Early Assessment of Chemotherapy Response in Advanced Non-Small Cell Lung Cancer with Circulating Tumor DNA.

Monitoring treatment efficacy early during therapy could enable a change in treatment to improve patient outcomes. We report an early assessment of response to treatment in advanced NSCLC using a plasma-only strategy to measure changes in ctDNA levels after one cycle of chemotherapy. Plasma samples were collected from 92 patients with Stage IIIB-IV NSCLC treated with first-line chemo- or chemoradiation therapies in an observational, prospective study. Retrospective ctDNA analysis was performed using next-generation sequencing with a targeted 198-kb panel designed for lung cancer surveillance and monitoring. We assessed whether changes in ctDNA levels after one or two cycles of treatment were associated with clinical outcomes. Subjects with ≤50% decrease in ctDNA level after one cycle of chemotherapy had a lower 6-month progression-free survival rate (33% vs. 58%, HR 2.3, 95% CI 1.2 to 4.2, log-rank p = 0.009) and a lower 12-month overall survival rate (25% vs. 70%, HR 4.3, 95% CI 2.2 to 9.7, log-rank p < 0.001). Subjects with ≤50% decrease in ctDNA level after two cycles of chemotherapy also had shorter survival. Using non-invasive liquid biopsies to measure early changes in ctDNA levels in response to chemotherapy may help identify non-responders before standard-of-care imaging in advanced NSCLC.

Assessment of a Highly Curated Somatic Oncology Database to Aid in the Interpretation of Clinically Important Variants in Next-Generation Sequencing Results.

This study evaluated the accuracy of NAVIFY Mutation Profiler, a cloud-based CE-IVD software that aids in interpreting clinically relevant variants detected in somatic oncology next-generation sequencing tests. This tool reports tiered classifications based on different levels of clinical evidence from a highly curated, regularly updated database derived from medical guidelines, drug approvals, and peer-reviewed literature. A retrospective analysis was performed on next-generation sequencing results from 37 lung cancer cases treated with chemotherapy (n = 10), EGFR tyrosine kinase inhibitor (TKI) (n = 5), or ALK TKI (n = 22). Several aspects were assessed, including accuracy of interpretation compared with manual curation, validity of curation content updates over time, and agreement with public databases. For chemotherapy cases with no targetable biomarkers, NAVIFY Mutation Profiler did not identify any targeted therapies. In EGFR and ALK TKI cases, the software associated appropriate targeted therapies and accurately interpreted variant combinations containing drug-resistance variants. Of the nine unique ALK mutations conferring resistance to crizotinib, NAVIFY Mutation Profiler provided correct annotation for all mutations, whereas OncoKB and Catalogue of Somatic Mutations in Cancer indicated crizotinib resistance for eight of nine mutations. For 145 variants analyzed, NAVIFY Mutation Profiler and OncoKB showed substantial agreement (Cohen κ = 0.62) for classifying actionable mutations. Furthermore, NAVIFY Mutation Profiler presented accurate targeted therapies across different regions and remained up-to-date with evolving regional approvals and medical guidelines.

The Clinical and Economic Impact of Inaccurate EGFR Mutation Tests in the Treatment of Metastatic Non-Small Cell Lung Cancer.

Advances in personalized medicine are supported by companion diagnostic molecular tests. Testing accuracy is critical for selecting patients for optimal therapy and reducing treatment-related toxicity. We assessed the clinical and economic impact of inaccurate test results between laboratory developed tests (LDTs) and a US Food and Drug Administration (FDA)-approved test for detection of epidermal growth factor receptor (EGFR) mutations. Using a hypothetical US cohort of newly diagnosed metastatic non-small cell lung cancer (NSCLC) patients and EURTAC (erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer) clinical trial data, we developed a decision analytic model to estimate the probability of misclassification with LDTs compared to a FDA-approved test. We estimated the clinical and economic impact of inaccurate test results by quantifying progression-free and quality-adjusted progression-free life years (PFLYs, QAPFLYs) lost, and costs due to incorrect treatment. The base-case analysis estimated 2.3% (n = 1422) of 60,502 newly diagnosed metastatic NSCLC patients would be misclassified with LDTs compared to 1% (n = 577) with a FDA-approved test. An average of 477 and 194 PFLYs were lost among the misclassified patients tested with LDTs compared to the FDA-approved test, respectively. Aggregate treatment costs for patients tested with LDTs were approximately $7.3 million more than with the FDA-approved test, due to higher drug and adverse event costs among patients incorrectly treated with targeted therapy or chemotherapy, respectively. Invalid tests contributed to greater probability of patient misclassification and incorrect therapy. In conclusion, risks associated with inaccurate EGFR mutation tests pose marked clinical and economic consequences to society. Utilization of molecular diagnostic tests with demonstrated accuracy could help to maximize the potential of personalized medicine.

Lung cancer screening: utility of molecular applications in conjunction with low-dose computed tomography guidelines.

Finding early-stage lung cancer where there is a higher chance for patient survival remains a major healthcare challenge. Low-dose spiral computed tomography for high-risk patients can increase the detection of cancers with certain tradeoffs, such as increased radiation exposure and surgical risks for false-positive cases. New molecular markers and assays show considerable promise to further reduce healthcare costs and improve lung cancer survival rates but require further validation. This review summarizes and discusses the current state of research in lung cancer screening and highlights developments in biomarker research for lung cancer diagnostics.

Assessment of EGFR and KRAS mutation status from FNAs and core-needle biopsies of non-small cell lung cancer.

BACKGROUND: Molecular testing to determine gene mutation status is now the recommended standard of care for patients with advanced or metastatic Non-small cell lung cancer (NSCLC). Because the majority of patients with NSCLC present with metastatic disease, minimally invasive procedures are necessary for diagnosis, staging, and molecular analysis. However, the resulting samples have perceived limitations in the oncology community, and most commercially available tests have not been validated for these sample types. The current study was undertaken to assess the feasibility of determining epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status in fine-needle aspirates (FNAs) and core-needle biopsies (CNBs) after staining with Papanicolaou or hematoxylin and eosin, respectively. METHODS: Gene mutation status was determined in 140 NSCLC tumor samples with proprietary tests for EGFR and KRAS mutations (cobas tests) followed by Sanger sequencing of exons 18 through 21 of the EGFR gene and exon 2 of the KRAS gene. The results were analyzed based on FNA (n = 91) or CNB (n = 49) sampling. RESULTS: The cobas tests yielded valid results in the majority of FNA and CNB samples for both EGFR (97.9%) and KRAS (93.6%). Moreover, valid results were obtained for 90% of samples that had DNA concentrations below the values recommended by the manufacturer. For samples with valid results from both cobas testing and Sanger sequencing, 95.7% and 93% agreement were observed for EGFR status and KRAS status, respectively. CONCLUSIONS: Gene mutation testing can be successfully performed on cytology and CNB samples, expanding the potential of personalized cancer treatment to patients who have limited tissue samples.