Friday, 25 November 2016

FoundationOne test now includes "Tumor Mutational Burden" quantification

To my surprise, I just learned that FoundationOne reports now include a quantification of "tumor mutational burden" expressed as number of mutations per megabase of DNA.  This would be the most accurate test for hypermutation.

Foundation One webpage

I believe there is a link between MGMT methylation status, and risk of hypermutated recurrence, which could help explain the increased risk of progression to hypermutated secondary GBM recurrences for IDH1-mutant low grade gliomas (which are usually MGMT methylated) treated with TMZ.

I'd especially recommend FoundationOne for recurrences of MGMT methylated gliomas post-TMZ treatment. This test would tell you if the tumor is hypermutated and therefore if further TMZ could actually make the situation worse.  Unfortunately patients outside the US must self-pay, and the discounted price as of September 2014 was $4600 US.


  1. Very cool that we can now test our mutational burden. Another piece of the puzzle! Excellent.

  2. Awesome Stephen. Do you have any literature on treatment strategies for recurrent hypermutated secondary GBM?

  3. There is very little on this subject, since most GBM recurrences are not specifically tested for hypermutation. There was one case report of a childhood hypermutated GBM with a germline mutation in PMS2 (a mismatch repair gene) being treated successfully with nivolumab. And there has also been studies on greater response rates to PD-1 inhibitors for patients with higher mutational burden in other types of cancers. These studies can be found in the libarary: Immunology folder, Checkpoint inhibitor subfolder.

    The latest study with relevance to this question was an abstract presented at this year's SNO conference.


    This is the follow-up study to the study I summarized in the last Astrocytoma Options update, on NAMPT inhibitors.

    "Importantly, this TMZ-induced vulnerability was main-
    tained under mismatch repair (MMR) deficiency, a common TMZ-resistance
    mechanism after long term treatment exposure."

    The finding was that temozolomide, by inducing DNA damage repair by PARP, further sensitized IDH-mutant glioma cells to NAMPT inhibitors. The reason being that PARP is an enzyme that consumes NAD+, and NAMPT inhibitors block one of the main NAD+ salvage pathways. IDH-mutant cells are hypersensitive to therapies that deplete NAD+.

    It's not clear whether the quote above refers to results with TMZ alone or to the combination of TMZ with NAMPT inhibitors. Hopefully the study will see publication soon. There are no NAMPT inhibitors that are FDA approved, and there is only one in trials - an early stage trial for advanced solid tumors or non-Hodgkins lymphoma.

    1. Hi Stephen. Have you ever heard of anyone using this company as well?

      Ashion Analytics

    2. No I hadn't heard of this company, but this sounds very much like FoundationOne. I wonder how the pricetag compares with FoundationOne, and if this company also offers a mutational burden analysis as Foundation is now doing.

  4. Thank you Stephen. Awesome info as always.

    Makes sense that more mutations would correlate to a better response to immunotherapy or checkpoint inhibitors as tumor may look more foreign. Swelling of course a big issue but hopefully they will find a safe and effective dosing schedule.

    Question however. Do you hypothesize that that the cocktail therapy (> than 8 different drugs) with TMZ would work on recurrent or hypermutated GBM?