crizotinib and Carcinoma--Adenosquamous

The prevalence and clinical pathologic characteristics of MET amplification and overexpression in Chinese patients with non-small-cell lung cancer (NSCLC) remain unknown. In this multicenter study, we sought to reveal the frequency and clinical pathologic characteristics of MET amplification and to explore the predictive value of MET amplification and overexpression status in relation to survival in Chinese NSCLC patients.. MET amplification was detected by fluorescence in-situ hybridization in 791 patients with EGFR wild-type samples. MET protein expression was detected by immunohistochemistry.. In total, 8 of 791 NSCLC patients with EGFR wild type patients were identified as harboring MET amplification. Among these 8 patients, 1 had adenosquamous carcinoma histology and 7 adenocarcinoma. There was no statistically significant difference among age, sex, smoking status, and histologic type between patients with and without MET amplification. MET amplification was more frequent in advanced-stage disease and in the solid predominant subtype of adenocarcinoma. MET protein expression was performed in 395 patients, and 138 were positive. Patients positive for MET protein expression had worse overall survival (OS) compared to those without MET protein expression (45.0 vs. 65.8 months; P = .001). Multivariate analysis revealed that MET expression was an independent prognostic factor for poor OS (R = 1.497, P = .017), while MET amplification had weak relevance for OS (hazard ratio = 1.974, P = .251).. MET amplification was rare in Chinese NSCLC patients without EGFR mutation, with a prevalence of about 1%. MET expression but not amplification could be an independent prognostic factor for shorter OS among these EGFR wild-type NSCLC patients.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Adenosquamous; Carcinoma, Non-Small-Cell Lung; Crizotinib; ErbB Receptors; Female; Follow-Up Studies; Gene Amplification; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Staging; Prognosis; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Retrospective Studies; Survival Rate

Crizotinib was approved for the treatment of ROS1-rearranged non-small cell lung cancer (NSCLC) patients in the US on 11 March, 2016. Interestingly no one companion diagnostic test (CDx) has been approved simultaneously with this approval of crizotinib. Hence, an ideal and adequate CDx will have to be able to identify ROS1 fusions without the knowledge of the fusion partners to ROS1, and as to date there are 13 fusion partners reported for ROS1 in NSCLC. Here we report a novel TPD52L1-ROS1 fusion variant in NSCLC. This novel TPD52L1-ROS1 fusion variant is generated by the fusion of exons 1-3 of TPD52L1 on chromosome 6q22-23 to the exons 33-43 of ROS1 on chromosome 6q22, likely from an intra-chromosomal deletion and subsequent fusion event similar to the generation of EML4-ALK. The predicted TPD52L1-ROS1 protein product contains 655 amino acids comprising of the N-terminal amino acids 1-95 of TPD52L1 and C-terminal amino acids of 1789-2348 of ROS1. In summary, TPD52L1-ROS1 is a novel ROS1 fusion variant in NSCLC identified by comprehensive genomic profiling and should be included in any ROS1 detecting assays that depend on identifying the corresponding fusion partners, such as reverse transcriptase-polymerase chain reaction (RT-PCR).

Topics: Aged; Carcinoma, Adenosquamous; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy, Adjuvant; Crizotinib; Exons; Genomics; Humans; Lung Neoplasms; Male; Neoplasm Proteins; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Pyridines

To explore the automated immunostainer screening anaplastic lymphoma kinase (ALK) gene fusion non-small cell lung cancer (NSCLC) and clinicopathological characteristics of the molecular subtype lung cancers. Methods Five hundred and sixty-six cases of NSCLC were collected over a 16 month period. The test for ALK was performed by Ventana automated immunostainer with anti-ALK D5F3. The histological features, treatment and outcome of patients were assessed. Results Thirty-eight cases (6.7%, 38/566) of NSCLC showed ALK gene fusion. The frequency of ALK gene fusion was higher in male (7.1%, 25/350) than that in female (6.0%, 13/216) patients, but not achieving statistical significance (chi2 = 0.270, P = 0.604). ALK + NSCLC was more significantly more frequent in patients < or = 60 years (9.9%, 28/282) than >60 years (3.5% , 10/284) of age. Histologically, the ALK + NSCLCs were mostly adenocarcinoma (81.6%, 31/38) , among which eighteen cases were solid predominant subtype with mucin production; nine cases were acinar predominant subtype; one case was papillary predominant subtype and three cases were invasive mucinous adenocarcinoma. The ALK + non-adenocarcinoma included three cases of squamous cell carcinoma, three cases of adenosquamous carcinoma and one case of pleomorphic carcinoma. Among the ALK + NSCLC patients, the number of non/light cigarette smokers (86. 8% , 33/38) was more than that of heavy smokers. Twenty-nine cases were stages III and IV; twenty-nine cases showed lymph node metastasis; twenty cases showed metastases mostly to brain and bone; and one case showed EGFR gene mutation coexisting with ALK gene fusion. Twelve of fifteen patients received crizotinib therapy and remained stable. Conclusions NSCLC with ALK gene rearrangement shows distinctive clinical and histological features. Ventana-IHC may he a feasible and valid technique for detection of ALK rearrangement in NSCLC.

Topics: Adenocarcinoma; Anaplastic Lymphoma Kinase; Carcinoma, Adenosquamous; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Crizotinib; Female; Gene Fusion; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Sex Factors