Next-Generation Sequencing in the Clinical Setting Clarifies Patient Characteristics and Potential Actionability

Abstract

Enhancements in clinical-grade next-generation sequencing (NGS) have fueled the advancement of precision medicine in the clinical oncology field. Here we survey the molecular profiles of 1,113 patients with diverse malignancies who successfully underwent clinical-grade NGS (236 to 404 genes) in an academic tertiary cancer center. Among the individual tumors examined, the majority showed at least one detectable alteration (97.2%). Amongst 2,045 molecular aberrations was involvement of 302 distinct genes. The most commonly altered genes were TP53 (47.0%), CDKN2A (18.0%), TERT (17.0%), and KRAS (16.0%), and the majority of patients had tumors that harbored multiple alterations. Tumors displayed a median of four alterations (range, 0–29). Most individuals had at least one potentially actionable alteration (94.7%), with the median number of potentially actionable alterations per patient being 2 (range, 0–13). A total of 94.2% patients exhibited a unique molecular profile, with either genes altered or loci within the gene(s) altered being distinct. Approximately 13% of patients displayed a genomic profile identical to at least one other patient; although genes altered were the same, the affected loci may have differed. Overall, our results underscore the complex heterogeneity of malignancies and argue that customized combination therapies will be essential to optimize cancer treatment regimens.

GNAS, GNAQ,andGNA11alterations in patients with diverse cancers

“…1,7 The advent of next-generation sequencing has unearthed diverse genomic aberrations that are associated with different cancer types. [8][9][10][11][12] Specifically, recent deep sequencing analysis has revealed that 4.4% of tumors carry GNAS aberrations. 1 Several studies have shown that GNAS aberrations span a wide variety of endocrine tumors, including those originating from the pituitary (28%), pancreas (12%), thyroid (5%), and parathyroid (3%), ovary (3%), endometrium (2%).…”

Impact of molecular testing in clinical practice in gynecologic cancers

“…Intrapatient variability, with changes in the molecular profile from primary to metastatic disease and over the course of treatment, presents challenges to personalized medicine. [13][14][15][16] Furthermore, some authors have even attempted to classify potentially actionable alterations into categories with little success due to the rapidly evolving technology and knowledge. 17 Published results vary widely depending on tissue type, but 39%-83% are predicted to have a mutation for which matched therapy exists.…”

Precision oncology: the intention-to-treat analysis fallacy

“…1 Even with shared histopathologies or organ of origin, genomics has unveiled a remarkably complicated biologic landscape, with metastatic malignancies manifesting molecular complexity that differs from tumor to tumor. [2][3][4] In order to impact heterogeneous cancers in a precise manner, one must customize (or personalize) the therapeutic regimen. This new precision-personalized model differs from conventional strategies for cancer management in that it reflects a patientcentric, rather than drug-centric approach.…”