Identification Of Non-small Cell Lung Cancer Patients Research Articles

Clinical performance of a comprehensive novel liquid biopsy test for identifying non-small cell lung cancer (NSCLC) patients for treatment with osimertinib.

9553 Background: Genotyping is required to identify cancer patients (pts) eligible for targeted therapy; however, many do not receive biomarker testing, in part due to limitations associated with tissue-only genotyping practices and the growing list of biomarkers recommended to be tested. Liquid biopsy overcomes many of these limitations but is not yet fully adopted. We report here the clinical performance of a comprehensive liquid biopsy test based on next generation sequencing (NGS) of circulating tumor DNA (ctDNA) for the identification of NSCLC patients with EGFR exon 19 deletions (ex19del) or L858R mutations ( EGFRm) or EGFR T790M, eligible for treatment with osimertinib. Methods: 441 (79%) of 556 pts randomized in FLAURA (NCT02296125; first-line osimertinib vs comparator EGFR TKI in EGFRm NSCLC) and 300 (72%) of 419 pts from AURA3 (NCT012151981; osimertinib vs chemotherapy in NSCLC pts with T790M at progression on EGFR TKI) were retrospectively tested with Guardant360 (G360), a 74-gene ctDNA NGS assay assessing single nucleotide variants, insertion-deletions, amplifications, and fusions in genes relevant to targeted therapy selection as well as microsatellite instability. Progression-free survival (PFS) of pts with EGFRm or T790M detected by G360 was compared to pts detected by the cobas EGFR Mutation Test (cobas) using tissue or plasma with an unadjusted cox model. Results: Treatment with osimertinib was associated with a significant PFS benefit relative to control therapy in NSCLC pts with EGFRm (FLAURA) and T790M (AURA3) detected using G360 (Table). Observed clinical benefit for pts with EGFRm or T790M detected by G360 was similar to that for pts with EGFRm or T790M identified by cobas using tissue or plasma specimens. Conclusions: This analysis demonstrates that G360 accurately identifies pts for osimertinib therapy while simultaneously providing comprehensive genotyping for other therapeutic molecular targets. The application of NGS liquid biopsy has the potential to increase rates of pts genotyped and access to precision medicine. [Table: see text]

Higher expression of miR-133b is associated with better efficacy of erlotinib as the second or third line in non-small cell lung cancer patients.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (gefitinib, erlotinib and afatinib) are indicated as first-line therapy in patients with non-small cell lung cancer (NSCLC) whose tumors harbor activating mutations in the EGFR gene. Erlotinib is also used in second and third-line therapy for patients whose tumors have wild type EGFR but to date there are no validated biomarkers useful to identify which patients may benefit from this treatment. The expression level of four miRNAs: miR-133b, -146a, -7 and -21 which target EGFR was investigated by real-time PCR in tumor specimens from NSCLC patients treated with erlotinib administered as the second or third line. We found that miR-133b expression level better discriminated responder from non-responder patients to erlotinib. Higher levels of miR-133b in NSCLCs were associated with longer progression-free survival time of patients. Functional analyses on miR-133b through transfection of a miR-133b mimic in A549 and H1299 NSCLC cell lines indicated that increasing miR-133b expression level led to a decreased cell growth and altered morphology but did not affect sensitivity to erlotinib. The detection of miR-133b expression levels in tumors help in the identification of NSCLC patients with a better prognosis and who are likely to benefit from second and third-line therapy with erlotinib.

Abstract A82: Identification of NSCLC patients with high tumor glucose uptake by 18F-FDG-PET

Abstract Introduction: One of the hallmarks of cancer is reprogramming of energy metabolism whereby cancer cells become dependent on aerobic glycoysis, making high glucose uptake essential. To optimally utilize novel therapeutics targeting these processes, it is important to identify patients with tumors highly dependent on glucose uptake and to be informed about intra-patient heterogeneity. 2-deoxy-2-[fluorine-18]fluoro-D-glucose emission tomography (18F-FDG-PET) non-invasively visualizes whole body glucose uptake and could be used for this purpose. We aimed to identify a subset of non-small cell lung cancer (NSCLC) patients with high tumor glucose uptake using 18F-FDG-PET scans and to determine intra-patient heterogeneity and patient and tumor characteristics in this group. Methods: Primary diagnostic 18F-FDG-PET/CT scans of NSCLC patients were retrospectively selected from 2418 consecutive scans performed at the University Medical Center Groningen (UMCG) in 2013. Exclusion criteria were: another active malignancy and inadequate fasting prior to the scan. Included were 32 patients with concurrent type 2 diabetes mellitus (T2DM) and 32 consecutive eligible control patients. All 18F-FDG-PET/CT scans were performed and analyzed according to the European Association of Nuclear Medicine Research Ltd (EARL) accreditation standards ensuring standardized data collection. A region of interest (ROI) was drawn around each visible 18F-FDG avid tumor lesion, and in normal tissue: liver, heart, peripheral muscle and abdominal fat. Subsequently, for all ROIs, standardized uptake values (SUVs) mean 40% were determined. High tumor uptake was defined as a SUVmean >5 and very high tumor uptake as a SUVmean >8. The metabolic tumor burden was evaluated by determining whole body metabolic tumor volume (MTV), defined as the volume corresponding to regions in which the SUVmean was measured. The analysis of glucose uptake was only performed for lesions with a volume≥1 mL due to underestimation of SUV values in smaller lesions due to partial volume effects. IBM SPSS Statistics 22 was used for conducting the Chi-square tests. Results: 673 18F-FDG-PET avid lesions were analyzed in 64 patients. The mean age was 63 years, 63% was male, 56% had adeno- and 39% had squamous cell carcinoma histology. Median number of tumor lesions per patient was 3 (1-90). There was a large heterogeneity in tumor glucose uptake both within and between patients. The highest measured SUVmean was 15.8 and the lowest 0.5. In the patient with the highest heterogeneity the absolute difference between the highest and lowest measured SUVmean in tumor lesions was 14. In 8/64 patients all lesions were very highly active (SUVmean >8), in 14/64 patients more than half of the lesions were very highly active and 28/64 patients had at least one very highly active lesion. In 17/64 patients all lesions were highly active (SUVmean >5) and in 28/64 patients more than half of the lesions were highly active, this was more often the case in patients with T2DM (14/32 vs 3/32 p=0.002 and 19/32 vs 9/32 p=0.012 respectively) and more often the case in patients with squamous cell carcinoma (11/25 vs 4/36 p=0.003 and 15/25 vs 10/36 p=0.012). In 46/64 patients there was at least one highly active lesion. In 18/64 patients all lesions had a SUVmean≤5. The volume of each tumor lesion (lesion MTV) and whole body tumor volume (MTV) did not correlate with tumor glucose uptake as measured using 18F-FDG. Conclusion: In a significant subset of NSCLC patients the majority of lesions are highly metabolically active. These patients may be especially sensitive to drugs targeting glucose uptake or glycolysis. Citation Format: Anne M. Hendriks, Adrienne H. Brouwers, Joop D. Lefrandt, Wim J. Sluiter, Wim Timens, Harry J. M. Groen, Elisabeth G. E. de Vries, Mathilde Jalving. Identification of NSCLC patients with high tumor glucose uptake by 18F-FDG-PET. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A82.

Prognostic Significance of Serum Inflammatory Response Markers in Newly Diagnosed Non-Small Cell Lung Cancer before Chemoirradiation.

Purpose. To identify whether the serum's baseline C-reactive protein (CRP) and albumin (Alb) levels related to clinicopathological parameters and overall survival (OS) in non-small cell lung cancer (NSCLC). Methods. In total, 100 consecutive patients (mean age = 68.38 ± 10.85 years) that underwent chemoradiotherapy were studied. Measurements of CRP and Alb were performed before any treatment. Results. Serum CRP levels were significantly associated with histological grade (P < 0.001), TNM stage (P < 0.001), PS (P = 0.009), and Alb (P < 0.001). Additionally CRP and Alb levels were found significantly associated with overall survival in univariate analysis (log-rank test, P < 0.001 and P = 0.002, resp.) and CRP remained significant after controlling for age, alcohol, performance status, and TNM stage, whereas albumin showed a borderline effect on the hazard rate (P = 0.052). Conclusions. CRP and Alb are both promising biomarkers in identification of NSCLC patients with poor prognosis and form a possible target for intensifying their therapies.

Cetuximab in advanced non-small cell lung cancer (NSCLC): the showdown?

Cetuximab in advanced non-small cell lung cancer (NSCLC): the showdown?

Detection of EML4-ALK in serum RNA from lung cancer patients using MassARRAY platform.

10569 Background: The presence of the transforming fusion gene EML4-ALK in non–small cell lung cancer (NSCLC) is a predictive marker for the efficacy of ALK kinase inhibitors. The break apart fluorescence in situ hybridization (FISH) assay has served as the standard test for identification of NSCLC patients with ALK gene rearrangement. Circulating RNA in plasma/serum is an emerging field for noninvasive molecular diagnosis. We previously developed a MassARRAY assay to detect nine types of EML4-ALK fusion gene (variants 1, 2, 3a, 3b, 4, 5a, 5b, 6, and 7). The assay is based upon region-specific PCR followed by specific single-base primer extension reactions; the extended products are resolved using MALDI-TOF mass spectrometry. In this study, we evaluated whether EML4-ALK fusion RNA could be detected in serum obtained from NSCLC patients. Methods: The RNA was extracted from serum obtained from 12 lung cancer patients with ALK rearrangements by FISH analysis. The extracted RNA was reverse transcribed into cDNA, and the resultant cDNA was amplified by nested PCR. The PCR product was subjected to MassARRAY assay to identify EML4-ALK variants. Results: The EML4-ALK RNA (variant 1 and 3) was detected in serum from 2 of 12 patients. These are confirmed by subcloning and sequencing. Conclusions: The detection of EML4-ALK in serum RNA samples by MassARRAY assay is feasible. This noninvasive assay will be useful in patients with insufficient or unavailable tumor specimens. Additional experiments will reveal the sensitivity and specificity of this detection system.

Cytokeratin-19 fragments, nucleosomes and neuron-specific enolase as early measures of chemotherapy response in non-small cell lung cancer

To investigate the reduction in the serum level of cytokeratin-19 fragments (CYFRA 21-1), nucleosomes and neuron-specific enolase (NSE) as early measures of the response to chemotherapy in non-small cell lung cancer (NSCLC). Forty-two consecutive patients with locally advanced NSCLC were included. All patients received platinum-based chemotherapy. Staging investigations and quantification of CYFRA 21-1, nucleosomes and NSE (using enzyme-linked immunosorbent assay, ELISA) were performed before the start of treatment and after the second cycle of chemotherapy. According to the response to chemotherapy, patients were classified into 3 groups: (I) disease regression, (II) stable disease, and (III) progressive disease. The reduction in the levels of tumor markers was correlated with the response to chemotherapy. After the second cycle of chemotherapy, groups I and II had significantly decreased serum levels of CYFRA 21-1 (p<0.05). Similarly, the concentration of nucleosomes was significantly lower than the baseline levels in groups I (p=0.0008) and II (p=0.003). The reduction of both CYFRA 21-1 and nucleosome levels was not significant for patients in group III. In all groups the reduction of NSE levels in response to chemotherapy was not significant. As a marker of response to chemotherapy, CYFRA 21-1 showed the highest sensitivity (88.9%) and specificity (77.4%) compared with nucleosomes (77.8% and 58.1% respectively) and NSE (66.7% and 51.8% respectively). The reduction in the serum level of CYFRA 21-1 and nucleosomes may be used for early identification of NSCLC patients with good response to chemotherapy.