing. They’re not foolproof. I would concentrate on what I need to focus on now. Having family members regularly screened for CR is always a good idea. No need for genome test for that.

[NHMike]

Ok, I would not freak out about genetic testing. They’re not foolproof. I would concentrate on what I need to focus on now. Having family members regularly screened for CR is always a good idea. No need for genome test for that.

A genetic test is a test on the patient. A genomic test is a test on the tumor. The genomic test tells you what your mutations are and knowing the mutations may or may not be useful for treatment. Genomic tests are only done on those people with cancer.

[Spazzyjanet]

I'm still trying to fathom HOW I have so many mutations when I know no-one else in my family that has had CRC.
As far as Cancer, my uncle had Prostate cancer, his daughter has low-stage melanoma but that is it.

Heck, my mother was an alcoholic, anorexic and bulimic, which drove osteoporosis anaemia and cirrhosis, but no cancer! She made it to 59..
I did yoga, meditated, took probiotics and supplements and find cancer spread through two internal organs at 40..

[NHMike]

I sent a private note on my son's response to my question on multiple mutations. I had a quick look around for papers on multiple mutations and found one from 2000 and one from 2003. They may be worth reading for an overview of ideas. I'd guess that there are more current papers but it would take some effort to find them. These papers are usually highly technical. I found some web pages that were for general audiences and they talk in such vague terms so as not to be that useful.

It can be nice to know how it came about and I have an idea as to how it happened to me but, at this point, you need to focus on treatment to get rid of it.

I asked my GI guy why I got cancer and he said that I turned 50. I have a closer idea as to what caused it but it didn't ultimately matter for treatment.

[GrouseMan]

The vast majority of people that I've read about who know their mutation have only one mutation. I have seen some with a few mutations. I sent an email to my son to see if he has any comments on this sort of thing happening. That said, if this is contained to the tumor and they remove the tumor (or kill it with radiation or chemo), then it shouldn't be a problem. But I'm curious as to why there would be a large number of mutations.
I don't know that it would make the treatment different at this point.

Mike - this is a little bit misleading - True most people on here have one major mutation that is reported, but the tumor genome has many mutations compared to the tissue that it sprang from. The problem is in most genetic screening tests these are not usually tested for. Just the major mutational drivers that are known about for particular tumor types are run. There are hundreds more that are not tested because there may be limited or no evidence so far that they contribute to the tumors growth or stability. On top of that we are finding more gene products involved all the time. We are learning more every day.

Some time ago I believe I posted a link to a presentation I saw where much more detailed genetic screening was done. In fact whole DNA sequencing of normal tissue, primary and metastasized tumors from the same patient. This is too expensive to do in a clinical setting. The results showed that tumors often had a number of mutations compared to the surrounding normal tissue, and that the metastatic tumors that are derived from the primary often had a completely different set of mutations and drivers. Additionally within a given tumor or metastases some tumor cells had different mutations than others within the same solid tumor. Its not an easy disease to work on. Perhaps the only one worse is Alzheimer's where we still don't really understand anything about how or why it develops despite the many billons of dollars being spent. At least in cancer we are making some progress!

Genetic screening for the layman is over simplified. Even for an oncologist its not usually detailed enough that its going to set off flags more often than not. For them its useful to enable them not to apply a treatment method that is likely not to work all that well (EGFr inhibitors for example and KRAS status) But as we get more detailed in testing sub populations sometime interesting insights occur. More recently its been discovered that the KRAS G13D mutant tumors may actually be sensitive to treatment with third generation EGFr inhibitors. See discussion here:

viewtopic.php?f=1&t=60996&p=483247&hilit=Kras+mutations#p483247

So the general statement that if you have a Kras mutation EGFr inhibitors may not work is too generalized now and not always true. Additionally - As I mentioned most of the time in CRC the genetic tests are run on the primary after a resection. This like as not will not apply to any metastatic tumors found. Finally - while undergoing treatment the stress of chemo therapy is actually causing the tumors to further undergo genetic changes, and drug resistance starts to take place. Oncologists walk a fine line.

Being a cancer research as was DK37 we both had a pretty solid background in the science of Cancer. Despite that it didn't really do more than help guide his treatment and my wife's treatments. That said - in the end DK and my wife still lost their battle with CRC. Genetic testing has its uses but mostly to guide. I would not read anything into the success or failure of an individual's treatment based on genomic testing right now. Some people with what appears to be pretty bad mutations come out of this in good shape. Others not so good. My wife's genetic screening didn't turn up much of value really. She was Kras wild for example, but MSS. So standard treatment was about all that could be offered. DK had some promising leads from his testing, but the time line for treatment didn't favor it. The clinical trials for what would likely favored his mutations being used to target treatment where only just getting started.

So Spazzyjanet - Your Genomic testing might look bad, but it also may not in the end turn out that way. There is really no way to know. Plenty of people before genetic testing have beat this maybe you will be one of them. Everyone is unique.

Good Luck everyone
GrouseMan

[NHMike]

Mike - this is a little bit misleading - True most people on here have one major mutation that is reported, but the tumor genome has many mutations compared to the tissue that it sprang from. The problem is in most genetic screening tests these are not usually tested for. Just the major mutational drivers that are known about for particular tumor types are run. There are hundreds more that are not tested because there may be limited or no evidence so far that they contribute to the tumors growth or stability. On top of that we are finding more gene products involved all the time. We are learning more every day.

Some time ago I believe I posted a link to a presentation I saw where much more detailed genetic screening was done. In fact whole DNA sequencing of normal tissue, primary and metastasized tumors from the same patient. This is too expensive to do in a clinical setting. The results showed that tumors often had a number of mutations compared to the surrounding normal tissue, and that the metastatic tumors that are derived from the primary often had a completely different set of mutations and drivers. Additionally within a given tumor or metastases some tumor cells had different mutations than others within the same solid tumor. Its not an easy disease to work on. Perhaps the only one worse is Alzheimer's where we still don't really understand anything about how or why it develops despite the many billons of dollars being spent. At least in cancer we are making some progress!

Genetic screening for the layman is over simplified. Even for an oncologist its not usually detailed enough that its going to set off flags more often than not. For them its useful to enable them not to apply a treatment method that is likely not to work all that well (EGFr inhibitors for example and KRAS status) But as we get more detailed in testing sub populations sometime interesting insights occur. More recently its been discovered that the KRAS G13D mutant tumors may actually be sensitive to treatment with third generation EGFr inhibitors. See discussion here:

viewtopic.php?f=1&t=60996&p=483247&hilit=Kras+mutations#p483247

So the general statement that if you have a Kras mutation EGFr inhibitors may not work is too generalized now and not always true. Additionally - As I mentioned most of the time in CRC the genetic tests are run on the primary after a resection. This like as not will not apply to any metastatic tumors found. Finally - while undergoing treatment the stress of chemo therapy is actually causing the tumors to further undergo genetic changes, and drug resistance starts to take place. Oncologists walk a fine line.

Being a cancer research as was DK37 we both had a pretty solid background in the science of Cancer. Despite that it didn't really do more than help guide his treatment and my wife's treatments. That said - in the end DK and my wife still lost their battle with CRC. Genetic testing has its uses but mostly to guide. I would not read anything into the success or failure of an individual's treatment based on genomic testing right now. Some people with what appears to be pretty bad mutations come out of this in good shape. Others not so good. My wife's genetic screening didn't turn up much of value really. She was Kras wild for example, but MSS. So standard treatment was about all that could be offered. DK had some promising leads from his testing, but the time line for treatment didn't favor it. The clinical trials for what would likely favored his mutations being used to target treatment where only just getting started.

So Spazzyjanet - Your Genomic testing might look bad, but it also may not in the end turn out that way. There is really no way to know. Plenty of people before genetic testing have beat this maybe you will be one of them. Everyone is unique.

Good Luck everyone
GrouseMan

I know very little about Genetic Testing outside of what was done on me to determine course of treatment. I'd agree that cancer is very difficult to work on from reading a lot of papers. The Undruggable RAS papers are good examples. I've also read a few on adaptations of tumors to evade chemo or other treatments. I generally only talk about Genomic testing. For me, it may be helpful that I know that I'm KRAS G12D - it would also be helpful to know Alleles which would determine if I'm a candidate for the NCI trial for immunotherapy should I get a recurrence. In the end, knowing didn't change my treatment but I think that it might be worth knowing if it were BRAF V600E or something else that's aggressive.

[Spazzyjanet]

I'm a fairly intelligent person, but honestly this exhausts me.

For what it's worth, I have my own genetic tests and have run those through studies and my personal genes turn up bad for Avastin and Cetuximab as well. Because of that, I sort of anticipated this coming but still had hope since my Oncologist blew me off to wait for the Genome testing, which was done on the primary tumor for purposes of drugs to treat liver metastasis. See below for what my genetic testing said:

MY SNPs:
1 ) rs2946834 linked to the gene IGF1. Your genotype is GG, which is observed in 38% of all individuals reported.
The Major "G" allele is associated with resistance to treatment with the drug Cetuximab in colon cancer patients. In one study, none of the patients with the AG genotype experienced any tumor response to the drug [R].

In univariate and multivariate analyses, five IGF pathway single-nucleotide polymorphisms were significantly associated with progression-free survival (PFS) and/or overall survival (OS). In multivariate combined risk allele analysis, the additive model for PFS and OS was significantly associated with the number of risk alleles in wt KRAS patients (P = 0.001 and P = 0.02, respectively). In addition, wt KRAS patients harboring IGF1 rs2946834 A/A genotype had a 50% objective response rate compared with 0% for A/G genotype.
CONCLUSIONS: These results indicate that IGF1 pathway polymorphisms are potential predictive/prognostic molecular markers for cetuximab efficacy in wt KRAS mCRC patients. Prospective biomarker-embedded clinical trials are warranted to validate our findings.

2) rs6220 linked to the gene IGF1. Your genotype is AA, which is observed in 41% of all individuals reported. G= increase in circulating Insulin-like Growth Factor (IGF) levels [R, R2]. AG individuals had a 5.6 ng/ml increase from AA individuals, while those with the GG genotype had an 11.1 ng/ml increase[R]. The "A" allele is associated with: Shorter overall survival in Metastatic Colorectal Cancer patients treated with the drug Bevacizumab, who have the AA genotype [R].

Looks like there is some hope in trials associated with the ERBB2 amplification that have shown success with Trastuzumab combined with Lapatinib. I will talk to the specialist on Tuesday, but I am pretty sure that I am out of luck and just have to hope that current and future metastasis continue to be operable.