<p>Supplementary Figure S5. Western blot of phospho-ERK1/2 and phospho-Akt from protein lysate of healthy lungs and lung tumors from EGFR/rhob mice, with corresponding quantifications</p>
Identifying patients who will experience lung cancer recurrence after surgery remains a challenge. We aimed to evaluate whether mutant forms of epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) (mEGFR and mKRAS) are useful biomarkers in resected non-small cell lung cancer (NSCLC).We retrospectively reviewed data from 841 patients who underwent surgery and molecular testing for NSCLC between 2007 and 2012.mEGFR was observed in 103 patients (12.2%), and mKRAS in 265 (31.5%). The median overall survival (OS) and time to recurrence (TTR) were significantly lower for mKRAS (OS: 43 months; TTR: 19 months) compared with mEGFR (OS: 67 months; TTR: 24 months) and wild-type patients (OS: 55 months; disease-free survival (DFS): 24 months). Patients with KRAS G12V exhibited worse OS and TTR compared with the entire cohort (OS: KRAS G12V: 26 months vs60 months; DFS: KRAS G12V: 15 months vs24 months). These results were confirmed using multivariate analyses (non-G12V status, hazard ratio (HR): 0.43 (confidence interval: 0.28-0.65), P<0.0001 for OS; HR: 0.67 (0.48-0.92), P=0.01 for TTR). Risk of recurrence was significantly lower for non-KRAS G12V (HR: 0.01, (0.001-0.08), P<0.0001).mKRAS and mEGFR may predict survival and recurrence in early stages of NSCLC. Patients with KRAS G12V exhibited worse OS and higher recurrence incidences.
Anaplastic lymphoma kinase (ALK) inhibitors have been successfully developed for non-small cell lung carcinoma (NSCLC) displaying chromosomal rearrangements of the ALK gene, but unfortunately resistance invariably occurs. Blockade of the PD-1-PD-L1/2 inhibitory pathway constitutes a breakthrough for the treatment of NSCLC. Some predictive biomarkers of clinical response to this therapy are starting to emerge, such as PD-L1 expression by tumor/stromal cells and infiltration by CD8+ T cells expressing PD-1. To more effectively integrate all of these potential biomarkers of clinical response to immunotherapy, we have developed a multiparametric immunofluorescence technique with automated immune cell counting to comprehensively analyze the tumor microenvironment of ALK-positive adenocarcinoma (ADC). When analyzed as either a continuous or a dichotomous variable, the mean number of tumor cells expressing PD-L1 (p = 0.012) and the percentage of tumor cells expressing PD-L1 were higher in ALK-positive ADC than in EGFR-mutated ADC or WT (non-EGFR-mutated and non-KRAS-mutated) NSCLC. A very strong correlation between PD-L1 expression on tumor cells and intratumoral infiltration by CD8+ T cells was observed, suggesting that an adaptive mechanism may partly regulate this expression. A higher frequency of tumors combining positive PD-L1 expression and infiltration by intratumoral CD8+ T cells or PD-1+CD8+ T cells was also observed in ALK-positive lung cancer patients compared with EGFR-mutated (p = 0.03) or WT patients (p = 0.012). These results strongly suggest that a subgroup of ALK-positive lung cancer patients may constitute good candidates for anti-PD-1/-PD-L1 therapies.
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e21014 Background: Although mutations in the kinase domain of MET are well described in papillary renal cell carcinoma, they are rare and poorly studied in lung cancer, but could constitute a new therapeutic target given the availability of potent MET inhibitors. The characteristics of patients with MET kinase mutation in lung cancer are still unknown. Our objective was to describe the demographic, clinical and biological characteristics of these patients, and analyze their survival. Methods: We conducted a multicenter retrospective study including patients with lung cancer harboring a MET kinase mutation. Patients who had already received treatment with a MET TKI before the MET kinase mutation was found were excluded. Results: We identified 37 patients with a MET kinase mutation. Among them, 2 had already received a MET inhibitor and in 8 cases, the data were not accessible. A total of 27 patients were included in the final analysis, including 17 males (63%) and only 2 (8%) never smokers. The median age was 64 (range 43-86). Most patients had adenocarcinoma (n = 25, 93%). 19 patients were diagnosed at an advanced stage. The main metastatic sites were brain (n = 8, 42%), bones (n = 7, 37%) and lungs (n = 5, 19%). PDL1 expression level was available for 21 patients, and was < 1%, 1-49% and ≥50% in 4 (19%), 5 (24%) and 12 (57%) patients respectively. MET kinase mutations involved exon 15, 16, 17, 18 or 19 in 6 (22%), 7 (26%), 7 (26%), 3 (11%) and 4 (15%) patients respectively. The 2 most common mutations were H1112Y (4 patients) and H1097R (3 patients). 18 patients (67%) had a concurrent alteration by NGS including TP53 mutations (n = 11, 41%), KRAS mutations (n = 6, 22%) and NRAS mutations (n = 3, 11%). Overall, co-alterations involving known driver oncogenes were detected in 13 patients (48%). 19 patients received a first-line systemic treatment for advanced disease. Median progression-free survival with chemotherapy and immunotherapy was 10.5 and 6.4 months, respectively (p = 0.55). Median overall survival was 12.2 months. No patient received a MET inhibitor. Conclusions: MET kinase mutations are not associated with specific clinical characteristics and frequently occur together with other oncogene mutations. These results suggest that these mutations may not be sufficient to drive carcinogenesis by themselves.
