So the genetic testing came back on my partner’s tumor (GBM, first recurrence), and while researching the mutations, I found Stephen W’s account of the hyperprogression study linking use of checkpoint inhibitors with accelerated progression in people with certain mutations, including amplification in MDM2 or MDM4. All 6 of the people in the cohort with MDM2/MDM4 amplifications experienced hyperprogression (across 5 different cancer types, none of which were primary CNS, although several had metastases in the brain; 5 were MDM2 amplified, 1 was MDM4).
My partner’s genetic report includes copy number gain in MDM4. No indication of the size of the gain; I’ve asked the company if they can clarify.
As it happens, we started pembrolizumab 2 weeks ago. I figured the worst that would happen was that it was ineffective; it never occurred to me that it might accelerate progression.
The study doesn’t prove that checkpoint inhibitors caused the hyperprogression. It’s possible that MDM2/MDM4 amplification caused the hyperprogression on its own. The possible mechanism seems understood: MDM2 suppresses p53, a major tumor suppressor (p53 is mutated in over 50% of all cancers). I found one study that showed MDM2 amplification is prognostic for poor survival in breast cancer. On other hand, the chart at the end of the hyperprogression study sure makes it look like acceleration began with the onset of checkpoint therapy.
My partner’s tumor showed high expression of PD-L1 (50%), and also has mutations in NF1 and TERT. All three of those are correlated with better response to PD-1 inhibitors in other cancers.
The next pembro infusion is scheduled for March 19. We have to decide by then whether to continue with it or not. Thankfully we’ll have an MRI that morning. The tough call will be if there’s no evidence of progression. I know there’s no clearcut rationale for making a decision either way, but I’m curious if anyone here has any advice.
Other biologically relevant mutations found are TERT, PTPN11, NFE2L2, PTEN, and CDKN2A. IDH1 is wildtype. MGMT is reported as unmethylated by sequencing. The tumor mutational burden increased from 2.05 to 5, and the MSI status is stable (i.e., no mismatch repair defect).
Our current regimen: CCNU, pembrolizumab, Vitamin D, melatonin, PSK, curcumin (also levetiracetam, Vimpat, Xarelto)
Planned additions: boswellia
Actively considering: ECGC, THC/CBD, Hydro+ALA, celexocib, metformin, everolimus
Thanks,
Brandon
