Circulating tumor DNA to help differentiate true progression of melanoma vs pseudoprogression in patients treated with anti-PD-1

I've been yelling for some time about the need to develop, refine and put into practice valid, reliable blood assays....whether they are measuring circulating DNA, tumor cells, various other tumor makers, white blood cells, any other floating bits and bobs...in order to diagnosis melanoma, determine the most effective treatment, and recognize progression and/or effectiveness of that treatment.  Here is a link to a zillion of those reports/rants:  Blood assays, tumor markers, circulating DNA, you name it!!!! 

In fact, the report below is a follow-up report and specific look at pseudoprogression from this study:  2017: Circulating DNA predicts response to anti-PD1

Now, there's this -

Association Between Circulating Tumor DNA and Pseudoprogression in Patients With Metastatic Melanoma Treated With Anti-Programmed Cell Death 1 Antibodies.Lee, Long, Menzies, et al. JAMA Oncol. 2018 Feb 8.  

Longitudinal circulating tumor DNA (ctDNA) has been shown to predict response and survival in patients with metastatic melanoma treated with anti-programmed cell death 1 (PD-1) antibodies. Pseudoprogression, defined as radiologic finding of disease progression prior to response, has been a challenge to clinicians.

To establish whether ctDNA at baseline and up to week 12 of treatment can differentiate between the radiologic findings of pseudoprogression and true progression in patients with metastatic melanoma.

This explorative biomarker study examined circulating BRAF and NRAS mutations in a cohort of 125 patients with melanoma receiving PD-1 antibodies alone or in combination with ipilimumab between July 3, 2014, and May 24, 2016. Pseudoprogression was defined retrospectively as radiologic progression not confirmed as progressive disease at the next radiologic assessment. Plasma samples of ctDNA at baseline and while receiving treatment were taken for analysis prospectively over the first 12 weeks of treatment. Favorable ctDNA profile (undetectable ctDNA at baseline or detectable ctDNA at baseline followed by greater than 10-fold decrease) and unfavorable ctDNA profile (detectable ctDNA at baseline that remained stable or increased) were correlated with response and prognosis.

Early differentiation of pseudoprogression from true progression using longitudinal ctDNA profile.

According to guidelines by Response Evaluation Criteria in Solid Tumors (RECIST), progressive disease occurred in 29 of the 125 patients (23.2%). Of the 29 patients, 17 (59%) were 65 years or younger, 18 (62%) were men, 9 (31%) had pseudoprogression, and 20 (69%) had true progression. Of the 9 patients (7%) with confirmed pseudoprogression, all patients had a favorable ctDNA profile. At a median follow-up of 110 weeks, 7 of 9 patients (78%) were alive. All but 2 patients with true progression had an unfavorable ctDNA profile. Sensitivity of ctDNA for predicting pseudoprogression was 90% and specificity was 100%. The 1-year survival for patients with RECIST-defined progressive disease and favorable ctDNA was 82% vs 39% for unfavorable ctDNA. Overall survival was longer in patients with a partial response (54 of 125 patients [43%]) compared with patients with progressive disease and a favorable ctDNA profile (11 of 125 patients [9%]).

The results demonstrate that ctDNA profiles can accurately differentiate pseudoprogression from true progression of disease in patients with melanoma treated with PD-1 antibodies. Results of this blood test performed at regular intervals during systemic treatment reflect tumor biology and have potential as a powerful biomarker to predict long-term response and survival.

Here researchers looked at 125 melanoma patients with BRAF and NRAS mutations treated with anti-PD-1 alone or in combination with ipi between July 2014 and May 2016.  They drew their blood before and during the first 12 weeks of their treatment and correlated those findings with the patient's response and prognosis.  Per the RECIST scale, progressive disease occurred in 29 of the 125.  9 had pseudoprogression and 20 had real progression.  "All but 2 of the patients with true progression had an unfavorable ctDNA profile.  Sensitivity of ctDNA for predicting pseudoprogression was 90% and specificity was 100%."  The 1 year survival for the folks with RECIST defined progression but WITH the favorable blood test ctDNA was 82%, while for folks with an unfavorable ctDNA it was only 39%.  "The results demonstrate that ctDNA profiles can accurately differentiate pseudoprogression from true progression of disease in patients with melanoma treated with PD-1 antibodies."

I think we've yammered about this stuff enough.  Consistent, available, defined blood assays need to be made readily available for melanoma patients!!!! C'mon man!!!! - c