title: 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.
abstract: 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.
authors.affiliation: City of Hope Comprehensive Cancer Center, 1500 E. Duarte Road, Duarte, CA, 91010-3000, USA. rsalgia@coh.org.
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.affiliation: Florida Cancer Specialists, St. Petersburg, FL, USA.
authors.forename: R Waide
authors.initials: RW
authors.lastname: Weaver
authors.affiliation: Florida Cancer Specialists, Fort Myers, FL, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: McCleod
authors.affiliation: The Chorus Group, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Stille
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: S Betty
authors.initials: SB
authors.lastname: Yan
authors.affiliation: The Chorus Group, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Roberson
authors.affiliation: The Chorus Group, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: John
authors.initials: J
authors.lastname: Polzer
authors.affiliation: PharPoint Research Inc., Durham, NC, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Flynt
authors.affiliation: The Chorus Group, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Eyas
authors.initials: E
authors.lastname: Raddad
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Peek
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Sameera R
authors.initials: SR
authors.lastname: Wijayawardana
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Suzane L
authors.initials: SL
authors.lastname: Um
authors.affiliation: Janssen Diagnostics, Johnson and Johnson Company, Raritan, NJ, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Gross
authors.affiliation: Janssen Diagnostics, Johnson and Johnson Company, Raritan, NJ, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Connelly
authors.affiliation: Janssen Diagnostics, Johnson and Johnson Company, Raritan, NJ, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Morano
authors.affiliation: Janssen Diagnostics, Johnson and Johnson Company, Raritan, NJ, USA.
authors.forename: Madeline
authors.initials: M
authors.lastname: Repollet
authors.affiliation: Janssen Diagnostics, Johnson and Johnson Company, Raritan, NJ, USA.
authors.forename: Renouard
authors.initials: R
authors.lastname: Sanders
authors.affiliation: Janssen Diagnostics, Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: Kurt
authors.initials: K
authors.lastname: Baeten
authors.affiliation: Janssen Diagnostics, Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: D'Haese
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Spigel
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood*; D016190:Carboplatin / Q000494:pharmacology* / Q000627:therapeutic use; D002452:Cell Count; D018572:Disease-Free Survival; D005047:Etoposide / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D009360:Neoplastic Cells, Circulating; D010456:Peptides, Cyclic / Q000494:pharmacology* / Q000627:therapeutic use; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000097:blood / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C527276:CXCR4 protein, human; C000595455:LY2510924; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4; D005047:Etoposide; D016190:Carboplatin
keywords: CXCR4 expression; Carboplatin-etoposide; Circulating tumor cells; LY2510924; Small cell lung cancer