Important stuff floating in our blood - tumor DNA, micro RNA, cytokines - can determine tumor burden, predict response, and side effects for melanoma patients!!!

Continuing from yesterday.....  Our blood is a fairly accessible information rich soup that can tell us all sorts of things about our bodies!!!  One important ingredient for melanoma patients is circulating tumor DNA.  Here's a load of prior reports: Circulating tumor DNA - to determine diagnosis, disease burden, response to therapy, etc  Here are a couple more reports:

Correlation between circulating tumour DNA and metabolic tumour burden in metastatic melanoma patients.  McEvoy, Warburton, Al-Ogaili, et al. BMC Cancer. 2018 Jul 9.

Circulating tumour DNA (ctDNA) may serve as a measure of tumour burden and a useful tool for non-invasive monitoring of cancer. However, ctDNA is not always detectable in patients at time of diagnosis of metastatic disease. Therefore, there is a need to understand the correlation between ctDNA levels and the patients' overall metabolic tumour burden (MTB).  Thirty-two treatment naïve metastatic melanoma patients were included in the study. MTB and metabolic tumour volume (MTV) was measured by 18F-fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT). Plasma ctDNA was quantified using droplet digital PCR (ddPCR).  CtDNA was detected in 23 of 32 patients. Overall, a significant correlation was observed between ctDNA levels and MTB. CtDNA was not detectable in patients with an MTB of greater than/= to 10, defining this value as the lower limit of tumour burden that can be detected through ctDNA analysis by ddPCR.  We showed that ctDNA levels measured by ddPCR correlate with MTB in treatment naïve metastatic melanoma patients and observed a limit in tumour size for which ctDNA cannot be detected in blood. Nevertheless, our findings support the use of ctDNA as a non-invasive complementary modality to functional imaging for monitoring tumour burden.

From validity to clinical utility: the influence of circulating tumor DNA on melanoma patient management in a real-world setting. Rose, Luber, Makell, et al. Mol Oncol. 2018 Aug 16.

Melanoma currently lacks a reliable blood-based biomarker of disease activity, although circulating tumor DNA (ctDNA) may fill this role. We investigated the clinical utility (i.e., impact on clinical outcomes and interpretation of radiographic data) of measuring ctDNA in patients with metastatic or high-risk resected melanoma. Patients were prospectively accrued into greater than/= to 1 of 3 cohorts, as follows. Cohort A: patients with radiographically-measurable metastatic melanoma who underwent comparison of ctDNA measured by a BEAMing digital PCR assay to tissue mutational status and total tumor burden; when appropriate, determinations about initiation of targeted therapy were based on ctDNA data. Cohorts B and C: patients with BRAF- or NRAS-mutant melanoma who had either undergone surgical resection of high-risk disease (cohort B) or were receiving or had received medical therapy for advanced disease (cohort C). Patients were followed longitudinally with serial ctDNA measurements with contemporaneous radiographic imaging to ascertain times to detection of disease activity and progressive disease, respectively. The sensitivity and specificity of the ctDNA assay was 86.8% and 100%, respectively. Higher tumor burden and visceral metastases were found to be associated with detectable ctDNA. In 2 patients in cohort A, ctDNA test results revealed a targetable mutation where tumor testing had not; both patients experienced a partial response to targeted therapy. In 4 of 30 patients with advanced melanoma, ctDNA assessments indicated evidence of melanoma activity that predicted radiographic evidence of disease progression by 8, 14, 25 and 38 weeks, respectively. CtDNA was detectable in 3 of these 4 patients coincident with radiographic evaluations that alone were interpreted as showing no evidence of neoplastic disease. Our findings provide evidence for the clinical utility of integrating ctDNA data in managing patients with melanoma in a real-world setting.

Among the many bio-markers present in our blood, there's also circulating RNA.   Prior reports:  RNA and biomarkers generally  Now, this:

Extracellular microvesicle microRNAs as predictive biomarkers for targeted therapy in metastastic cutaneous malignant melanoma.  Svedman, Loncharoenkal, Bottaj, et al. PLoS One. 2018 Nov.

Mitogen activated-protein kinase pathway inhibitors (MAPKis) improve treatment outcome in patients with disseminated BRAFV600 mutant cutaneous malignant melanoma (CMM) but responses are of limited duration due to emerging resistance. Although extensive research in mechanisms of resistance is being performed, predictive biomarkers for durable responses are still lacking. We used miRNA qPCR to investigate if different levels of extracellular microvesicle microRNA (EV miRNA) in matched plasma samples collected from patients with metastatic IV BRAFV600 mutated CMM before, during and after therapy with MAPKis could serve as predictive biomarkers.  EV miRNAs were extracted from plasma samples from 28 patients collected before and during therapy, measured by quantitative PCR-array and correlated to therapy outcome. Increased levels of EV let-7g-5p during treatment compared to before treatment were associated with better disease control with MAPKis. Elevated levels of EV miR-497-5p during therapy were associated with prolonged progression free survival (PFS).  EV miRNAs let-7g-5p and miR-497-5p were identified as putative novel predictive biomarkers of MAPKi treatment benefit in metastatic CMM patients highlighting the potential relevance of assessing EV miRNA during and after treatment to unravel novel mechanisms of resistance.

Circulating cytokines are substances like interleukin, interferon, and growth factors, that cells in our immune system secrete in order to affect other cells. Here's a report for a little background:  Eosinophilia with Nivo and Pembro - A predictor of success?!!
Here they are being examined as predictors of toxicity to immunotherapy:

Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1-based immunotherapy. Lim, Lee, Gide, et al. Clin Cancer Res. 2018 Nov 8.  

Combination PD-1 and CTLA-4 inhibitor therapy has dramatically improved the survival of patients with advanced melanoma but is also associated with significant immune-related toxicities. This study sought to identify circulating cytokine biomarkers of treatment response and immune-related toxicity.  The expression of 65 cytokines was profiled longitudinally in 98 melanoma patients treated with PD-1 inhibitors, alone or in combination with anti-CTLA-4, and in an independent validation cohort of 49 patients treated with combination anti-PD-1 and anti-CTLA-4. Cytokine expression was correlated with RECIST response and immune-related toxicity, defined as toxicity that warranted permanent discontinuation of treatment and administration of high dose steroids.

Eleven cytokines were significantly upregulated in patients with severe immune-related toxicities at baseline and early during treatment. The expression of these eleven cytokines was integrated into a single toxicity score, the CYTOX score, and the predictive utility of this score was confirmed in the discovery and validation cohorts. 

The CYTOX score is predictive of severe immune-related toxicity in melanoma patients treated with combination anti-CTLA-4 and anti-PD-1 immunotherapy. This score, which includes pro-inflammatory cytokines such as IL-1a, IL-2 and IFNa2, may help in the early management of severe, potentially life-threatening immune-related toxicity.

Hoping for much more consistency and use of these relatively simple tests in order to reap better treatment outcomes for melanoma patients in 2019!!! - c