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      Prognostic and predictive value of circulating tumor cells and CXCR4 expression as biomarkers for a CXCR4 peptide antagonist in combination with carboplatin-etoposide in small cell lung cancer: exploratory analysis of a phase II study

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          Background Circulating tumor cells (CTCs) and chemokine (C-X-C motif) receptor 4 (CXCR4) expression in CTCs and tumor tissue were evaluated as prognostic or predictive markers of CXCR4 peptide antagonist LY2510924 plus carboplatin-etoposide (CE) versus CE in extensive-stage disease small cell lung cancer (ED-SCLC). Methods This exploratory analysis of a phase II study evaluated CXCR4 expression in baseline tumor tissue and peripheral blood CTCs and in post-treatment CTCs. Optimum cutoff values were determined for CTC counts and CXCR4 expression in tumors and CTCs as predictors of survival outcome. Kaplan-Meier estimates and hazard ratios were used to determine biomarker prognostic and predictive values. Results There was weak positive correlation at baseline between CXCR4 expression in tumor tissue and CTCs. Optimum cutoff values were H-score ≥ 210 for CXCR4 + tumor, ≥7% CTCs with CXCR4 expression (CXCR4 + CTCs), and ≥6 CTCs/7.5 mL blood. Baseline H-score for CXCR4 + tumor was not prognostic of progression-free survival (PFS) or overall survival (OS). Baseline CXCR4 + CTCs ≥7% was prognostic of shorter PFS. CTCs ≥6 at baseline and cycle 2, day 1 were prognostic of shorter PFS and OS. None of the biomarkers at their respective optimum cutoffs was predictive of treatment response of LY2510924 plus CE versus CE. Conclusions In patients with ED-SCLC, baseline CXCR4 expression in tumor tissue was not prognostic of survival or predictive of LY2510924 treatment response. Baseline CXCR4 + CTCs ≥7% was prognostic of shorter PFS. CTC count ≥6 at baseline and after 1 cycle of treatment were prognostic of shorter PFS and OS.

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          Most cited references28

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          Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo.

          Resistance to chemotherapy is a principal problem in the treatment of small cell lung cancer (SCLC). We show here that SCLC is surrounded by an extensive stroma of extracellular matrix (ECM) at both primary and metastatic sites. Adhesion of SCLC cells to ECM enhances tumorigenicity and confers resistance to chemotherapeutic agents as a result of beta1 integrin-stimulated tyrosine kinase activation suppressing chemotherapy-induced apoptosis. SCLC may create a specialized microenvironment, and the survival of cells bound to ECM could explain the partial responses and local recurrence of SCLC often seen clinically after chemotherapy. Strategies based on blocking beta1 integrin-mediated survival signals may represent a new therapeutic approach to improve the response to chemotherapy in SCLC.
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            Circulating tumor cells in small-cell lung cancer: a predictive and prognostic factor.

            Initial response of small-cell lung cancer (SCLC) to chemotherapy is high, and recurrences occur frequently, leading to early death. This study investigated the prognostic value of circulating tumor cells (CTCs) in patients with SCLC and whether changes in CTCs can predict response to chemotherapy. Patients and methods In this multicenter prospective study, blood samples for CTC analysis were obtained from 59 patients with SCLC before, after one cycle, and at the end of chemotherapy. CTCs were measured using CellSearch systems. At baseline, lower numbers of CTCs were observed for 21 patients with limited SCLC (median = 6, range 0-220) compared with 38 patients with extensive stage (median = 63, range 0-14,040). Lack of measurable CTCs (27% of patients) was associated with prolonged survival (HR 3.4; P ≤ 0.001). CTCs decreased after one cycle of chemotherapy; this decrease was not associated with tumor response after four cycles of chemotherapy. CTC count after the first cycle of chemotherapy was the strongest predictor for overall survival (HR 5.7; 95% CI 1.7-18.9; P = 0.004). Absolute CTCs after one cycle of chemotherapy in patients with SCLC is the strongest predictor for response on chemotherapy and survival. Patients with low initial CTC numbers lived longer than those with higher CTCs.
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              CXCR4 over-expression and survival in cancer: A system review and meta-analysis

              C-X-C chemokine receptor 4 (CXCR4) is frequently over-expressed in various types of cancer; many agents against CXCR4 are in clinical development currently despite variable data for the prognostic impact of CXCR4 expression. Here eighty-five studies with a total of 11,032 subjects were included to explore the association between CXCR4 and progression-free survival (PFS) or overall survival (OS) in subjects with cancer. Pooled analysis shows that CXCR4 over-expression is significantly associated with poorer PFS (HR 2.04; 95% CI, 1.72-2.42) and OS (HR=1.94; 95% CI, 1.71-2.20) irrespective of cancer types. Subgroup analysis indicates significant association between CXCR4 and shorter PFS in hematological malignancy, breast cancer, colorectal cancer, esophageal cancer, renal cancer, gynecologic cancer, pancreatic cancer and liver cancer; the prognostic effects remained consistent across age, risk of bias, levels of adjustment, median follow-up period, geographical area, detection methods, publication year and size of studies. CXCR4 over-expression predicts unfavorable OS in hematological malignancy, breast cancer, colorectal cancer, esophageal cancer, head and neck cancer, renal cancer, lung cancer, gynecologic cancer, liver cancer, prostate cancer and gallbladder cancer; these effects were independence of age, levels of adjustment, publication year, detection methods and follow-up period. In conclusion, CXCR4 over-expression is associated with poor prognosis in cancer.
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                Author and article information

                Contributors
                (626) 471-9200 , rsalgia@coh.org
                Journal
                Invest New Drugs
                Invest New Drugs
                Investigational New Drugs
                Springer US (New York )
                0167-6997
                1573-0646
                15 March 2017
                15 March 2017
                2017
                : 35
                : 3
                : 334-344
                Affiliations
                [1 ]ISNI 0000 0004 0421 8357, GRID grid.410425.6, , City of Hope Comprehensive Cancer Center, ; 1500 E. Duarte Road, Duarte, CA 91010-3000 USA
                [2 ]GRID grid.428633.8, , Florida Cancer Specialists, ; St. Petersburg, FL USA
                [3 ]GRID grid.428633.8, , Florida Cancer Specialists, ; Fort Myers, FL USA
                [4 ]ISNI 0000 0000 2220 2544, GRID grid.417540.3, The Chorus Group, , Eli Lilly and Company, ; Indianapolis, IN USA
                [5 ]ISNI 0000 0000 2220 2544, GRID grid.417540.3, Lilly Research Laboratories, , Eli Lilly and Company, ; Indianapolis, IN USA
                [6 ]PharPoint Research Inc., Durham, NC USA
                [7 ]GRID grid.417429.d, Janssen Diagnostics, , Johnson and Johnson Company, ; Raritan, NJ USA
                [8 ]ISNI 0000 0004 0623 0341, GRID grid.419619.2, Janssen Diagnostics, , Janssen Pharmaceutica, ; Beerse, Belgium
                [9 ]ISNI 0000 0004 0459 5478, GRID grid.419513.b, , Sarah Cannon Research Institute, ; Nashville, TN USA
                Article
                446
                10.1007/s10637-017-0446-z
                5418321
                28299514
                6e4cf354-c74e-4995-87ca-059961f2bcf1
                © The Author(s) 2017

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 19 December 2016
                : 23 February 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100004312, Eli Lilly and Company;
                Categories
                Phase II Studies
                Custom metadata
                © Springer Science+Business Media New York 2017

                Pharmacology & Pharmaceutical medicine
                ly2510924,cxcr4 expression,circulating tumor cells,small cell lung cancer,carboplatin-etoposide

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