Treatment receipt and outcomes among lung cancer patients with depression.

AIMS: Among lung cancer patients, depression has been associated with increased mortality, although the mechanisms are unknown. We evaluated the association of depression with mortality and receipt of cancer therapies among depressed veterans with lung cancer. MATERIALS AND METHODS: A retrospective, cohort study of lung cancer patients in the Veterans Affairs-Northwest Health Network from 1995 to 2010. Depression was defined by ICD-9 coding within 24 months before lung cancer diagnosis. Multivariable Cox proportional analysis and logistic regression were used. RESULTS: In total, 3869 lung cancer patients were evaluated; 14% had a diagnosis of depression. A diagnosis of depression was associated with increased mortality among all stage lung cancer patients (hazard ratio = 1.14, 95% confidence interval: 1.03-1.27, P = 0.01). Among early-stage (I and II) non-small cell lung cancer (NSCLC) patients, the hazard ratio was 1.37 (95% confidence interval: 1.12-1.68, P = 0.003). There was no association of depression diagnosis with surgery (odds ratio = 0.83, 95% confidence interval: 0.56-1.22, P = 0.34) among early-stage NSCLC patients. A depression diagnosis was not associated with mortality (hazard ratio = 1.02, 95% confidence interval: 0.89-1.16, P = 0.78) or chemotherapy (odds ratio = 1.07, 95% confidence interval: 0.83-1.39, P = 0.59) or radiation (odds ratio = 1.04, 95% confidence interval: 0.81-1.34, P = 0.75) receipt among advanced-stage (III and IV) NSCLC patients. Increased utilisation of health services for depression was associated with increased mortality among depressed patients. CONCLUSIONS: Depression is associated with increased mortality in lung cancer patients and this association is higher among those with increased measures of depression care utilisation. Differences in lung cancer treatment receipt are probably not responsible for the observed mortality differences between depressed and non-depressed patients. Clinicians should recognise the significant effect of depression on lung cancer survival.

A phase I/II study of sepantronium bromide (YM155, survivin suppressor) with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer.

BACKGROUND: This phase I/II study examined the safety and efficacy of Sepantronium Bromide (S), a small-molecule selective survivin suppressant, administered in combination with carboplatin (C) and paclitaxel (P). PATIENTS AND METHODS: Forty-one patients were treated on study. Twenty-two patients received escalating doses of S (3.6-12 mg/m(2)) and 19 with untreated stage IV non-small-cell lung cancer (NSCLC) were treated with the maximum tolerated dose of 10 mg/m(2) in combination with standard doses of C (AUC6) and P (200 mg/m(2)) for six cycles. S was administered as a continuous intravenous infusion (CIVI) over 72 h in 21-day treatment cycles. Study end points included safety and toxic effect, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates. RESULTS: Treatment with S was well tolerated, and toxic effects were mostly hematological in the phase II study. Two (11%) partial responses were observed with a median PFS of 5.7 months and median OS 16.1 months. Pharmacodynamic analysis did not demonstrate an association with response. CONCLUSION: The combination of S (10 mg/m(2)/day 72-h CIVI) administered with C and P every 3 weeks exhibited a favorable safety profile but failed to demonstrate an improvement in response rate in advanced NSCLC. CLINICAL TRIAL NUMBER: NCT01100931.

From targets to targeted therapies and molecular profiling in non-small cell lung carcinoma.

Although tumor molecular-profile-directed therapy appears promising in early clinical studies, there are many practical challenges to its successful clinical application in non-small-cell lung cancer (NSCLC). These challenges may be broadly classified as those relating to tumor (heterogeneity), tissue (acquisition and processing), testing (assays for molecular profiling) and trials (clinical evaluation of molecular markers and drugs). Strategies to overcome these challenges include (i) understanding the biological basis of tumor heterogeneity and of carcinogenesis in the large subset of patients with no currently evident driver events; (ii) technological advances in minimally invasive acquisition of tumor and next-generation sequencing (NGS) which would enable single-platform analysis of molecular alterations in limited tissue at a reasonable turnaround time (TAT); (iii) deliberation in early stages of drug development as well as clinical trial design to identify, validate and assess the clinical utility of biomarkers in conjunction with drugs and (iv) collaboration to improve understanding of and accrual to trials enrolling patients with rare molecular alterations.

Characterization of epidermal growth factor receptor mutations in non-small-cell lung cancer patients of African-American ancestry.

Epidermal growth factor receptor (EGFR) mutations are predictive markers for response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC). The most common mutations, exon 19 short deletions and exon 20 point mutation (L858R), activate the tyrosine kinase and confer sensitivity to EGFR-TKIs. However, the function and sensitivity of rare mutations to EGFR-TKIs are unknown. In this study, we found five EGFR mutations out of 16 patients with NSCLC of African-American descent. The frequency of such mutations in this patient population appears to be significantly higher than previously reported. Two of them (N771GY and A767-V769dup) are rare insertion mutations located in exon 20. Using YFP-tagged EGFR mutants, we demonstrated that the mutations confer increased kinase activity, but no sensitivity to erlotinib at clinically available concentrations. In addition, we examined efficacy of PF00299804, an irreversible EGFR-TKI. Although the drug failed to show efficacy to T790M and S768N mutations, the exon 20 insertion mutations were sensitive to PF00299804. These data suggest that rare mutations in exon 20 are resistant to erlotinib but may be sensitive to irreversible inhibitors.