Molecular pathways and therapeutic targets in lung cancer

Lung cancer is still the leading cause of cancer death worldwide. Both histologically and molecularly lung cancer is heterogeneous. This review summarizes the current knowledge of the pathways involved in the various types of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. It describes the major pathways and molecular alterations implicated in the development and progression of non-small cell lung cancer (adenocarcinoma and squamous cancer), and of small cell carcinoma, emphasizing the molecular alterations comprising the specific blueprints in each group. The approved and investigational targeted therapies as well as the immune therapies, and clinical trials exploring the variety of targeted approaches to treatment of lung cancer are the main focus of this review

Third-generation chemotherapy agents in the treatment of advanced non-small cell lung cancer: A meta-analysis [2]

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Treatment of stage IV non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American college of chest physicians evidence-based clinical practice guidelines

Stage IV non-small cell lung cancer (NSCLC) is a treatable, but not curable, clinical entity in patients given the diagnosis at a time when their performance status (PS) remains good

Alliance Foundation Trial 09: A randomized, multicenter, phase 2 trial evaluating two sequences of pembrolizumab and standard platinum-based chemotherapy in patients with metastatic NSCLC

INTRODUCTION: The sequence of chemotherapy and pembrolizumab may affect antitumor immune response and efficacy of immunotherapy. METHODS: This multicenter, randomized, phase 2 trial was designed to evaluate the efficacy of two sequences of chemotherapy and pembrolizumab in patients with stage 4 NSCLC. Both arms were considered investigational, and the study used a pick a winner design. The primary end point was objective response rate by independent radiologic review after eight cycles (24 wk). Patients were randomized 1:1 to arm A (chemotherapy for four cycles followed by pembrolizumab for four cycles) or arm B (pembrolizumab for four cycles followed by chemotherapy for four cycles). Patients in both arms without disease progression after the initial eight cycles continued pembrolizumab until disease progression, unacceptable toxicity, or a maximum of 2 years. RESULTS: From March 2016 to July 2018, a total of 90 eligible patients were randomized (43 patients to arm A and 47 patients to arm B). The objective response rate at 24 weeks in arms A and B was 39.5 % (95 % confidence interval [CI]: 24.9%-54.1 %) and 40.4 % (95 % CI: 26.4%-54.5 %), respectively ( CONCLUSIONS: Additional evaluation of either sequence in a phase 3 trial is not warranted

A Predictive 7-Gene Assay and Prognostic Protein Biomarkers for Non-small Cell Lung Cancer

This study aims to develop a multi-gene assay predictive of the clinical benefits of chemotherapy in non- small cell lung cancer (NSCLC) patients, and substantiate their protein expression as potential therapeutic tar- gets. Patients and methods: The mRNA expression of 160 genes identified from microarray was analyzed in qRT-PCR assays of independent 337 snap-frozen NSCLC tumors to develop a predictive signature. A clinical trial JBR.10 was included in the validation. Hazard ratio was used to select genes, and decision-trees were used to construct the predictive model. Protein expression was quantified with AQUA in 500 FFPE NSCLC samples. Results: A 7-gene signature was identified from training cohort (n = 83) with accurate patient stratification (P = 0.0043) and was validated in independent patient cohorts (n = 248, P b 0.0001) in Kaplan-Meier analyses. In the predicted benefit group, there was a significantly better disease-specific survival in patients receiving adjuvant chemotherapy in both training (P = 0.035) and validation (P = 0.0049) sets. In the predicted non-benefit group, there was no survival benefit in patients receiving chemotherapy in either set. The protein expression of ZNF71 quantified with AQUA scores produced robust patient stratification in separate training (P = 0.021) and validation (P = 0.047) NSCLC cohorts. The protein expression of CD27 quantified with ELISA had a strong correlation with its mRNA expression in NSCLC tumors (Spearman coefficient = 0.494, P b 0.0088). Multiple sig- nature genes had concordant DNA copy number variation, mRNA and protein expression in NSCLC progression. Conclusions: This study presents a predictive multi-gene assay and prognostic protein biomarkers clinically appli- cable for improving NSCLC treatment, with important implications in lung cancer chemotherapy and immunotherapy

Do gastrointestinal complaints increase the risk for subsequent medically certified long-term sickness absence? The HUSK study

<p>Abstract</p> <p>Background</p> <p>Gastrointestinal complaints are very common in the general population and very often co-occur with common mental disorders. We aimed to study the prospective impact of gastrointestinal complaints on long term sickness absence, and address the contribution from co-occurring common mental disorders and other somatic symptoms.</p> <p>Method</p> <p>Health data on 13 880 40-45 year olds from the Hordaland Health Study (1997-99) were linked to national registries on sickness absence. As part of a wider health screening, gastrointestinal complaints were ascertained. Participant's anxiety and depression, and the presence of other somatic symptoms were evaluated. In Cox regression models, we predicted sickness absences over an average 5.4 years follow-up, with adjustment for confounders, anxiety and depression and other somatic symptoms.</p> <p>Results</p> <p>After adjusting for gender, level of education and smoking, those reporting GI complaints had higher risk for later sickness absence (HR = 1.42, 95% CI 1.34-1.51). GI complaints were associated with both anxiety (OR = 3.66, 95% CI 3.31-4.04) and depression (OR = 3.28, 95% CI 2.89-3.72), and a high level of other somatic symptoms (OR = 8.50, 95% CI 7.69-9.40). The association of GI complaints was still independently associated with future sickness absence (HR = 1.17, 95% CI 1.10-1.16) adjusting for mental illness and other somatic symptoms.</p> <p>Discussion</p> <p>Sickness absence is a complex behavioural outcome, but our results suggest GI complaints contribute by increasing the risk of long term sickness absence independently of comorbid mental illness and presence of other somatic symptoms. Occupational consequences of illness are important, and should also be addressed clinically with patients presenting with GI complaints.</p

A multicenter phase II trial of carboplatin and cetuximab for treatment of advanced nonsmall cell lung cancer

Purpose: To investigate the activity of carboplatin and cetuximab in NSCLC. Patients and Methods: This was a single arm, multicenter phase II trial, and the primary objective was response rate. Results: The overall response rate observed was 9% (95% confidence interval [CI], 3–19), the progression-free survival was 2.9 months (95% CI, 1.9–3.6), the median overall survival was 8.2 months (95% CI, 4.9–10.5), and 1-year survival rate was 33% (95% CI, 21–45). Conclusion: The combination of carboplatin and cetuximab demonstrated lower activity than double agent platinum-based therapy and does not warrant further developmen