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Melanoma is a malignancy of pigment-producing cells that is driven by a variety of genetic mutations and aberrations. In most cases, this leads to upregulation of the mitogen-activated protein kinase (MAPK) pathway through activating mutations of upstream mediators of the pathway including BRAF and NRAS. With the advent of effective MAPK pathway inhibitors, including the US FDA-approved BRAF inhibitors vemurafenib and dabrafenib and MEK inhibitor trametinib, molecular analysis has become an integral part of the care of patients with metastatic melanoma. In this article, the key molecular targets and strategies to inhibit these targets therapeutically are presented, and the techniques of identifying these targets, in both tissue and blood, are discussed.

The bone marrow (BM) microenvironment contains numerous cell types, including immunosuppressive tumor-associated macrophages (TAM), that promote the growth and survival of multiple myeloma (MM) cells. TAMs are recruited to the site of MM within the BM and help to create a permissive microenvironment that promotes the homing of MM cells. Prior studies have shown that the relative amount of BM-associated TAMs correlates with patient poor outcome in MM (Suyaný et al. 2013). Emerging evidence suggests that the absolute monocyte count (AMC) in peripheral blood may reflect the level of TAM recruitment at the tumor site and its prognostic significance has been shown in other lymphoid malignancies. Absolute lymphocyte count (ALC) as a surrogate marker for host immune system has prognostic significance. Early lymphocyte recovery after induction therapy or autologous stem cell transplant correlates with better survival for MM patients. The aim of the present study was to investigate the prognostic significance of the ratio of ALC, as a surrogate of host immune status, to AMC, which reflects the MM-immune microenvironment, in predicting clinical outcome among newly diagnosed MM patients. Methods: The study included 372 MM patients (pts), diagnosed 2004-2014 at the University Hospitals in Cleveland, OH and University of Cincinnati, Cleveland OH who had CBC differentials at diagnosis. The primary end-point of the study was progression free survival (PFS) calculated from the time of diagnosis. The Cox proportional hazards model was used to evaluate ALC/AMC at diagnosis as a prognostic factor for PFS as well as to assess and adjust of other know prognostic factors. Results: Median pt age was 67.3 years (range: 30-92), 53% were male and 47% female. Distributions of detailed baseline characteristics are presented in Table-1. The median follow up was 33.5 months (range: 1.16 - 122.9). Pts who were lost to follow up were censored from the survival analysis. At the time of this analysis 92 pts (24%) had died, 75 (20%) of them was due MM. The median AMC, ALC and ALC/AMC ratio at diagnosis was 412 cells/µL, 1,461 cells/µL and 3.9, respectively. ALC neither AMC was associate with different PFS or overall survival (OS). ALC/AMC as a continuous variable was identified as a predictor of PFS [Hazard ratio (HR) = 0.62, (95% CI: 0.52 - 0.75), p-value: 0.001]. To define a cut-off point, the choice of ALC/AMC ≥ 3.6 yielded the greatest differential in survival, based on the chai-squarevalue (χ2 = 94·4, P < 0·01) analyzed at different cut-off points between the 25% and 75% quartiles (2.9 - 4.3), from the log-rank test. Pts with an ALC/AMC ≥ 3.6 (n=236) experienced a superior median PFS compared to patients with an ALC/AMC < 3.6 (n=136) [Median PFS, 24 vs. 43 months respectively, P-value < 0.001] (Figure-1). Multivariate analysis including ALC, age, ISS stage and treatment type (autologous stem cell transplant vs. no transplant) showed that ALC/AMC as well as treatment type remained an independent prognostic factor of PFS after the step-wise fashion analysis. Out of 372 patients 192 patients had cytogenetics analysis at diagnosis. Univariate analysis demonstrated that low ALC, high AMC and a low ALC/AMC ratio were correlated with presence of del (17p) and t(4,14) and light chain myeloma. Multivariate analysis indicated that the ALC and AMC were not associated with any specific cytogenetic group. However, the ALC/AMC ratio independently predict 17p and t(4,14) abnormalities (p-value = .041). Low ALC, high AMC, and low ALC/AMC ratio were associated with poor prognostic factors such as high β2-microglobulin. Conclusions: In our cohort, myeloma patients with a higher ALC/AMC at diagnosis enjoyed a longer PFS (either as a continuous or dichotomized variable). Also, multivariate analysis demonstrated that patient with tumors that harbored del (17p) or t(4, 14) had low ALC/AMC ratio suggesting possible immunoparesis. ALC at diagnosis was not associated with OS, in contrast to prior studies, possibly due to the shorter follow-up duration used here and inadequate power to predict OS. Taken together, our data potentially suggest the ALC/AMC ratio as a readily available surrogate marker to assess the relative strength of host immune system to myeloma-induced immunoparesis. The ratio can serve as a biomarker to stratify patients for future immunological therapies. Also, our findings indicate that the host immune status should be carefully monitored. Disclosures No relevant conflicts of interest to declare.

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e16621 Background: Hepatocellular carcinoma (HCC) when localized to liver is typically diagnosed with Characteristic radiographic features while tumor tissue sampling is not warranted anymore. Recently, circulating tumor DNA (ctDNA) has been used to evaluate mutational profile in solid tumors in order to personalize treatments. However, it is not established well in HCC, specifically in Hispanic patients. This study aims to describe the mutational profile of Hispanic patients with ctDNA analysis as a single center experience. Methods: We enrolled 33 patients with diagnosis of HCC from 1/2016 to 12/2019. Diagnosis of HCC was based on Characteristic radiological features, defined by Liver Imaging Reporting and Data System (LI-RADS category 5). 18 patients self-identified as Hispanic while remaining were mainly Caucasians. FoundationOne Liquid genomic testing by Foundation Medicine was used for profiling of 77 most commonly mutated genes of sampled blood. Results: Baseline patient characteristics were similar between Hispanic and non-Hispanic population. Median age of diagnosis was 64 in this cohort with 23(70%) males and 10(30%) females. 30 patients had underlying cirrhosis with hepatitis C present in 19(58%) and heavy alcohol abuse in 15(45%) of cirrhotic. 32 patients had liver-only disease, while we had one patient with extrahepatic disease. 22 of these 33 patients had a single HCC lesion while 11 had multifocal HCC. 20 patients (60.6%) had at least 1 pathogenic mutation. 13 patients (39.4%) did not have any pathogenic mutations. The frequency of commonly mutated genes for our Hispanics versus non-Hispanics were following: CTNNB1(45.5% vs 44.4%), TERT (45.5% vs 55.6%), TP53(36.4% vs 55%), CNK2A (18.2% vs 0). Median of Allele frequency percentage was 0.81%. Mutations in TP53 was commonly detected at codon 249(R249S). Presence of these pathogenic mutations were associated with poor clinical features such as multifocal disease and higher AFP values > 59 as compared to 15 without mutations. Other mutations present at lower percentage include ERBB2, PIK3CA, DNMT3A, GNAS, KDR, RB1, PTEN and their frequency was similar in both Hispanic and non-Hispanic groups. Conclusions: Genomic profiling of ctDNA by liquid biopsy in our Hispanic patients with HCC appears similar to established mutational profile of HCC in Caucasian and Asian populations. These findings can be verified in heterogeneous populations in order to serve as a potential prognostic tool and help with personalized medicine.