Foundation One results

[TheTopBanana]

Hello, very thankful for any help in deciphering anything from this results that my father got back today! His doctor said it was unclear.

Genomic Signatures

Blood Tumor Mutational Burden - 3 Muts/Mb

Microsatellite status - MSI-High Not Detected

Tumor Fraction - Cannot Be Determined

Gene Alterations

For a complete list of the genes assayed, please refer to the Appendix.

No reportable genomic alterations were detected. See below for more

information.

Blood Tumor

Mutational Burden 3 Muts/Mb

Microsatellite status MSI-High Not Detected

Tumor Fraction Cannot Be Determined

POTENTIAL TREATMENT STRATEGIES

On the basis of clinical evidence in NSCLC and HSNCC, increased bTMB may be associated with greater sensitivity to immunotherapeutic agents, including anti-PD-L11-2 and anti-PD-13 therapies.

In NSCLC, multiple clinical trials have shown patients with higher bTMB derive clinical benefit from immune checkpoint inhibitors following single agent or combination treatments with either CTLA4 inhibitors or chemotherapy, with reported high bTMB cutpoints ranging from 6 to 16 Muts/Mb1. In HNSCC, a Phase 3 trial showed that bTMB ≥16 Muts/Mb (approximate equivalency ≥8 Muts/Mb as measured by this assay) was associated with improved survival from treatment with a PD-L1 inhibitor alone or in combination with a CTLA-4 inhibitor 4.

FREQUENCY & PROGNOSIS

Average bTMB levels in solid tumors other than NSCLC have not been evaluated (cBioPortal, COSMIC, PubMed, Mar 2021)5-7. The effects of hypermutation on prognosis and clinical features in prostate cancer have not been extensively investigated (PubMed, Feb 2021).

FINDING SUMMARY

Blood tumor mutational burden (bTMB, also known as mutation load) is a measure of the number of somatic protein-coding base substitution and insertion/deletion mutations from circulating tumor DNA in blood. TMB is affected by a variety of causes, including exposure to mutagens such as ultraviolet light in melanoma8-9 and cigarette smoke in lung cancer 10-11, treatment with temozolomide-based

chemotherapy in glioma12-13, mutations in the proofreading domains of DNA polymerases encoded by the POLE and POLD1 genes14-18, and microsatellite instability (MSI)14,17-18. High bTMB levels were not detected in this sample. It is

unclear whether the bTMB levels in this sample would be predicted to be associated with sensitivity to PD-1- or PD-L1-targeting immune checkpoint inhibitors, alone or in combination with other agents1-3. Depending on the clinical

context, TMB testing of an alternate sample or by another methodology could be considered.

NOTE One or more variants of unknown significance (VUS) were detected in this patient's tumor. These variants may not have been adequately characterized in

the scientific literature at the time this report was issued, and/or the genomic context of these alterations makes their significance unclear. We choose to

include them here in the event that they become clinically meaningful in the future.

ASXL1

G643V

DNMT3A

L637P

DOT1L

A854T

IDH1

T19fs*7

RAD51C

S16G

TSC1

H732Y

[LearnAll]

IMO..This report is favorable. There is no major mutation reported. Your father's bTMB is very low ,only 3 muts/MB. This is great news because only after 8 muts/MB, it is significant mutational tumor burden. So, this reading of 3 muts/MB does not need any special or specific treatment. VUS are useless noise and has no clinical importance.. just ignore it .To summarize...Your father's report is very good. There is no reason to alter his current treatment if it is working, Time to relax and reassure him.

[TheTopBanana in reply to LearnAll]

Thank you!! I highly appreciate it! My father had wished that it was 0 muts, and this answer from Foundation One confused me:

”It should be noted that currently the algorithmic prediction model used to measure bTMB can include somatic alterations from sources such as clonal hematopoiesis (CH) and clonal hematopoiesis of indeterminate potential (CHIP).” Aging cells that can indicate risk for blood cancer and heart disease?

mayoclinicproceedings.org/a...

science.sciencemag.org/cont...

[LearnAll in reply to TheTopBanana]

Some minor ,meaningless mutations happen in almost every older person. Its in fact part of normal aging. Some DNA damage is normal in people who have lived for over 60 years .

[TheTopBanana in reply to LearnAll]

One question, if you dont mind, my father’s doctor said that since the bTMB was so low it might not matter. Does this mean that my father’s cancer might not be active right now?

[LearnAll in reply to TheTopBanana]

low or high bTMB does not indicate whether the cancer is active or not. bTMB is more a measure of whether cancer is less aggressive or more aggressive. Its more like Gleason Grade which indicates how bad the cancer cells are distorted and thus it tell degree of aggressivenes.If you truly want to know whether cancer is active or not...Ga68 PSMA PET CT tells you in real time where and how much cancer activity is going on. (applicable for high PSA producing type only...Not Low PSA type or Neuro Endo type)

Another way to how active the cancer is to measure biomarkers...if his PSA is very low less than 1.0 (with intact prostate) and Bone ALP is less than 20 mcgm/L ,then

you can assume that cancer is inactive. based on what you told I think your father's cancer is in remission and it can remain like this for a long time.

[j-o-h-n in reply to LearnAll]

I've said this before, If I were playing poker I would love having you in a dealth hand.Four Aces....

Good Luck, Good Health and Good Humor.

j-o-h-n Saturday 04/10/2021 7:10 PM DST

[TheTopBanana]

Thank you very much for the help!! Very thankful for yours and LearnAlls reply.

[TheTopBanana]

One question, if you dont mind, my father’s doctor said that since the bTMB was so low it might not matter. Does this mean that my father’s cancer might not be active right now?

[Tall_Allen]

It's a very typical genomic report - useless for guiding therapy. The TMB is low. If it were high, he might respond to a checkpoint blockade - but, even then, results are equivocal. There may be some effectiveness of a PARP inhibitor against RAD51B, but there were only 4 in the PROfound trial.

The thing about genomics is that genomic breakdown increases over time and as there are new metastases. You may get more actionable results from a tissue-based biopsy after there are new metastases.

[TheTopBanana in reply to Tall_Allen]

Thank you! Does the TMB say anything about how active the cancer is?

[Tall_Allen in reply to TheTopBanana]

Tumor Mutational Burden just tells you how many mutations have occurred so far. It will probably increase over time.

[TheTopBanana in reply to Tall_Allen]

My father’s doctor said also normal cells can give off cfDNA?

[Tall_Allen in reply to TheTopBanana]

Yes. All cells undergoing apoptosis release their DNA into the serum. Healthy cells undergo apoptosis more than cancerous cells. That's why cell-free DNA tests do not distinguish germline from somatic. The advantage over a biopsy sample is it gives a picture of the person's total DNA profile (healthy, cancerous, old metastases, new metastases). The disadvantage is that it doesn't provide info on the most recent metastases specifically. I find metastasis cell histology and IHC to often be more useful.

[TheTopBanana in reply to Tall_Allen]

Thank you for explaining. Does my father’s results say anything regarding amount of cancer?

[Tall_Allen in reply to TheTopBanana]

Nope.

[Tall_Allen in reply to Tall_Allen]

It seems like they never explained to you what you could reasonably expect. It's a very expensive test - I hope your insurance covered it. In the few cases where it tells you something actionable, it is useful. But that is rare.

[Dett in reply to Tall_Allen]

Can I ask a question, TA? At the time of his diagnosis, my husband was advised by his MO to have a genetic test that supposedly looked for potentially actionable genes for his cancer. Nothing unusual was found, despite a long family history of cancer. I’ve been considering eating the cost of the Foundation One test, but I don’t know if it’s worth it. It sounds like you don’t think that it is. Any observations?

Top Banana - Just want to say that you have been such a great daughter! Your Dad is very lucky.

[Tall_Allen in reply to Dett]

It sounds like he had a germline test. If there are no BRCA2 mutations on a germline test, there is nothing else that is actionable. It's possible to have somatic mutations that occur in metastases later. Considering the cost, and the low probability of finding something actionable, you may want to wait for some new metastases to biopsy. The other thing to do is not genomic - you can biopsy a recent met looking at the histology, the degree of expression of AR, PSA, PSMA, MSH2, MSH6, PDL1, CGA, SPY, NSE, CD56. That might provide more actionable data.

[Dett in reply to Tall_Allen]

As always, thanks!

[HopingForTheBest1 in reply to Dett]

Foundation One offers a "scholarship" for patients with low income, irrespective of how much assets you may have. For example, if you are retired and on a fixed income you may likely qualify for a discount. At least that's what happened to me back in early 2019 when I qualified for a substantial discount and my BCBS insurance didn't cover it.

Don't know if they still offer it, but it doesn't hurt to ask.

[Dett in reply to HopingForTheBest1]

Thanks. Husband is still working, so we wouldn’t qualify, but that’s good to know.

[TheTopBanana in reply to Dett]

Thank you Dett, how kind of you to write that, the very same to you as a wife!