Abstract
SummaryBackground 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.
Highlights
Small cell lung cancer (SCLC) accounts for approximately 10–15% of all lung cancer cases and is characterized by aggressive growth, early development of metastases, high mortality, and initial response to chemotherapy followed by Invest New Drugs (2017) 35:334–344 relapse [1]
Baseline CXCR4+ Circulating tumor cells (CTCs) ≥7% was prognostic of shorter progression-free survival (PFS)
CTC count ≥6 at baseline and after 1 cycle of treatment were prognostic of shorter PFS and overall survival (OS)
Summary
Small cell lung cancer (SCLC) accounts for approximately 10–15% of all lung cancer cases and is characterized by aggressive growth, early development of metastases, high mortality, and initial response to chemotherapy followed by Invest New Drugs (2017) 35:334–344 relapse [1]. 60–70% of patients with SCLC have extensive-stage disease (ED) [2]. The 5year survival rate for patients with SCLC is only 7% [3]. Patients with ED-SCLC have a median survival of 7–11 months with currently available therapy, and longterm disease-free survival is rare [4]. Despite development of targeted therapies for non-small cell lung cancer (NSCLC), there have been few advances in treatment options for patients with SCLC. A meta-analysis showed that elevated chemokine (C-X-C motif) receptor 4 (CXCR4) expression correlated with shorter overall survival (OS) in patients with NSCLC and suggested a poor prognostic outcome of this disease [5]. A lack of preclinical models or access to patient tissues samples, as surgery is rarely used to treat SCLC, yields few tumor specimens for research. Repeat biopsies are even more problematic, which compounds the challenges
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