Friday, June 23, 2017

ASCO 2017: Circulating DNA to measure response in melanoma

Wouldn't it be great if we could do a simple lab draw to determine the type of tumor, as well as tumor burden a patient has??  With such a test we could minimize use of painful biopsies, decrease repeated exposure to radiation via scans, and could much more rapidly determine whether a patient's tumor burden is decreasing in a positive response to a given therapy....or not!

I've been posting studies addressing these possibilities for a while...
From 2014:  With immunotherapy tumors can grow or reappear...even though it is working. Will DNA analysis clarify response???

From 2015:  PCR testing for melanoma

PCR testing for circulating melanoma mo one!!

Circulating Tumor they may eventually impact melanoma diagnosis and response to therapy

From 2016:  Here, I actually broke down all the various biomarkers, what they are and what they mean ~ Biomarkers - blood components, circulating tumor cells AND of the tumor itself

Then there were these:  BRAF testing via blood rather than tumor tissue

Blood tests to diagnose, check response to therapy, and use as follow-up in melanoma!

From 2017:  Circulating DNA predicts response to anti-PD-1

Circulating tumor DNA provide valid way to monitor response to anti-PD-1 therapy for melanoma....AGAIN!!!

Now...there's this:

Circulating tumor DNA as a predictor for response to treatment in BRAF V600E mutant malignant melanoma.
ASCO 2017. J Clin Oncol 35, 2017. Braune, Buboff, Follo, et al.

Background: Available biomarkers LDH and S100B possess limited sensitivity and specificity to predict outcome in melanoma. In this pilot study we evaluated the use of circulating tumor (ct)DNA harboring BRAF and NRAS mutations as a predictive biomarker for treatment response and progression-free survival (PFS) in patients with locally advanced or metastatic melanoma. Methods: We analyzed 89 retrospective plasma samples from 32 unselected pts, and 158 samples from 12 pts included in a prospective trial (DRKS00009507). We included stage III disease with planned resection or stage IV disease before initiation or change of medical treatment. Blood samples were taken at baseline at d +8, d +28, and thereafter at 3 months intervals for up to two years. We developed a hydrolysis probe based, Locked Nucleic Acid assay to detect BRAF V600E and wild type ctDNA by droplet digital PCR. Results were correlated with LDH, S100B and PFS. Results: Sensitivity of BRAF V600E specific assay was 0.01% with a limit of Blank of 0.28 copies/well. Of 31 stage IV pts with retrospective samples, 23 were positive for BRAF V600E ctDNA at least once (74%). Positive pts had a mean of 9 (range: 1-17) and 483 (range: 0.1-16,388) BRAF V600E copies/mL for stage III and stage IV respectively. The presence of ctDNA at baseline predicted poor PFS. A negative slope in BRAF V600E ctDNA was a favorable prognostic factor for PFS with a median PFS of 3.42 vs. 2.56 months (Range 1.87-8.9 vs. 0.89-5.02). Residual ctDNA at the first time point after initiation or change of treatment was related to a shorter PFS. Based on 144 measurement pairs, BRAF ctDNA strongly correlated with S100 and LDH. Conclusions: Residual ctDNA early after change or institution of treatment predicted tumor progression at first clinical response assessment. A positive to negative conversion or a decrease indicated a more favorable course. These data support the use of ctDNA as an early predictive marker for treatment response. We will examine whether two or more detected mutations indicate clonal heterogeneity and confer adverse prognosis. 

Here, using a blood test to check for bits of circulating tumor DNA for BRAF V600E and wild type, the researchers looked at 89 previously drawn blood samples from 32 patients along with 158 blood samples from 12 patients in this trial.  These samples were collected at baseline, and in roughly 1 week, 1 month and then q 3 months for up to 2 years.  Examination of the previously drawn samples showed that 23 of the 31 Stage IV patients were positive for BRAF V600E circulating tumor cells in their blood at least once (74%).  The presence of circulating DNA from tumor cells at baseline was a poor indicator for PFS (progression free survival), while decreasing levels of same was a favorable prognostic factor for PFS.  Patients that still had circulating DNA from tumor cells in their blood "early after a change or institution of treatment predicted tumor progression at first clinical response assessment".  If the test changed from being positive for the ctDNA to negative for it, or if there was a decrease in the level measured, the patients had a more favorable course.

Makes sense, right?  If you have a lot of circulating tumor DNA in your blood...that's not good.  If you still have ctDNA floating around after you have started a new doesn't bode well for you to respond well to that treatment.  However, if you have little ctDNA period, or if the amount you have is decreasing with your is likely that you will do well!!!  Think how much more quickly we could get a patient on the treatment that works for them with a tool like this!!!  I think we've beat around this bush for long enough!!!  Let's make peripheral blood sample testing for circulating tumor DNA a reality!! - c

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