LKB1 (Phospho-Ser428) ELISA Kit

Background: Programmed cell death 1 (PD-1) and PD-ligand 1 (PD-L1) inhibitors represent novel therapeutic options for advanced non-small cell lung cancer (NSCLC). However, approximately 50% of patients do not benefit from therapy and experience rapid disease progression. PD-L1 expression is the only approved biomarker of benefit to anti-PD-1/PD-L1 therapy. However, its weakness has been evidenced in many studies. More recently, tumor mutational burden (TMB) has proved to be a suitable biomarker, but its calculation is difficult to obtain for all patients. Methods: We tested specific NSCLC genetic alterations as potential immunotherapy biomarkers. Tumor DNA was obtained from advanced NSCLC patients treated with anti-PD-1 monoclonal antibody nivolumab (n=44) or pembrolizumab (n=3). The mutational status of 22 genes was assessed by targeted next-generation sequencing and the association with survival was tested in uni- and multivariate models. The association between gene mutations and clinical benefit was also investigated. Results: The most frequently mutated genes were TP53 (49%), KRAS (43%), ERBB2 (13%), SMAD4 (13%), DDR2 (13%), STK11 (9%), ERBB4 (6%), EGFR (6%), BRAF (6%), and MET (6%). We confirmed that KRAS(mut) patients have a better response to PD-1 inhibitors, showing a longer progression-free survival (PFS) and overall survival (OS) than KRAS(wt) patients. In addition, we observed that patients with ERBB-family mutations, including EGFR, ERBB2, and ERBB4 all failed to respond to PD-1 antibodies, independently of KRAS status. Conclusions: This study suggests that the analysis of KRAS and ERBB-family gene mutational status is valuable when assessing the clinical practice for the selection of NSCLC patients to treat with PD-1 inhibitors.

Rectal neuroendocrine tumors (NETs) are the most common gastrointestinal (GI) NETs with an uncertain malignant potential despite their small size. There are limited data about driver mutations in rectal NETs, which may explain the tumors' unexpected behavior or common histologic morphology with other GI-NETs. Here, we investigated the clinically and pathologically relevant mutations of rectal and nonrectal NETs and compared the frequency and clinical significance of detected mutations between them. We sequenced 84 primary GI-NETs (69 rectal, 7 gastric, 5 appendiceal, and 3 sigmoid colon NETs) and 3 metastatic GI-NETs using targeted next-generation sequencing. Twenty-one rectal NETs (30.4%) showed at least 1 mutation in 24 cancer-related genes; the most common mutations were TP53 (10.1%) and FBXW7 (7.2%), of which 73% were pathogenic/likely pathogenic mutations. TP53 (p.R337C and p.R213*), PTEN (p.W111*, p.Q214*), CDKN2A (p.W110*), FBXW7 (p.R465H), and AKT1 (p.R23Q) were repetitive mutations found exclusively in rectal NETs, whereas SMAD4 (p.R361C) and STK11 (p.D176N) were repetitive mutations found only in gastric NETs. PTEN (p.G129K), EGFR (p.E709K), and KIT (p.V5551) were shared mutations between rectal and appendiceal NETs, whereas SMAD4 (p.R361C), ALK (p.G1202R), VHL (p.Q132*), and IDH1 (p.R132H) were concurrently detected between rectal and gastric NETs. GI-NETs with higher histologic grades, lymphovascular invasion, or recurrence tended to have higher numbers of mutation variants than other tumors; however, there was no significant difference. In conclusion, rectal NETs commonly carried pathogenic/likely pathogenic mutations. Because most mutations were identified in nonhotspot positions, next generation sequencing is useful in identifying potential drug targets in rectal NETs. (C) 2019 The Author(s). Published by Elsevier Inc.