C. Mascaux

Pemetrexed for advanced stage nonsquamous non-small cell lung cancer: latest evidence about its extended use and outcomes

Non-small cell lung cancer (NSCLC) is still the leading cause of cancer-related death, and the treatment of advanced NSCLC relies on systemic treatments. During the last decade, pemetrexed, an antifolate agent, gradually became a key component of the treatment for patients with advanced nonsquamous NSCLC. It has indeed been shown to be efficient for first-line, maintenance and second- or third-line treatment in this subgroup of NSCLC. Moreover, it is usually well tolerated, with few grade 3 and 4 toxicities. Several studies have tried to identify predictive biomarkers of pemetrexed efficacy. Due to pemetrexed’s mechanism of action, thymidilate synthase expression predictive value was investigated but could not be demonstrated. Currently, more than 400 trials of pemetrexed for the treatment of nonsquamous NSCLC are ongoing.

Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small cell lung cancer (NSCLC).

INTRODUCTION TP53 mutations are common in non-small cell lung cancer (NSCLC) and have been reported as prognostic of poor outcome. The impact of TP53 co-mutations in epidermal growth factor receptor (EGFR)-mutated NSCLC is unclear. MATERIALS AND METHODS Tissue from 105 patients with EGFR-mutated NSCLC at Princess Margaret Cancer Centre was analyzed by next-generation or Sanger sequencing to determine TP53 mutational status. Associations between TP53 status and baseline patient and tumor characteristics, treatments and outcomes (relapse-free survival [RFS] after surgical resection, overall survival [OS], overall response rate [ORR] and progression-free survival [PFS] on EGFR tyrosine kinase inhibitors [TKIs]), were investigated. RESULTS Dual TP53/EGFR mutations were found in 43/105 patients (41%). Among 76 patients who underwent surgical resection, neither RFS (HR 0.99, CI 0.56-1.75, p=0.96) nor OS (HR 1.39, CI 0.70-2.77; p=0.35) was associated with TP53 status. Sixty patients (24 TP53 MUT; 36 TP53 WT) received first-generation EGFR TKIs for advanced disease. ORR was not significantly different (TP53 MUT 54%, WT 66%, p=0.42). There was a non-significant trend towards shorter PFS on EGFR TKIs with TP53 mutation (HR 1.74, CI 0.98-3.10, p=0.06). When limited to TP53 missense mutations (n=17), PFS was significantly shorter (HR 1.91, CI 1.01-3.60, p=0.04). Among 11 evaluable patients treated with T790M inhibitors, ORR was not significantly different (TP53 MUT 3/3 [100%], WT 7/8 [88%]). CONCLUSIONS Patients with dual TP53/EGFR mutations, especially missense mutations, had marginally lower response rates and shorter PFS when treated with EGFR TKI therapy. Larger datasets are required to validate these observations.

Valproic acid improves second-line regimen of small cell lung carcinoma in preclinical models

With 5-year survival rates below 5%, small cell lung carcinoma (SCLC) has very poor prognosis and requires improved therapies. Despite an excellent overall response to first-line therapy, relapses are frequent and further treatments are disappointing. The goal of the study was to improve second-line therapy of SCLC. The effect of chemotherapeutic agents was evaluated in cell lines (apoptosis, reactive oxygen species, and RNA and protein expression) and in mouse models (tumour development). We demonstrate here that valproic acid, a histone deacetylase inhibitor, improves the efficacy of a second-line regimen (vindesine, doxorubicin and cyclophosphamide) in SCLC cells and in mouse models. Transcriptomic profiling integrating microRNA and mRNA data identifies key signalling pathways in the response of SCLC cells to valproic acid, opening new prospects for improved therapies. Valproic acid improves second-line regimen of SCLC response in preclinical models http://ow.ly/Rsyd8

Personalised medicine for nonsmall cell lung cancer

After years of standard care prescribed to cancer patients without any selection except the primary site and histology of the tumour, the era of precision medicine has revolutionised cancer care. Personalised medicine refers to the selection of patients for specific treatment based on the presence of specific biomarkers which indicate sensitivity to corresponding targeted therapies and/or lower toxicity risk, such that patients will have the greatest chance of deriving benefit from the treatments. Here, we review personalised medicine for nonsmall cell lung cancer. Herein we review personalised medicine for nonsmall cell lung cancer http://ow.ly/LiiI30fXUlJ

Drug repurposing in malignant pleural mesothelioma: a breath of fresh air?

Drug repurposing is the use of known drugs for new indications. Malignant pleural mesothelioma (MPM) is a rare cancer with a poor prognosis. So far, few treatments have been approved in this disease. However, its incidence is expected to increase significantly, particularly in developing countries. Consequently, drug repurposing appears as an attractive strategy for drug development in MPM, since the known pharmacology and safety profile based on previous approvals of repurposed drugs allows for faster time-to-market for patients and lower treatment cost. This is critical in low- and middle-income countries where access to expensive drugs is limited. This review assesses the published preclinical and clinical data about drug repurposing in MPM. In this review, we identified 11 therapeutic classes that could be repositioned in mesothelioma. Most of these treatments have been evaluated in vitro, half have been evaluated in vivo in animal models of MPM and only three (i.e. valproate, thalidomide and zoledronic acid) have been investigated in clinical trials, with limited benefits so far. Efforts could be coordinated to pursue further investigations and test promising drugs identified in preclinical experiments in appropriately designed clinical trials. Drug repurposing is an interesting research area for mesothelioma, which has a very poor outcome and few drugs approved http://ow.ly/igTq30hSloC

The prognostic effect of single and multiple cancer-related somatic mutations in resected non-small-cell lung cancer

INTRODUCTION Somatic mutations are becoming increasingly important biomarkers for treatment selection and outcome in patients with non-small-cell lung cancer (NSCLC). The role of multiple somatic mutations in early-stage NSCLC is unclear. METHODS Tissue from 214 patients with resected NSCLC at the Princess Margaret Cancer Centre was analyzed by next-generation sequencing by Mi-SEQ or Sequenom multiplex platforms. Associations between mutation status, baseline patient characteristics and outcomes (disease-free survival (DFS) after surgical resection and overall survival (OS)) were investigated. RESULTS Somatic mutations were identified in 184 patients with resected stage I-III NSCLC: None (n = 30), single (n = 101) and multiple (≥2, n = 83). Multiple mutations were significantly associated with younger age (p = 0.0006), female sex (p = 0.012), smoking status (p = 0.002) and adenocarcinoma histology (p = 0.0001).TP53, KRAS and EGFR were the most common mutations. TP53 mutation was the most frequent co-mutation occurring in 72% of patients with multiple mutations. In resected stage I-III patients, multiple mutations were significantly associated with worse DFS (HR = 2.56, p = 0.003) but not OS on univariate analysis. Patients with KRAS and EGFR mutations were also associated with shorter DFS (HR = 2.52, p = 0.016 and HR = 4.37, p = 0.001 respectively) but no OS difference. TP53 mutation was associated with both shorter DFS (HR = 2.21, p = 0.02) and OS (HR = 3.08, p = 0.02). In subgroup univariate analysis, poorer DFS was associated with multiple mutations (p = 0.0015), EGFR (HR = 3.14, p = 0.006), and TP53 (HR = 2.46, p = 0.018) in patients with stage I disease. CONCLUSION The presence of known somatic mutations is associated with worse DFS in resected NSCLC. The differences are both statistically significant and clinically relevant. The presence of EGFR, KRAS and TP53 mutations was also associated with adverse outcomes. Larger datasets are required to validate whether mutational status is an independent prognostic factor in early stage NSCLC.

Proteogenomic Analysis of Surgically Resected Lung Adenocarcinoma

Introduction: Despite apparently complete surgical resection, approximately half of resected early‐stage lung cancer patients relapse and die of their disease. Adjuvant chemotherapy reduces this risk by only 5% to 8%. Thus, there is a need for better identifying who benefits from adjuvant therapy, the drivers of relapse, and novel targets in this setting. Methods: RNA sequencing and liquid chromatography/liquid chromatography–mass spectrometry proteomics data were generated from 51 surgically resected non–small cell lung tumors with known recurrence status. Results: We present a rationale and framework for the incorporation of high‐content RNA and protein measurements into integrative biomarkers and show the potential of this approach for predicting risk of recurrence in a group of lung adenocarcinomas. In addition, we characterize the relationship between mRNA and protein measurements in lung adenocarcinoma and show that it is outcome specific. Conclusions: Our results suggest that mRNA and protein data possess independent biological and clinical importance, which can be leveraged to create higher‐powered expression biomarkers.

Helicase-like transcription factor expression is associated with a poor prognosis in Non-Small-Cell Lung Cancer (NSCLC)

BackgroundThe relapse rate in early stage non-small cell lung cancer (NSCLC) after surgical resection is high. Prognostic biomarkers may help identify patients who may benefit from additional therapy. The Helicase-like Transcription Factor (HLTF) is a tumor suppressor, altered in cancer either by gene hypermethylation or mRNA alternative splicing. This study assessed the expression and the clinical relevance of wild-type (WT) and variant forms of HLTF RNAs in NSCLC.MethodsWe analyzed online databases (TCGA, COSMIC) for HLTF alterations in NSCLC and assessed WT and spliced HLTF mRNAs expression by RT-ddPCR in 39 lung cancer cell lines and 171 patients with resected stage I-II NSCLC.ResultsIn silico analyses identified HLTF gene alterations more frequently in lung squamous cell carcinoma than in adenocarcinoma. In cell lines and in patients, WT and I21R HLTF mRNAs were detected, but the latter at lower level. The subgroup of 25 patients presenting a combined low WT HLTF expression and a high I21R HLTF expression had a significantly worse disease-free survival than the other 146 patients in univariate (HR 1.96, CI 1.17–3.30; p = 0.011) and multivariate analyses (HR 1.98, CI 1.15–3.40; p = 0.014).ConclusionA low WT HLTF expression with a high I21R HLTF expression is associated with a poor DFS.

Abstract 1419: Characterization of the evolution of immune response in lung squamous carcinogenesis

Molecular profiling of from pre-invasive bronchial lesions, and particularly the evolution of immune response, may identify promising new biomarkers for early detection and targets for chemoprevention/treatment of lung cancer. mRNA expression was analyzed (Agilent microarrays) from fresh frozen human bronchial biopsies (N = 122, 77 patients) at successive morphological stages of lung squamous carcinogenesis. Modules of co-expressed genes were identified among the stage associated genes, selected using a linear mixed-effects model adjusting for smoking status, gender, and history of cancer as fixed effects and patient as a random effect. Cell type specific signatures were applied to the genes co-expressed in these modules in order to identify the immune response signal through the stages of lung carcinogenesis. Genes expression alterations were grouped into 4 successive molecular steps. Based on their behavior across the 4 steps, 8 modules of genes with different patterns were observed: gene modules primarily up-regulated among the early or late steps, up-regulated in a linearly across the 4 steps, as well as down- then up-regulated (biphasic). Genes signing the presence of activating CD8 and CD4 T cells, as well as some memory B cells were progressively and linearly up-regulated from metaplasia through all stages of carcinogenesis. At the later stages, the transition to high-grade dysplasia, the most significant gene expression changes included immune/inflammatory response genes. At this stage a very strong adaptive immune response is noted involving T cells - mainly Th1 and T regulators - and dendritic cells. In addition, immunosuppressive signals, corresponding to negative co-inhibitory molecules, also significantly appears at the high-grade dysplasia stage. The adaptive CD4/CD8 related immune response starts from the earlier stages (metaplasia) of lung carcinogenesis. The significant modification of inflammatory/immune response genes in association with high-grade lesions suggests, at this critical stage of carcinogenesis, a major role of the surrounding microenvironment with an adaptive immune response, driven by Th1 and Treg cells, and but also, before tumor invasion across the basal membrane, a tumor versus host immunosuppressive response. Citation Format: Celine Mascaux, Mihaela Angelova, Jennifer Beane, Kahkeshan Hijazi, Geraldine Antoine, Karen Willard Gallo, Vincent Ninane, Arsene Burny, Jean-Paul Sculier, Avrum Spira, Jerome Galon. Characterization of the evolution of immune response in lung squamous carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1419.

Abstract 4478: EGFR tyrosine kinase inhibitors overcome resistance to chemotherapy in malignant pleural mesothelioma

Background: Malignant pleural mesothelioma (MPM) is a cancer of the pleura mainly caused by exposure to asbestos fibers. Current treatments are unsatisfactory due to intrinsic chemoresistance of the tumor. We hypothesized that chemoresistance was due to epigenetic errors and evaluated the ability of HDAC inhibitors to improve treatment efficacy. We previously showed that valproic acid (VPA) improves the first line regimen of MPM both in vitro and in vivo (Vandermeers et al, 2009, Clinical Cancer Research 15: 2818). A clinical trial also demonstrated that VPA in combination with doxorubicin increases the response rate of second line patients (Scherpereel et al, 2011, European Respiratory Journal 37:129). Methods: Transcriptomic profiling was performed by microarray analyses (Agilent). Gene expression was validated by quantitative RT-qPCR. Modulation of TGFα expression was performed by shRNA interference and transfection of a cDNA vector. Onset of apoptosis was assessed with the Annexin V assay. Results: To evaluate the mechanisms associated with the response to chemotherapy, we compared two types of MPM cell lines (M14K and H28) characterized by a difference in sensitivity to doxorubicin+VPA. Microarray analyses and bioinformatic modeling of gene expression profiles revealed the most relevant candidate genes associated with sensitivity or resistance to this regimen. Among these, TGFα expression was associated with resistance to doxorubicin + VPA in a series of MPM cell lines. Silencing of TGFα by RNA interference in H28 cells correlated with a significant increase in apoptosis. On the other hand, overexpression of TGFα desensitized M14K cells to doxorubicin+VPA -induced apoptosis. Since TGFα interacts with the EGF receptor, we evaluated pharmacological inhibition using EGFR tyrosine kinase inhibitors (erlotinib and gefitinib) and the dual HDAC/EGFR inhibitor CUDC-101. As predicted, these TKI inhibitors improved efficacy of doxorubicin+VPA. Conclusions: Our data demonstrate that TGFα is involved in resistance of MPM to chemotherapy and that TKI inhibitors overcome resistance to second line regimen. Citation Format: Bernard Staumont, Chrisostome Costa, Fabian Vandermeers, Sathya Neelature Sriramareddy, Celine Mascaux, Arnaud Scherpereel, Bernard Duysinx, Renaud Louis, Philippe Delvenne, Pascale Hubert, Luc Willems. EGFR tyrosine kinase inhibitors overcome resistance to chemotherapy in malignant pleural mesothelioma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4478.