Molecular testing and targeted therapy for non-small cell lung cancer: Current status and perspectives.

Molecular testing has become a mandatory component of the non-small cell lung cancer (NSCLC) management. The detection of EGFR, BRAF and MET mutations as well as the analysis of ALK, ROS1, RET and NTRK translocations have already been incorporated in the NSCLC diagnostic standards, and the inhibitors of these kinases are in routine clinical use. There are emerging biomarkers, e.g., KRAS G12C substitutions and HER2 activating alterations, which are likely to enter NSCLC guidelines upon the approval of the corresponding drugs. In addition to genetic examination, NSCLCs are usually subjected to the analysis of PD-L1 protein expression in order to direct the use of immune checkpoint inhibitors. Comprehensive NSCLC testing for multiple predictive markers requires the analysis of distinct biological molecules (DNA, RNA, proteins) and, therefore, the involvement of different analytical platforms (PCR, DNA sequencing, immunohistochemistry, FISH). There are ongoing efforts aimed at the integration of multiple NSCLC molecular assays into a single diagnostic pipeline.

Treating non-small cell lung cancer with selumetinib: an up-to-date drug evaluation.

INTRODUCTION: RAS-RAF-MEK-ERK signaling is implicated in tumor development by promoting cell proliferation and other cancer hallmarks. MEK1/2 kinases are up-regulated in the majority of human cancers due to activation of tyrosine kinase receptors, RAS proteins, BRAF kinase, or some other members of the MAPK pathway. Targeting of MEK1/2 kinases may counterbalance cancer progression. AREAS COVERED: The authors analyze the scientific publications relevant to selumetinib (AZD6244, ARRY-142886) systematically and provide their expert opinion. EXPERT OPINION: Selumetinib is an oral selective allosteric inhibitor of MEK1 and MEK2 kinases. Single-agent selumetinib is usually administered in hydrogen sulfate capsules 75 mg twice a day; combination with other therapeutic compounds may or may not require reduced dosing of this drug. The established dose for pediatric patients is 25 mg per square meter twice a day. Selumetinib was extensively evaluated in non-small cell lung cancer (NSCLC) patients. Studies utilizing this drug as a monotherapy did not confirm its efficacy toward NSCLC. A phase II trial showed that the addition of selumetinib to docetaxel improved response rates and progression-free survival (PFS) in chemotherapy-pretreated KRAS-mutated NSCLC patients; however, a subsequent phase III study did not confirm these findings. There are several highly successful non-NSCLC selumetinib trials involving, e.g., patients with neurofibromatosis type 1 related tumors and children with low-grade BRAF-driven gliomas.

High efficacy of first-line gefitinib in non-Asian patients with EGFR-mutated lung adenocarcinoma.

BACKGROUND: Several Asian studies demonstrated feasibility of front-line administration of gefitinib for the treatment of non-small cell lung carcinomas (NSCLCs) harboring intragenic epidermal growth factor receptor (EGFR) mutations. The experience of the use of this EGFR tyrosine kinase inhibitor (TKI) in non-Asian subjects remains limited. PATIENTS AND METHODS: The study included lung adenocarcinoma (AC) patients treated at the N.N. Petrov Institute of Oncology (Russia). RESULTS: DNA analysis of 192 consecutive AC revealed 38 (20%) TKI-sensitizing mutations. Presence of the exon 19 deletion (del19) or L858R was strongly correlated with nonsmoking status (smokers: 8/98 (8%); non-smokers: 30/94 (32%); p = 0.00004). The efficacy of first-line gefitinib therapy was evaluated in 25 patients with EGFR-mutated advanced AC. Twelve (48%) cases demonstrated tumor response (1 (4%) complete response, 11 (44%) partial responses; 10/17 (59%) patients with del19 mutation vs. 2/8 (25%) cases with L858R substitution, p = 0.11). The remaining 13 (52%) patients experienced disease stabilization. Median progression-free survival was 8.0 months. Grade 3 toxicity was the maximal adverse event, being observed only in 4 (16%) cases. CONCLUSION: Gefitinib may be considered as an upfront treatment option for EGFR-mutated NSCLC.

Down-staging of EGFR mutation-positive advanced lung carcinoma with gefitinib followed by surgical intervention: follow-up of two cases.

BACKGROUND: Non-small cell lung carcinomas (NSCLC) carrying a mutation in the epidermal growth factor receptor (EGFR) gene show unprecedented sensitivity to gefitinib or erlotinib. CASE REPORTS: We present the follow-up data of 2 EGFR mutation-positive stage IV NSCLC patients who received upfront 250 mg gefitinib daily, then underwent potentially curative surgery, and resumed gefitinib therapy in the adjuvant setting. Patient 1 was diagnosed with a rightsided adenocarcinoma of the upper lobe with multiple metastases to the middle lobe. After 2 months of gefitinib treatment, only a small primary lesion was seen, and a bilobectomy with lymph node dissection was performed. The patient remained disease-free during a scheduled 12-month adjuvant therapy but relapsed 9 weeks after cessation of this treatment. Patient 2 presented with adenocarcinoma of the lower lobe of the right lung and a single metastasis to the left adrenal. After 3 months of receiving gefitinib, the metastasis was no longer detectable, and the primary tumor was significantly reduced. Surgery included lobectomy and adrenalectomy. This patient relapsed with metastasis in the remaining adrenal 4 months after the start of adjuvant therapy. CONCLUSION: Gefitinib can be used preoperatively for the management of advanced EGFR mutation-positive NSCLC. It remains to be established whether surgical intervention indeed renders survival advantage for this category of patients.

Coding polymorphisms in Casp5, Casp8 and DR4 genes may play a role in predisposition to lung cancer.

Apoptosis plays a role in the elimination of DNA-damaged cells thus protecting the host from cancer development. Some data indicate that normal variations within the sequence of apoptotic genes may lead to suboptimal apoptotic capacity and therefore increased cancer risk. We tested 19 coding apoptotic gene SNPs in 2-stage molecular epidemiological study. For the preliminary sorting of SNP candidates, we employed a "comparison of extremes" approach, where 111 patients with highly pronounced LC susceptibility (non-smokers or young-onset light smokers) were analyzed against 110 subjects with the evidence for LC tolerance (elderly tumor-free heavy smokers). Three genotypes demonstrated possible association with LC risk (Leu/Leu-homozygotes for Casp5 Val318Leu versus other genotypes: OR=2.47 (95% CI: 1.07-5.69), p=0.03; His-carriers for Casp8 His302Asp: OR=2.26 (95% CI: 1.18-4.31), p=0.02; Arg-carriers for DR4 Lys441Arg: OR=1.89 (95% CI: 1.05-3.40), p=0.03), and therefore were selected for the validation. The extended study included 2 case-control series, namely subjects from Russia (351 LC cases and 538 controls) and Moldova (296 LC cases and 295 controls). Interestingly, all three candidate genotypes consistently demonstrated OR above 1 both in Russian and in Moldovian groups. Although the combined Mantel-Haenszel analysis yet failed to reach statistical significance (OR=1.22 (95% CI: 0.90-1.65), p=0.21; OR=1.17 (95% CI: 0.92-1.50), p=0.21; OR=1.19 (95% CI: 0.95-1.51), p=0.14, respectively), the obtained data indicate that Casp5, Casp8 and DR4 gene polymorphisms may deserve consideration in large-scale case-control studies of LC risk modifiers.