Massively parallel sequencing (MPS) of circulating DNA in patients with metastatic colorectal cancer (mCRC): Prognostic significance and early changes during chemotherapy (CT).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11015-11015 ◽  
Author(s):  
Jeanne Tie ◽  
Isaac Kinde ◽  
Hui-Li Wong ◽  
Joseph James McKendrick ◽  
Peter Gibbs ◽  
...  
Keyword(s):  
Massively Parallel Sequencing ◽  
Prognostic Significance ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
Rank Test ◽  
Cancer Center ◽  
Circulating Dna ◽  
Plasma Samples ◽  
Mutational Status

11015 Background: Prognostic and predictive biomarkers in mCRC are urgently needed. Circulating tumor cells are a promising blood biomarker, but are detectable in only a minority of pts. Recently, analysis of circulating tumor DNA (ctDNA) has shown promise as a liquid biopsy, reflecting the evolving mutational status of the tumor. Here we explored baseline ctDNA as a prognostic marker, and early changes in ctDNA as a marker of CT response. Methods: Serial plasma samples and CEA were collected at baseline (D1), day 3 (D3) and cycle 2 day 1 (C2D1) from 40 mCRC pts receiving standard combination CT. Restaging scans performed at 8 weeks were centrally assessed using RECIST criteria. Samples were analyzed at Johns Hopkins Kimmel Cancer Center. Initially tumor tissue was analyzed for hotspot mutations in TP53, APC, KRAS, BRAF, PIK3CA and FBXW7. The same mutation was queried and quantified in plasma using a MPS platform (Safe-SeqS). Log-rank test was used to compare survival curves and Wilcoxon matched pairs test was used to compare paired plasma samples. Results: Preliminary data is available on 19 pts in this ongoing study. Using our initial panel at least 1 mutation was found in 16 of 19 (84.2%) tumors (7 KRAS, 3 TP53, 3 BRAF, 2 APC and 1 PIK3CA), with matching ctDNA found for each pt. For the remaining 3 cases a further panel of mutations is being analyzed. Median D1 cell free DNA (cfDNA) and ctDNA levels were 1.98 ng/ul (0.15 – 57.18) and 523 mutant fragments (frag)/ml (0.4 – 109,876), respectively. Pts with D1 cfDNA of ≥ 2.5 compared with < 2.5 had shorter median overall survival (OS; 6.9 v 12.2 months, p = 0.0086), with a trend for shorter progression-free survival (PFS; 3.6 v 8.2 months, p = 0.3477). A surge of ctDNA level from D1 to D3 was typically observed (median increase: 91.2 frag/ml, p = 0.0313), followed by a drop (median decrease from D1 to C2D1: 208.8 frag/ml, p = 0.0098). All pts with a decrease in ctDNA at C2D1 had a reduction in tumor size at 8 weeks. Conclusions: In all cases of mCRC where tumor mutation was identified, matching ctDNA was detected in plasma. Circulating DNA is a promising marker of prognosis. Early changes in DNA levels may be a useful marker of tumor response.

scholarly journals Frequency and Prognosis of Epidermal Growth Factor Receptor Variant III Mutations in Glioblastoma Multiforme among Indian Patients: A Single-Institution Study

2020 ◽  
Vol 09 (03) ◽  
pp. 126-129
Author(s):  
Wesley Mannirathil Jose ◽  
Vinayak Munirathnam ◽  
V. Narendranath ◽  
Arun Philip ◽  
Pavithran Keechilat
Keyword(s):  
Growth Factor ◽  
Glioblastoma Multiforme ◽  
Epidermal Growth Factor ◽  
World Literature ◽  
Mutational Analysis ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Rank Test ◽  
Cancer Center ◽  
Epidermal Growth

Abstract Background Glioblastoma multiforme (GBM) is a disease with poor outcome. Alterations or mutations in epidermal growth factor receptors (EGFRs) are found in GBM and may be targeted to improve outcomes. Aims We analyzed the frequency of EGFR variant III (vIII) mutations in patients with GBM and their outcomes after standard treatment. Materials and Methods This is a retrospective study conducted in a single tertiary cancer center in south India. Forty patients with GBM who had their entire treatment done at this center were identified, and their primary tumor tissue blocks were retrieved. Genomic DNA was extracted, and molecular analysis was performed and analyzed. The results of mutational analysis were correlated with treatment outcome of the patients. Statistical Analysis Survival outcome was analyzed using the Kaplan–Meier method. The log-rank test was used to assess the association between the groups and various parameters. Results Our study showed a similar incidence of EGFR vIII alterations as published in world literature, but we did not find any difference in overall survival (OS) and progression-free survival (PFS) in patients with EGFR vIII mutation compared with nonmutant cohort. Conclusions Contrary to the existing literature which indicated EGFR vIII alterations to be a negative prognostic indicator, our study did not find it to be an independent predictor of prognosis among Indian GBM patients treated with present standard of care.

scholarly journals Phase Ib/II trial evaluating the safety, tolerability and immunological activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab (anti-CTLA-4) combined with FOLFOX in patients with metastatic colorectal cancer

ESMO Open ◽  
2018 ◽  
Vol 3 (4) ◽  
pp. e000375 ◽  
Author(s):  
Jean-David Fumet ◽  
Nicolas Isambert ◽  
Alice Hervieu ◽  
Sylvie Zanetta ◽  
Jean-Florian Guion ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Target Therapy ◽  
Performance Status ◽  
Human Monoclonal Antibody ◽  
Eastern Cooperative Oncology Group ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Mutational Status

Background5-Fluorouracil plus irinotecan or oxaliplatin alone or in association with target therapy are standard first-line therapy for metastatic colorectal cancer (mCRC). Checkpoint inhibitors targeting PD-1/PD-L1 demonstrated efficacy on mCRC with microsatellite instability but remain ineffective alone in microsatellite stable tumour. 5-Fluorouracil and oxaliplatin were known to present immunogenic properties. Durvalumab (D) is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This study is designed to evaluate whether the addition of PD-L1 and CTLA-4 inhibition to oxaliplatin, fluorouracil and leucovorin (FOLFOX) increases treatment efficacy.MethodsThis phase II study (ClinicalTrials.gov NCT03202758) will assess the efficacy and safety of FOLFOX/D/T association in patients with mCRC (n=48). Good performance status patients (Eastern Cooperative Oncology Group <2) with untreated, RAS mutational status mCRC will be eligible. Prior adjuvant therapy is allowed provided recurrence is >6 months postcompletion. There is a safety lead in nine patients receiving FOLFOX/D/T. Assuming no safety concerns the study will go on to include 39 additional patients. Patients will receive folinic acid (400 mg/m²)/5-fluorouracil (400 mg/m² as bolus followed by 2400 mg/m2 as a 46-hour infusion)/oxaliplatin (85 mg/m2) every 14 days with D (750 mg) D1 every 14 days and T (75 mg) D1 every 28 days. After six cycles of FOLFOX only D/T will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is safety and efficacy according to progression-free survival (PFS); secondary endpoints include overall response rate and quality of life. Hypothesis is that a PFS of 50% at 6 months is insufficient and a PFS of 70.7% is expected (with α=10%, β=10%). Blood, plasma and tumour tissue will be collected and assessed for potential prognostic and predictive biomarkers.

Association of the neutrophil to eosinophil ratio with response to immunotherapy-based combinations in metastatic renal cell carcinoma.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 341-341
Author(s):  
Matthew D Tucker ◽  
Katy Beckermann ◽  
Kristin Kathleen Ancell ◽  
Kerry Schaffer ◽  
Renee McAlister ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Clinical Outcomes ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Objective Response ◽  
Progression Free Survival ◽  
Rank Test ◽  
Cancer Center ◽  
Exact Test

341 Background: Neutrophilia is known to be associated with worse prognosis in metastatic renal cell carcinoma (mRCC); however, less is known about the role of eosinophils in the response to immunotherapy (IO). We investigated the association of the baseline neutrophil to eosinophil ratio (NER) with outcomes to IO-based combination treatment in mRCC. Methods: Patients with mRCC treated with ipilimumab plus nivolumab, pembrolizumab plus axitinib, or avelumab plus axitinib at the Vanderbilt-Ingram Cancer Center were retrospectively identified. Patients on >10mg prednisone and patients with prior IO were excluded. Baseline NER (at time of first IO) and association with progression free survival (PFS), overall survival (OS), and objective response rate (ORR) were investigated. Data cutoff was 9/1/2020. Analysis for PFS and OS was performed using the log-rank test and Mantel-Haenszel method, and analysis of the odds ratio for ORR was performed using Fischer’s exact test. Results: Sixty-one patients were identified: 89% clear cell histology, 74% prior nephrectomy, 69% IMDC intermediate risk, and 72% treatment-naïve. Patients with baseline NER < median (N=31) had improved clinical outcomes compared to patients with baseline NER > median (N=30) (Table). Improvement in PFS by NER was maintained when stratified by anti-PD-1/CTLA-4 and anti-PD(L)-1/VEGF (p= 0.0062 and p= 0.049); however, differences in OS and ORR were no longer significant. The median baseline NER among patients with partial response (PR) was significantly lower at 22.7 (95% CI 18.9-31.1) vs. 51.6 (95% CI 39.5-93.1) among those with progressive disease (PD) (p= 0.0054). For comparison, the median neutrophil to lymphocyte ratio was not significantly different between PR (2.60) and PD (3.84, p= 0.056). Conclusions: Patients with a low baseline NER treated with IO-based combinations had improved clinical outcomes compared to patients with a high baseline NER. Additional investigation of this parameter in larger cohorts is warranted. [Table: see text]

scholarly journals Prognostic significance of MUC2, CDX2 and SOX2 in stage II colorectal cancer patients

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Sara Ribeirinho-Soares ◽  
Diana Pádua ◽  
Ana Luísa Amaral ◽  
Elvia Valentini ◽  
Daniela Azevedo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Chemotherapy ◽  
Prognostic Significance ◽  
Tumor Resection ◽  
Disease Free Survival ◽  
Predictive Biomarkers ◽  
Stage Ii ◽  
Health Concern ◽  
Rank Test ◽  
Low Expression

Abstract Background Colorectal cancer (CRC) remains a serious health concern worldwide. Despite advances in diagnosis and treatment, about 15 to 30% of stage II CRC patients subjected to tumor resection with curative intent, develop disease relapse. Moreover, the therapeutic strategy adopted after surgery is not consensual for these patients. This supports the imperative need to find new prognostic and predictive biomarkers for stage II CRC. Methods For this purpose, we used a one-hospital series of 227 stage II CRC patient samples to assess the biomarker potential of the immunohistochemical expression of MUC2 mucin and CDX2 and SOX2 transcription factors. The Kaplan-Meier method was used to generate disease-free survival curves that were compared using the log-rank test, in order to determine prognosis of cases with different expression of these proteins, different mismatch repair (MMR) status and administration or not of adjuvant chemotherapy. Results In this stage II CRC series, none of the studied biomarkers showed prognostic value for patient outcome. However low expression of MUC2, in cases with high expression of CDX2, absence of SOX2 or MMR-proficiency, conferred a significantly worst prognosis. Moreover, cases with low expression of MUC2 showed a significantly clear benefit from treatment with adjuvant chemotherapy. Conclusion In conclusion, we observe that patients with stage II CRC with low expression of MUC2 in the tumor respond better when treated with adjuvant chemotherapy. This observation supports that MUC2 is involved in resistance to fluorouracil-based adjuvant chemotherapy and might be a promising future predictive biomarker in stage II CRC patients.

Association of Elevated Circulating Proteasome Levels at Diagnosis with Poor Outcome in Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5140-5140
Author(s):  
Peter Liebisch ◽  
Stephan Sixt ◽  
Hagen S Bachmann ◽  
Ulrich H Frey ◽  
Juergen Peters ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Observation Interval ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
Ubiquitin Proteasome System ◽  
University Hospital ◽  
Rank Test ◽  
Healthy Controls ◽  
Serum Samples ◽  
Poor Outcome

Abstract Background: The proteasome is a proteolytic complex for intracellular degradation of ubiquitinated proteins which are involved in cell cycle regulation and apoptosis. A constitutively increased proteasome activity has been found in myeloma cells. Recent studies have shown that inhibition of the ubiquitin-proteasome system can be successfully used as a targeted therapy in multiple myeloma (MM). Recent data suggest a significant correlation between circulating proteasome levels (CPL) and outcome in patients with MM. Therefore, we investigated CPL in 110 patients in order to assess the role of CPL in MM. Experimental design: CPL were measured in serum samples from healthy controls (N=10) as well as from patients with monoclonal gammopathies of undetermined significance (N=27), indolent MM (N=15) and symptomatic MM (N=68) using enzyme-linked immunoabsorbent assay (ELISA) techniques detecting circulating 20S proteasome components. All serum samples were collected at the University Hospital in Ulm at time of diagnosis. Results: The median CPL were 123.5 ng/mL (range, 95–185 ng/mL) in healthy controls, 180 ng/mL (range, 100–485 ng/mL) in patients with MGUS (N=27) or indolent MM (N=15), and 227.5 ng/mL (range, 100–985 ng/mL) in patients with symptomatic MM (N=70). The CPL of patients with symptomatic MM were significantly elevated compared with healthy donors (p=0.0017) and to persons with asymptomatic gammopathies (p=0.046). While CPL were also significantly higher in the MGUS/indolent MM cohort as compared to controls (p=0.03), CPL in MGUS and indolent MM were comparable. Using ROC analysis in the symptomatic MM cohort patients with CPL &gt;150ng/mL (N=50) had a significantly shorter progression-free survival (PFS) time than patients (N=18) with CPL&lt;150 ng/mL levels (median PFS: 40 versus 57 months, log rank test p=0.026). Of note, all six patients who died in the observation interval had CPL &gt;150ng/mL. Conclusions: Here we demonstrate that increased CPL at diagnosis correlates with poor outcome in symptomatic MM patients. Evaluation of the prognostic significance of CPL in a larger cohort of uniformly treated patients with symptomatic MM is currently under way. This data will be presented at the meeting.

Cisplatin (CDDP) and radiation versus cetuximab (Cx) and radiation in locally advanced head and neck squamous cell cancer (SCHNC): A retrospective review.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e16009-e16009 ◽  
Author(s):  
Prakash Peddi ◽  
Runhua Shi ◽  
Lori Panu ◽  
Fred Ampil ◽  
Cherie-Ann Nathan ◽  
...  
Keyword(s):  
Performance Status ◽  
Cell Cancer ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Complete Response ◽  
Rank Test ◽  
Cancer Center ◽  
Ecog Performance Status ◽  
Chi Square ◽  
Group A

e16009 Background: SCHNC is a common malignancy and approximately 60% of patients present with locally advanced disease. There is paucity of data directly comparing Cx and CDDP with concurrent radiation in locally advanced SCHNC. We retrospectively reviewed charts of patients treated with CDDP and/or Cx along with radiation in locally advanced SCHNC comparing efficacy and outcomes in an academic cancer center. Methods: Ninety-five patients with locally advanced SCHNC were treated with concurrent CDDP (100 mg/m2 day 1, 22, 43) or Cx (400mg/m2 on day -7 and 250mg/m2 weekly) at our institution between January 2006 and June 2011. Forty-four patients were treated with CDDP (group A), 24 with Cx (group B) and 27 were initially started on CDDP but were switched to Cx secondary to toxicity (group C). All patients received concurrent radiation treatments (66-70 Gy, 2.0 Gy/fraction). The selection of CDDP versus Cx was largely based on ECOG performance status (PS) and baseline renal function of the patients. Chi-square test, analysis of variance, and log-rank test was used for analysis. The three groups had similar baseline characteristics except for mean age of 61, 56 and 55 years in group A, B and C respectively; T4 tumors consisted of 44%, 75% and 41% in groups A, B and C respectively. Groups A, B and C had a combined ECOG 0 and I (PS) of 93%, 75% and 92%. Patients with ECOG III PS were excluded. Results: Oropharynx was the most common treated site (38%) followed by Larynx (35%). Complete response (CR) was seen in 77%, 17% and 67% in groups A, B and C respectively (P<0.001). Median progression free survival (PFS) was 16.6, 4.3 and 22.8 in groups A, B and C respectively (P<0.001) and median overall survival (OS) was >35, 11.6 and >32 months in groups A, B and C respectively (P<0.0001). Conclusions: Concurrent CDDP with radiation leads to better response rate PFS and OS as opposed to Cx though many patients treated with CDDP could not complete treatment due to toxicity. Randomized trial comparing the two should be considered.

Whole blood FOLH1 mRNA expression and treatment response in metastatic castration-resistant prostate cancer (mCRPC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 188-188
Author(s):  
Edmond Michael Kwan ◽  
Sarah Q To ◽  
Heidi C Fettke ◽  
Maria M Docanto ◽  
Patricia Bukczynska ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Whole Blood ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Response Rates ◽  
Predictive Biomarker ◽  
Rank Test ◽  
Castration Resistant Prostate Cancer ◽  
Psa Response ◽  
Pre Treatment

188 Background: Identifying predictive biomarkers for mCRPC patients receiving androgen receptor signalling inhibitors (ARSI) or chemotherapy remains an unmet clinical need. FOLH1 encodes for Prostate-Specific Membrane Antigen (PSMA), a type II glycoprotein highly expressed on prostate cancer cells. We designed a whole blood assay to detect FOLH1 mRNA, and correlated expression with clinical outcomes in patients commencing ARSI (abiraterone or enzalutamide) or chemotherapy (docetaxel or cabazitaxel). Methods: mCRPC patients commencing ARSI or chemotherapy were prospectively recruited at three Australian centres from June 2016 to July 2018. A quantitative reverse transcription polymerase chain reaction assay was used to detect FOLH1 transcript from whole blood samples collected in PAXgene® RNA tubes. Pre-treatment FOLH1 expression was correlated with PSA response rate (Fisher’s exact test) and PSA progression-free survival (PSA-PFS) (log-rank test). Results: Median follow-up was 13.6 months (IQR 9.7–19.3). In total, 88 pre-treatment samples were analysed, of which 75 (85%) were FOLH1-positive. In patients receiving ARSI, outcomes favoured FOLH1-positive patients compared to FOLH1-negative patients, with higher PSA response rates (39/60, 65% vs. 2/7, 29%; p = 0.1) and longer PSA-PFS (median 9.0 months [95% CI, 7.2-10.8] vs. 2.8 months [95% CI, 2.3-3.3]; p = 0.03). Conversely, in chemotherapy-treated patients, inferior outcomes were observed in FOLH1-positive patients compared to FOLH1-negative patients, with lower PSA response rates (4/15, 27% vs. 5/6, 83%, p = 0.05) and shorter PSA-PFS (median 2.9 months [95% CI, 2.8-3.0] vs. 4.1 months [95% CI, 3.7-4.5]; p = 0.32). Conclusions: Pre-treatment FOLH1 expression may differentiate between outcomes on ARSI vs. chemotherapy in mCRPC patients. The utility of FOLH1 as a predictive biomarker in mCRPC warrants further evaluation in larger, independent cohorts. [Table: see text]

scholarly journals TERT Alterations Predict Tumor Progression in De Novo High-Grade Meningiomas Following Adjuvant Radiotherapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiaojiao Deng ◽  
Shuchen Sun ◽  
Jiawei Chen ◽  
Daijun Wang ◽  
Haixia Cheng ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Adjuvant Radiotherapy ◽  
De Novo ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Rank Test ◽  
High Grade ◽  
Who Grade ◽  
Kaplan Meier ◽  
Grade 3

BackgroundAdjuvant radiotherapy (RT) is one of the most commonly used treatments for de novo high-grade meningiomas (HGMs) after surgery, but genetic determinants of clinical benefit are poorly characterized.ObjectiveWe describe efforts to integrate clinical genomics to discover predictive biomarkers that would inform adjuvant treatment decisions in de novo HGMs.MethodsWe undertook a retrospective analysis of 37 patients with de novo HGMs following RT. Clinical hybrid capture-based sequencing assay covering 184 genes was performed in all cases. Associations between tumor clinical/genomic characteristics and RT response were assessed. Overall survival (OS) and progression-free survival (PFS) curves were plotted using the Kaplan–Meier method.ResultsAmong the 172 HGMs from a single institution, 42 cases (37 WHO grade 2 meningiomas and five WHO grade 3 meningiomas) were identified as de novo HGMs following RT. Only TERT mutations [62.5% C228T; 25% C250T; 12.5% copy number amplification (CN amp.)] were significantly associated with tumor progression after postoperative RT (adjusted p = 0.003). Potential different somatic interactions between TERT and other tested genes were not identified. Furthermore, TERT alterations (TERT-alt) were the predictor of tumor progression (Fisher’s exact tests, p = 0.003) and were associated with decreased PFS (log-rank test, p = 0.0114) in de novo HGMs after RT.ConclusionOur findings suggest that TERT-alt is associated with tumor progression and poor outcome of newly diagnosed HGM patients after postoperative RT.

scholarly journals IGF-1R/mTOR Targeted Therapy for Ewing Sarcoma: A Meta-Analysis of Five IGF-1R-Related Trials Matched to Proteomic and Radiologic Predictive Biomarkers

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1768 ◽  
Author(s):  
Hesham M. Amin ◽  
Ajaykumar C. Morani ◽  
Najat C. Daw ◽  
Salah-Eddine Lamhamedi-Cherradi ◽  
Vivek Subbiah ◽  
...  
Keyword(s):  
Ewing Sarcoma ◽  
Tumor Regression ◽  
Meta Analysis ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Total Lesion Glycolysis ◽  
Clinical Samples ◽  
Cancer Center ◽  
Clinical Benefits

Background : Ten to fourteen percent of Ewing sarcoma (ES) study participants treated nationwide with IGF-1 receptor (IGF-1R)-targeted antibodies achieved tumor regression. Despite this success, low response rates and short response durations (approximately 7-weeks) have slowed the development of this therapy. Methods: We performed a meta-analysis of five phase-1b/2 ES-oriented trials that evaluated the anticancer activity of IGF-1R antibodies +/− mTOR inhibitors (mTORi). Our meta-analysis provided a head-to-head comparison of the clinical benefits of IGF-1R antibodies vs. the IGF-1R/mTOR-targeted combination. Available pretreatment clinical samples were semi-quantitatively scored using immunohistochemistry to detect proteins in the IGF-1R/PI3K/AKT/mTOR pathway linked to clinical response. Early PET/CT imaging, obtained within the first 2 weeks (median 10 days), were examined to determine if reduced FDG avidity was predictive of progression-free survival (PFS). Results: Among 56 ES patients treated at MD Anderson Cancer Center (MDACC) with IGF-1R antibodies, our analysis revealed a significant ~two-fold improvement in PFS that favored a combination of IGF-1R/mTORi therapy (1.6 vs. 3.3-months, p = 0.042). Low pIGF-1R in the pretreatment specimens was associated with treatment response. Reduced total-lesion glycolysis more accurately predicted the IGF-1R response than other previously reported radiological biomarkers. Conclusion: Synergistic drug combinations, and newly identified proteomic or radiological biomarkers of IGF-1R response, may be incorporated into future IGF-1R-related trials to improve the response rate in ES patients.

scholarly journals Circulating tumor DNA (ctDNA) detection is associated with shorter progression-free survival in advanced melanoma patients

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Gabriella Taques Marczynski ◽  
Ana Carolina Laus ◽  
Mariana Bisarro dos Reis ◽  
Rui Manuel Reis ◽  
Vinicius de Lima Vazquez
Keyword(s):  
Somatic Mutations ◽  
Limit Of Detection ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
Advanced Melanoma ◽  
Plasma Samples ◽  
Free Survival ◽  
Melanoma Patients ◽  
Digital Polymerase Chain Reaction ◽  
Tumor Dna

Abstract BRAF, NRAS and TERT mutations occur in more than 2/3 of melanomas. Its detection in patient’s blood, as circulating tumor DNA (ctDNA), represents a possibility for identification and monitoring of metastatic disease. We proposed to standardize a liquid biopsy platform to identify hotspot mutations in BRAF, NRAS and TERT in plasma samples from advanced melanoma patients and investigate whether it was associated to clinical outcome. Firstly, we performed digital polymerase chain reaction using tumor cell lines for validation and determination of limit of detection (LOD) of each assay and screened plasma samples from healthy individuals to determine the limit of blank (LOB). Then, we selected 19 stage III and IV patients and determined the somatic mutations status in tumor tissue and track them in patients’ plasma. We established a specific and sensitive methodology with a LOD ranging from 0.13 to 0.37%, and LOB ranging from of 0 to 5.201 copies/reaction. Somatic mutations occurred in 17/19 (89%) patients, of whom seven (41%) had ctDNA detectable their paired plasma. ctDNA detection was associated with shorter progression free survival (p = 0.01). In conclusion, our data support the use of ctDNA as prognosis biomarker, suggesting that patients with detectable levels have an unfavorable outcome.

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