Biomarker mutations question

I am writing from Turkiye, my doctor told me that there is no information about the tempus test for pancreatic cancer, no data on this type of cancer. If anyone has any information or finds data, can they share it?

I am hesitant to reply here, as my medical knowledge is extremely small. I'm in a clinical trial at the NIH for Olaparib use on pancreatic acinar cell carcinoma. PACC is very rare and I learned from talking to the doctors at the NIH that Olaparib is not useful unless a person has the BRCA 2 mutation in their DNA. It has produced some positive results in my liver tumor since I've been on it according to CT scans. I do have the BRCA 2 mutation. I hope this helps in some way and please do some research on the internet to verify what I've written here. And I'm hoping you can find a 2nd opinion from another oncologist.

“A change in the amino acid residue at position 12 in the GTPase KRas protein where glycine has been replaced by arginine. [from NCI]”. I didn’t get the tempus, but got another type of testing of my tumor after surgery. No one ever explained any of it to me, always found out through the internet and what others have posted on this site. I have the KRAS12D mutation, TP53 and ATM; probably have more mutations by now. @stageivsurvivor and @markymarkfl can give you more complete answers. Also, sounds like ASAP you need to get a second opinion from a pancreatic center of excellence. Which state are you in?

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?

Treating ATM mutations associated with pancreatic and prostate cancers have been done using PARP inhibitors (PARPi) such as Olaparib and Rucaparib, although best results were achieved with germline BRCA mutations. Olaparib received FDA approval for treating metastatic BRCA 1 and BRCA2 germline mutations in December 2019.

Efficacy of Olaparib treating BRCA mutations is best seen in patients with tumors sensitive to platin agents such as oxaliplatin in Folfirinox and cis-platin used in the triplet regimen of Gemzar/Abraxane/cis-platin.

I was diagnosed in 2012 with a mixed tumor type of both PDAC and the rare PACC cell type. I had 11/22 lymph nodes positive, poorly differentiated, high grade, perineural invasion, peripancreatic invasion of soft tissue and significant spread to the liver that occurred prior to my Whipple with portal vein resection as it was below the threshold of sensitivity in detecting the metastatic spread by CT just prior to surgery.

I had a very good response to Folfirinox given at full dose for all cycles. The BRCA2 mutation responded very well to oxaliplatin. This led to moving to a PARPi clinical trial from 2014-2016. The excessive number of cycles of Folfirinox and 5-FU/Leucovorin in alternating groups of six cycles over 24 months is credited with resulting in cure at 12 years survival. The PARP inhibitor has prevented any new primary cancers from developing (pancreatic, male breast, prostate).

My treatments were done at two very large NCI designated centers of excellence in NYC and Philadelphia. The oncologists. I would recommend seeking additional consults with oncologists who specialize in the mutations you have. Contact the Pancreatic Cancer Action Network (#PanCAN.org) at 877.272.6226, M-F, 7:00am-5:00pm PT. A case manager can provide names on oncologists whose sub-specialty is at these large high volume pancreas centers and have expertise in treating specific mutations. If you live in the NE USA, Eileen O’Reilly at MSKCC and Kim Reiss-Binder at PennMedicine have substantial experience using PARP inhibitors and are considered experts.

I’m in southern Ohio but also have a home in Central Florida. I had most of my chemo and surgery done at the Moffitt center in Tampa. Unfortunately, my experience with their medical oncologist was not a good one. He also went by the algorithms and it was my research that found the Tempus report option .
I would be interested in your comment of going to a center of excellence if you have an opinion whether to go to Mayo or MD Anderson.
I thought that Moffitt was a center of excellence, but I’m not seen that description on any searches that I’ve done
Appreciate your feedback!

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…..