How do you know if your cancer has genetic mutations?

DISCLAIMER: I HAVE ZERO MEDICAL TRAINING!!! Just some experience navigating this path.

Everyone with a family history of cancer should get a germline DNA test to determine whether you inherited genes that make you more susceptible to cancer, and if so, which types.

IN SHORT:
GERMLINE (Inherited): Saliva or Blood
SOMATIC (Environmental): Blood or Tissue
NGS = "Next Generation Sequencing" = High-speed, computer based analysis of cancer DNA
IHC = "ImmunoHistoChemical" staining (I'll let the pros elaborate on this) tests on tissue
SoC = "Standard of Care" (Evidence-based (non-experimental) treatment approved by the FDA)
ctDNA = Circulating Tumor DNA (DNA from cancer cells circulating in your bloodstream)

I had the INVITAE germline test ( https://www.invitae.com/ ) done by a blood draw, but it can now also be done by saliva. It determined I have a mutated ATM gene, which (unsurprisingly) increases the risk of pancreatic cancer. Because of this, other members of my family were tested; some have it, some don't. With one relative, it triggered his doctors to perform advanced screening to determine current status, risk level, and schedule for future monitoring. Every cell in your body will have this mutation because they all originated from the same two cells (egg and sperm from your parents).

I also had a "liquid biopsy" for somatic mutations from GUARDANT ( https://www.guardantcomplete.com/products/guardant360-cdx ). This was only available as a blood test, and is only one of several similar tests now on the market. It determined both before and after Whipple surgery that I had an ATM mutation (DUH! 😉 ) simply because it's in every cell of my body. But they are smart enough to remind you that they're not looking for germline mutations, and that the frequency (~50%) was suspicious for germline mutation.

A third Guardant test performed recently also found a CHEK2 somatic mutation (not good), which suggests the cancer is adapting to the chemo we've bombarded it with for so long. In addition to mutations, a somatic test may also report other targetable cancer characteristics such as MSI (MicroSatellite Instability: high or low) and TMB (Tumor Mutational Burden, as a number). Guardant's test also returns a list of clinical trials relevant to the conditions they discover.

When I finally got my post-Whipple tissue tested (NGS at TEMPUS LABS; same lab used in PanCan's KYT program, but one of many offering analysis in this space as well). This test also revealed a somatic KRAS G12D mutation (targetable with inhibitors in newer trials).

"TISSUE IS THE ISSUE"
That is the exact quote I heard from an oncology research nurse last week. Numerous modern therapies are either based on having VERY detailed information about all your tumor characteristics (mutations, fusions, deletions, protein expressions, etc...). For research and clinical trials, this usually requires a very specific analysis of YOUR tumor tissue, and there's never enough to go around and satisfy all the researchers and therapy developers.

Fortunately there was enough tissue saved from my Whipple procedure to send out for both the Tempus test (general mutations) and a separate research facility as qualification for entry into a study.

There is no way to test for everything at once, although it helps to test for everything possible when a fractional piece of tissue is sent out. Some may be lost to slicing and sharing, some may get contaminated and become unusable, or you just might not have enough to start with in order to get all the tests you want done at multiple sites. Doing as many as possible at once provides better foreknowledge of your choices, both immediate and near/medium-term. Long-term is subject to a lot of change as research progresses and newer tests become available. You don't want to use up all your tissue at once, because more may be hard to come by later. It's a fine balancing act.

A common flow for pancreatic cancer treatment is:
ERCP/EUS with FNA biopsy to confirm diagnosis, save tissue
Neoadjuvant SoC chemo (and/or radiation)
Surgery (open or laparascopic) to resect tumors
Adjuvant therapy (SoC chemo and/or radiation)
Cancer recurrence
Different SoC chemo until resistance develops
Search for clinical trials
If trial found, may perform new biopsy (unless old tissue is available and adequate for the trial) to check to for additional somatic mutations and all the other tumor characteristics targetable by the trial.

Opportunities to collect tissue and the methods of doing so depend on various factors.

At initial diagnosis, EUS/ERCP typically does an FNA (Fine Needle Aspiration) which doesn't get much tissue at all. It may be enough for Pathology to make the cancer type determination, but rarely enough to send out for NGS, much less store for future research/therapy. This is unfortunate, because NGS up front might help determine the best FIRST treatment for you (chemo or surgery, and if chemo, which drugs).

A Core Needle Biopsy can be done percutaneously (through the skin) if the tumors are reachable. These collect more tissue than FNA, but still might not get enough for everybody who wants it. However, it's a good chance to ask the surgeon to take as much as safely possible provided the tissue can be banked somewhere. StoreMyTumor.com offers offsite storage in a "live" state for a fee, and Travera offers 2-day turnaround sensitivity testing against several drugs/combos.

If the surgeon has to go deeper (laparascopic or open), they would have an option to do FNA, Core Needle Biopsy, or completely resect a tumor. The more tissue they can get safely and save (with caveats), the better for your research / trial future.

A common scenario with the Whipple (and distal, I assume) procedures is to at least start with an exploratory / diagnostic laparascopy. They look for evidence of cancer spread beyond the resectable part of the pancreas, and decide whether to continue and close you up or finish the procedure. Reasons to abort the procedure are tumor wrapped around a vein/artery, or visual evidence of distant metastasis (among other reasons). Although both are undesirable outcomes for the patient, this type of surgery provides an excellent opportunity for the surgeon to at least take some tissue for analysis, often exceeding what could be done with FNA or Core Needle Biopsy. I don't hear of many doing that, but it's a good chance to ask your surgeon beforehand if this can be accommodated, especially if you have a tumor storage option or clinical trial in mind. I think closing the patient up and recommending systemic therapy without collecting enough tissue to determine the best therapy is the most undesirable outcome possible short of death on the operating table.

One caveat alluded to above is that tumor tissue which is taken out or debulked (reduced in size) is no longer available inside the body. Some clinical trials require "measurable disease" which means tumors of a certain size visible on their imaging equipment. They are often left in and used as "sentinels" to help monitor response to the treatment. If your tumor is too small (because your bigger tumors were debulked or resected), you might not qualify for the trial.

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FINAL THOUGHTS:

If you ask your medical and/or surgical oncologist for some of the tests by type (germline/somatic) or brand name (Invitae, Guardant, Tempus, Caris, etc...) they might think you've done some homework and be a little more willing to order them. (Sad, but true experience based on self, relatives, friends)

If you ask the surgeon for more biopsy tissue than normal, many will hem and haw with some story about why it's not practical or beneficial, when a lot of times it's just extra work (paper and surgical) for them. This can take a couple weeks before surgery to get everything in place for this to happen, so plan on starting early.

Thank you for sharing all your knowledge, advice, suggestions. So very much appreciated!