New biomarker Claudin 18.2

Thanks for posting! That's one I heard my oncologist mention several months ago, but not lately.

A quick search of the NCT site shows 14 clinical trials in the USA with a search term matching "Claudin" and status = currently recruiting.
https://clinicaltrials.gov/search?term=claudin&locStr=United%20States&country=United%20States&aggFilters=status:rec&limit=25&page=1
I haven't refined the filters down to see if there are more or less matching the keywords related to pancreatic cancer (PDAC, solid tumor, etc), expanded it to catch where they might only use the abbreviation (CLDN), or rule out other flavors of Claudin besides 18.2, include other countries outside the US, but you get the idea. 🙂

I hope something here works out for someone, and that they will share if it does!

Did your dr. suggest testing to see if you have that bio marker? My present GAC treatment is bringing down my CA19-9 numbers, but an ultrasound showed the growth in the peritoneum is still growing. My MRI today will show how accurate the ultrasound is. I will post if my drs advise any new treatments if it turns out I have the Claudin 18.2 marker. By the way, are your CA19-9 numbers decreasing yet?

My onc did not (yet) suggest getting tested for CLDN18.2. He only mentioned it several months ago as something possibly targetable in a future trial at his site. It's rather frustrating to only get tested in a onesey-twosey fashion for things like that, and only get information about trials open at his institution. If more info were available now, I could much better research opportunities and make plans for the near future, and with less risk of running out of banked tissue to test.

My CA19-9 reversed its upward trend (upward ~150% after missing one treatment due to covid) and came down by 1% after resuming. I will have my second post-covid treatment and a new CA19-9 data point this Thursday.

That’s good news about the CA19-9; glad your dr was incorrect about the reason it was increasing. My oncologist returns next week and I will post whatever I learn from him about Claudin 18.2.

Too early to say he's incorrect, but I'm hoping he is. We have at least shown that my cancer is very volatile and definitely will progress when untreated, but not yet demonstrated it has developed resistance to the GAC. My neuropathy from the Abraxane continues to build, but if the GAC combo keeps working, I'll do it as long as I can.

It's a fine line of getting into a trial when you're under control with stable disease. I don't want to be declared unable to tolerate more GAC if it's working -- the ideal would be to say I've had as much as I can handle at present, a break for a trial would be good, but I could come back to the GAC if the trial doesn't work. If they write it up as "resistant" or "unable to tolerate" as the "final word" then I might not have the option (by doctor or insurance) to revert.

My onc has proposed a new regimen based on Onivyde (the new liposomal irinotecan) and 5FU, but since the original Folfirinox didn't do much for me, I don't have high hopes for this option.

Hello markymarkfl,
I believe I read from a post on another topic that your biomarker is decreasing now, and that's great!
After beginning GAC in January, my biomarker (CA19-9) is decreasing so that it went from 3840 (just prior to 1st treatment) to 141, though it hasn't been measured for a few weeks now. Additionally, my recent MRI showed that 1 lesion on my liver is no longer visible, and the other has decreased in size. The soft tissue around the hepatic artery/celiac trunk and within the abdominal peritoneum are "stable"; so with this information my oncologist wants to keep me on the GAC regimen. According to my dr. (Wainberg), the treatment for the CLDN18.2 protein has proven successful for gastric cancer, so the clinical trials at UCLA (largest study on west coast) are to test if it will work for pancreatic cancer, also. Since the GAC is working, my dr. did feel inclined to take me off something that is working for something where the result is unknown. However, since we all know that chemo has its shelf limit, I going to ask if I can at least do the test to see if I have the CLDN18.2 protein, and then when GAC no longer is effective, I'm ready to go for this clinical trial. I also saw your post on the KRAS12-D, and I'm very interested in the study that may be forthcoming in 2-3 yrs. - Oh, well! I also have the ATM and KRAS12-D mutations and was reading today in simple words that ATM accelerates KRAS12-D carcinogenesis. There may be some ATM clinical trials out there (I'm just not very good at retrieving the info for what, when, etc.); it's something I'll consider once the GAC wears down. At the start of my journey, I knew very little about this disease (even though my dad had it over 23 years ago); however, the research regarding pancreatic cancer I feel is exploding right now and there may be a "cure" in my lifetime. What I know now is that with my 3 mutations (TP53 being the other), the chances of this spreading for me were 100%, even though only 1 lymph node was impacted. Please keep providing your fantastic graphs and links and info., as we are all helping each other by sharing this information!

Good thinking and good planning on your part!

My CA19-9 is only down a few points since resuming full-dose GAC after two reduced doses and one missed dose, but at least that reversed the upward trend. New data coming in two weeks...

Interesting news in my mutation department: We've known all along about my germline ATM mutation. When docs finally sent my 1.5-year old Whipple tissue to Tempus last month, it reported the KRAS G12D mutation. But, we also just sent new blood to Guardant, which reported a CHEK2 mutation but nothing on KRAS (despite reporting that it checks for "amplifications of this gene.")

It makes me wonder if Whipple got all the tissue with KRAS mutations. You'd think if that were an advantageous mutation and Whipple didn't get it all, that my recurrence would be flooded with KRAS by now. On the other hand, it may simply be that the tissue test was significantly more sensitive than the blood test.

On the other hand, CHEK2 was not reported in my two previous Guardant blood tests, and that one seems to correlate somewhat with chemo resistance in the literature and with my imaging/CA19 relapse.

It leaves me confused as to whether the best clinical trial for me should target ATM, KRAS, or CHEK2.

Hello @markymarkfl
I haven't heard of the CHEK2 mutation until now; at least it doesn't seem to be a triple threat for pancreatic cancer from what I've read, and that's fantastic! I would agree with you that a tissue test would be more sensitive than a blood test when testing for DNA sequences.
Also, from my readings it appears that the ATM accelerates the effect of the KRAS12-D gene. If you eliminate the KRAS12-D gene, I wonder if that makes the ATM gene somewhat ineffective? Once my GAC chemo stops working, hopefully there will be a KRAS12-D clinical still open for which I can register; my 2 oncology drs. haven't expressed any interest in providing me any type of radiation. I feel pretty good these days, even did my 2 mile walk again which I haven't done since last December, just sold our house for cash offer, and am busy preparing for phase 2 of my life; beginning my bucket list just in case those clinical trials don't coincide with my journey. I hope and pray that a cure is found soon! Good luck and please let us know of your progress!

KRAS, CHEK2 and ATM are entirely different pathways. The RAS/KRAS pathway of cell signaling is involved with cell growth and proliferation. CHEK2 and ATM serve different functions regarding DNA.

PARP inhibitors such as Olaparib, Rucaparib and Niraparib are being looked at in ATM and CHEK2 mutations.

KRAS G12D has a number of targeted therapies in clinical trials presently including MRTX1133, HRS-4642, and RMC-9805. Eli Lilly has a vaccine targeting KRAS in a phase II trial called ELI-002. The AMPIFY-201 trial is also looking promising.

Just above the G12 variations in the cell signaling path for RAS/KRAS/RAF/MEK/ERK is the RAS gene which serves as a master ON/OFF switch for cell growth and proliferation. The mutation causing uncontrolled growth causes the switch to be stuck in the “ON” position. There are a couple of trials for drugs considered a “pan” KRAS targeting small molecule drug designed to turn the RAS Master switch to OFF. RMC6236 and RSC-1255 are two trials underway.

^Indeed on the PARP inhibitors (PARPIs).^

My Guardant test, which reported both ATM Q268 and a CHEK2 splice site SNV, gives a list of clinical trials and drugs relevant to each mutation.

For ATM and CHEK2, it gave the same drug result: Olaparib or Talazoperib, both of which are PARPIs.

But those are only trials. There have been positive results and approvals for PARPIs on patients with BRCA1/2 and PALB mutations. Although ATM is similar in its impact on DDR (DNA Damage Response/Repair), early PARPI results have not been as promising on ATM. My oncologist is not even convinced the study conclusions were statistically significant for the BRCA/PALB patient population, but it's obviously working well for some patients in that group.

So... there might be a PARPi in my future, or a different oncologist, or both, or neither. One study I read (lost the link) suggested that by the time a cancer becomes resistant to platinum drugs, it is also resistant to PARPIs, so it might be getting too late for me to go that route.

My very limited understanding of cancer biology is that traditional, cytotoxic chemotherapy (Standard of Care) drugs mainly just attempt to "poison" fast-growing cells to death (explaining side effects like hair loss). In more detail, that may involve "breaking" some function they need in order to reproduce successfully.

By comparison, the more targeted genetic therapies can attack from two angles: 1) Turning on a switch that will help your immune system kill or suppress cancer cells; and 2) Turning off a switch that causes cancer cells to grow out of control.

The RAS-based therapies seem to be a promising version of #2 above, fighting cancer offensively and proactively on the front lines, rather than #1 which is more like fighting defensively and reactively inside your own territory. That's my non-medically trained analogy and visualization of it anyway... I hope it's correct, accurate, and helpful.