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Biomarker mutations question

Pancreatic Cancer | Last Active: Aug 7 12:06pm | Replies (7)

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@val64

I'm a molecular biologist who used to interpret sequencing tests like this for a living, so I can answer some of your questions, but not all. I have never looked at a Tempus report.

It sounds like they reported 8 biologically relevant mutations (ATM, CHEK2, KRAS, and 5 more), which seems like a reasonable number of mutations to detect. My wild guess, based on not much, is that the median for a pancreatic cancer is ~4-6. I'd be interested to know what people's actual experience is.

Proteins, such as KRAS, are strings of amino acids, and the terminology for mutations describes the change in a particular amino acid. The 12th amino acid in the normal KRAS protein is the amino acid glycine (abbreviated G). The KRAS mutation in your cancer changes this glycine to an arginine (R). So in p.G12R, "p." means it's referring to the protein's amino acid sequence; "G12" refers to the normal amino acid at position 12; and "R" refers to the altered amino acid. The vast majority of cancer-associated KRAS mutations are in glycine 12, but it can be changed to several different amino acids including aspartic acid (D) and cysteine (C). There are new drugs in clinical trials that specifically target the G12C and G12D mutations, but would not be expected to affect cancers with a G12R mutation. However, I believe there may also be a drug that is intended to target any of these G12 mutations.

The fraction 23.6% refers to the percentage of the KRAS gene in the specimen that has this mutation. This isn't all that informative, and is mainly dependent on how much normal, non-cancerous, tissue is in the specimen that they extracted. (So if this number were 10%, it wouldn't really say anything about the cancer, just that there was more normal tissue in the specimen.) Sometimes one or a few of the mutations in the cancer will be present at higher fractions than others, which can mean that there are differences in the number of copies of that gene that are present in the cancer.

What's the actual tumor mutation burden (TMB) number that they report? It's hard to know what 75th percentile means without knowing what they're comparing it to. A high TMB would be a good thing, and might suggest that an immunotherapy would be effective. Microsatellite instability is a different indication that immunotherapy might be effective, but since yours is stable, that's not the desired result.

I'm sorry to hear that your oncologist isn't interested in going beyond the paint-by-numbers standard of care. But I'm not surprised. My oncologist is certainly like that, and was also recommending standard of care treatments involving drugs that had already not worked. I finally came to the conclusion that following an algorithm is the job that he's paid to do, and that thinking is not. Are you being seen at a pancreatic cancer center of excellence? Can you look for a different oncologist who can help you navigate the next steps?

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Thank you for your in-depth response, I really appreciate it. I did see another oncologist yesterday who did look at the Tempus report. He confirmed what you said that immunotherapy would not be an option for me. But other than that, as I am finishing chemo radiation, his only advice was to get back to him after the next CT scan and Ca19-9 is done five weeks from now.
When I asked his opinion, give the positive lymph node and tumor marker of 450 what kind of timeline we might be looking at,he stated prepare for the worst but hope for the best. Can’t say that made me feel very hopeful…..