RESUMEN
PURPOSE: Guidelines advocate molecular profiling in the evaluation of advanced non-small-cell lung cancer (NSCLC) and support the use of plasma circulating tumor DNA (ctDNA)-based profiling for patients with insufficient tissue. Thorough prospective clinical validation studies of next-generation sequencing (NGS)-based ctDNA assays are lacking. We report the multicentered prospective clinical validation of the InVision ctDNA assay in patients with advanced untreated NSCLC. METHODS: A total of 264 patients with untreated advanced NSCLC were prospectively recruited, and their plasma was analyzed using a ctDNA NGS assay for detection of genomic alterations in 36 commonly mutated genes. Tumor tissue was available in 178 patients for molecular profiling for comparison with plasma profiling. The remaining 86 patients were included to compare ctDNA profiles in patients with and without tissue for profiling. RESULTS: Concordance of InVisionFirst with matched tissue profiling was 97.8%, with 82.9% positive predictive value, 98.5% negative predictive value, 70.6% sensitivity, and 99.2% specificity. Considering specific alterations in eight genes that most influence patient management, the positive predictive value was 97.8%, with 97.1% negative predictive value, 73.9% sensitivity, and 99.8% specificity. Across the entire study, 48 patients with actionable alterations were identified by ctDNA testing compared with only 38 by tissue testing. ctDNA NGS reported either an actionable alteration or an alteration generally considered mutually exclusive for such actionable changes in 53% of patients. CONCLUSION: The liquid biopsy NGS assay demonstrated excellent concordance with tissue profiling in this multicenter, prospective, clinical validation study, with sensitivity and specificity equivalent to Food and Drug Administration-approved single-gene ctDNA assays. The use of plasma-based molecular profiling using NGS led to the detection of 26% more actionable alterations compared with standard-of-care tissue testing in this study.
RESUMEN
In current medical practice, when a patient is diagnosed with cancer the treating physician generally follows a standard protocol, assigning the treatment that gives a favorable response in the largest proportion of patients. However, in many individual instances this approach may not be the most effective solution and, typically, treatment is only initiated or altered once the cancer has actually started progressing. During this process, patients will lose treatment time waiting to start chemotherapy or will endure severe side effects associated with toxic chemotherapeutic treatments. While some patients are undertreated because current diagnostic methods cannot provide accurate enough information regarding the aggressiveness or drug response of their disease, others with nonaggressive forms of cancer are overtreated and unnecessarily undergo the side effects associated with chemotherapeutic treatment. Epigenetic markers have been widely investigated and are considered key regulators of cellular transcription. Histone modifications and DNA methylation have been demonstrated to play key roles in maintaining stem-cell-like states, cellular differentiation and cancer. In particular, DNA methylation is a frequent, abundant and stable cancer mark, with an inherent role in oncogenesis and tumor progression. In this article, the potential of DNA methylation as a companion diagnostic is assessed, illustrated by exploring some development paths. Epigenetic silencing of MGMT is a key example of how biomarker development, biological pathways and clinical utility come together, serving as a hallmark of epigenetic companion diagnostics.
