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Sphingosine kinase-1 predicts overall survival outcomes in non-small cell lung cancer patients treated with carboplatin and navelbine.

ABSTRACT: Sphingosine 1-phosphate (S1P) is a bioactive lipid metabolite associated with cancer cell proliferation, survival, migration and regulation of tumor angiogenesis in various cellular and animal models. Sphingosine kinase-1 (SphK1) and S1P lyase are the main enzymes that respectively control the synthesis and degradation of S1P. The present study analyzed the prognostic and predictive value of SphK1 and S1P lyase expression in patients with non-small cell lung cancer (NSCLC), treated with either surgery alone or in combination with adjuvant carboplatin and navelbine. Formalin-fixed, paraffin-embedded tissue samples from 176 patients with NSCLC were stained immunohistochemically using antibodies against SphK1 and S1P lyase, and their expression was correlated with all available clinicopathological factors. Increased expression of SphK1 was significantly associated with shorter overall and disease free survival in patients treated with adjuvant platinum-based chemotherapy. No prognostic relevance for S1P lyase expression was observed. Collectively, the results suggest that the immunohistochemical detection of SphK1 may be a promising predictive marker in NSCLC patients treated with adjuvant platinum-based chemotherapy.

SUBMITTER: Gachechiladze M

PROVIDER: S-EPMC6607215 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Sphingosine kinase-1 predicts overall survival outcomes in non-small cell lung cancer patients treated with carboplatin and navelbine.

Gachechiladze Mariam M Tichý Tomáš T Kolek Vítězslav V Grygárková Ivona I Klein Jiří J Mgebrishvili Giorgi G Kharaishvili Gvantsa G Janíková Mária M Smičková Petra P Cierna Lucia L Pitson Stuart S Maddelein Marie-Lise ML Cuvillier Olivier O Škarda Jozef J

Oncology letters 20190607 2

Sphingosine 1-phosphate (S1P) is a bioactive lipid metabolite associated with cancer cell proliferation, survival, migration and regulation of tumor angiogenesis in various cellular and animal models. Sphingosine kinase-1 (SphK1) and S1P lyase are the main enzymes that respectively control the synthesis and degradation of S1P. The present study analyzed the prognostic and predictive value of SphK1 and S1P lyase expression in patients with non-small cell lung cancer (NSCLC), treated with either s ...[more]

PMID: 31423186

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Project description:PurposeIMpower133 (ClinicalTrials.gov identifier: NCT02763579), a randomized, double-blind, phase I/III study, demonstrated that adding atezolizumab (anti-programmed death-ligand 1 [PD-L1]) to carboplatin plus etoposide (CP/ET) for first-line (1L) treatment of extensive-stage small-cell lung cancer (ES-SCLC) resulted in significant improvement in overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET. Updated OS, disease progression patterns, safety, and exploratory biomarkers (PD-L1, blood-based tumor mutational burden [bTMB]) are reported.Patients and methodsPatients with untreated ES-SCLC were randomly assigned 1:1 to receive four 21-day cycles of CP (area under the curve 5 mg per mL/min intravenously [IV], day 1) plus ET (100 mg/m2 IV, days 1-3) with atezolizumab (1,200 mg IV, day 1) or placebo, and then maintenance atezolizumab or placebo until unacceptable toxicity, disease progression, or loss of clinical benefit. Tumor specimens were collected; PD-L1 testing was not required for enrollment. The two primary end points, investigator-assessed PFS and OS, were statistically significant at the interim analysis. Updated OS and PFS and exploratory biomarker analyses were conducted.ResultsPatients received atezolizumab plus CP/ET (n = 201) or placebo plus CP/ET (n = 202). At the updated analysis, median follow-up for OS was 22.9 months; 302 deaths had occurred. Median OS was 12.3 and 10.3 months with atezolizumab plus CP/ET and placebo plus CP/ET, respectively (hazard ratio, 0.76; 95% CI, 0.60 to 0.95; descriptive P = .0154). At 18 months, 34.0% and 21.0% of patients were alive in atezolizumab plus CP/ET and placebo plus CP/ET arms, respectively. Patients derived benefit from the addition of atezolizumab, regardless of PD-L1 immunohistochemistry or bTMB status.ConclusionAdding atezolizumab to CP/ET as 1L treatment for ES-SCLC continued to demonstrate improved OS and a tolerable safety profile at the updated analysis, confirming the regimen as a new standard of care. Exploratory analyses demonstrated treatment benefit independent of biomarker status.

Project description:ImportanceChemotherapy is a mainstay treatment of metastatic non-small cell lung cancer. However, little is known about the comparative risk of hospitalization associated with commonly used chemotherapy regimens.ObjectiveTo evaluate the real-world association of specific lung cancer chemotherapy regimens with measures of acute hospital care (primary objective) and survival (secondary objective).Design, setting, and participantsRetrospective, propensity-matched, cohort study using the Surveillance, Epidemiology, and End Results-Medicare linked data for cancer diagnoses between 2008 and 2013, with follow-up through 2014. Patients were Medicare beneficiaries 66 years of age or older receiving initial chemotherapy for treatment of stage IV, nonsquamous, non-small cell lung cancer. Analyses were performed between September 2017 and April 2018.ExposuresReceipt of chemotherapy with carboplatin-pemetrexed or carboplatin-paclitaxel, with or without concurrent bevacizumab.Main outcomes and measuresThe primary outcome was risk of hospitalization within 30 days of chemotherapy initiation. Secondary measures included cumulative 90-day hospitalizations, 90-day mean hospital-free survival time, and overall survival.ResultsOf the 3310 eligible patients, 1823 received carboplatin-pemetrexed, and 1487 received carboplatin-paclitaxel. The median age at diagnosis was 73 years (interquartile range, 69-77 years), 1784 patients (53.9%) were men, and 2909 patients (87.9%) were non-Hispanic white. In total, 2182 patients were included in the propensity-matched analysis. The 30-day hospitalization risk was 20.7% (95% CI, 18.3%-23.1%) among patients receiving carboplatin-pemetrexed vs 26.0% (95% CI, 23.4%-28.6%) among patients receiving carboplatin-paclitaxel (5.3% difference; P?=?.003). The 90-day cumulative hospitalizations did not differ significantly between the 2 treatment groups; however, the 90-day mean hospital-free survival time was improved for patients receiving carboplatin-pemetrexed (68.4 days [95% CI, 66.5-70.4 days] vs 63.6 days [95% CI, 61.6-65.7 days]; P?=?.001). The median survival time was 9.0 months (95% CI, 8.4-9.5 months) with carboplatin-pemetrexed therapy vs 7.6 months (95% CI, 7.0-8.4 months) with carboplatin-paclitaxel therapy (P?=?.005). Stratified analyses showed no association of bevacizumab use with hospitalization risk or survival when combined with either chemotherapy regimen.Conclusions and relevanceThe findings from this study suggest that patients receiving carboplatin-pemetrexed compared with those receiving carboplatin-paclitaxel have a lower 30-day hospitalization risk, a greater 90-day hospital-free survival, and improved overall survival. Information about hospitalization risk may provide valuable context for evaluating real-world cancer treatment outcomes.

Project description:The Japan Guidelines of Lung Cancer Therapy recommend epidermal growth factor receptor-tyrosine kinase inhibitors as a first-line therapy for advanced/recurrent non-small cell lung cancer patients with epidermal growth factor receptor mutation. Although survival periods in recent reports of epidermal growth factor receptor-tyrosine kinase inhibitor treatment have been getting longer, the reasons why are unclear. We investigated the survival, prognostic factors and real-world treatment of non-small cell lung cancer patients with epidermal growth factor receptor mutation in clinical practice.Non-small cell lung cancer patients (n = 1660) who started first-line treatment from January 2008 to December 2012 were enrolled. Patients were diagnosed with epidermal growth factor receptor mutation-positive advanced/recurrent non-small cell lung cancer by histology or cytology samples. The primary objective was to estimate overall survival. The secondary objectives were to determine prognostic factors, real-world treatment patterns and efficacy of gefitinib treatment. We calculated the treatment exposure rate for each treatment category using the following formula: exposure rate = person-years for the treatment category/total person-years × 100.The median overall survival was 30.8 months. Sex, age, histology, epidermal growth factor receptor mutation type, clinical stage and performance status affected overall survival. The exposure rates for all epidermal growth factor receptor-tyrosine kinase inhibitors, gefitinib and platinum-doublet chemotherapy were 62.1, 46.4 and 8.5% respectively. Overall 56.1% of patients were administered gefitinib as first-line therapy, and 39.0% were treated with ?2 epidermal growth factor receptor-tyrosine kinase inhibitor regimens. The median progression-free survival in the first-line gefitinib group was 11.4 months. Factors affecting prognosis were sex, histology, clinical stage and performance status.Epidermal growth factor receptor-tyrosine kinase inhibitors, especially gefitinib, are major components of the treatment regimens for epidermal growth factor receptor mutation-positive non-small cell lung cancer. Switching and re-challenging with epidermal growth factor receptor-tyrosine kinase inhibitors were also practiced in Japan.

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Sphingosine kinase-1 predicts overall survival outcomes in non-small cell lung cancer patients treated with carboplatin and navelbine.

Publications

Sphingosine kinase-1 predicts overall survival outcomes in non-small cell lung cancer patients treated with carboplatin and navelbine.

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