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 (236-404 genes) in an academic tertiary cancer center. Among the individual tumors examined, the majority showed at least one detectable alteration (97.2%). Among 2,045 molecular aberrations was the 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 1,048 (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. Cancer Res; 77(22); 6313-20. ©2017 AACR.

Figure 1. Distribution of tumors (n = 1113 patients)

This pie chart displays the frequency and distribution of tumors identified in patients (n=1113 total tumors). Disease groups include breast (n= 142), glioma/glioblastoma (n=122), lung (n=120), colorectal (n=119), melanoma (n=65), carcinoma of unknown primary (n=62), soft tissue sarcoma (n=46), myelodysplastic syndrome (n=38), appendiceal cancer (n=36), head & neck (n=36), gastric (n=32), liver (n=31), and all others (n=264). Other cancers include acute lymphocytic leukemia (n = 10), acute myeloid leukemia (n=20), b-precursor acute lymphoblastic leukemia (n=10), b-cell lymphoma (n=7), biliary (n=6), chronic lymphocytic leukemia (n=16), central nervous system non-glioma (n=9), carcinoma lymphocytic leukemia (n = 16), diffuse large B-cell lymphoma (n=12), lower GI (n=18), multiple myeloma (n=12), neuroendocrine (n=19), ovary (n=24), pancreas (n=25), prostate (n=8), renal (n=8), squamous cell carcinoma (n=12), skin (n=14), thyroid (n=26), and urinary (n=8). Abbreviations: CUP = carcinoma of unknown primary; CRC = colorectal cancer H&N = head and neck; MDS = myelodysplastic syndrome.

Figure 2

Figure 2A. The percent of individuals with the 50 most common alterations. This bar graph represents the percent of individuals with the most common molecular alterations. TP53 alterations were observed in the most number of patients. Types of alterations include multiple distinct alterations: rearrangement, deletion, amplification, and short variant. Figure 2B. Distributions of alterations among breast cancer. This bar graph represents the 5 most common molecular alterations identified in 142 patients with breast cancer. The y-axis represents the distributions of patients harboring the genetic alteration. Figure 2C. Distribution of alterations among glioma cancer. This bar graph represents the 5 most common molecular alterations identified in 122 patients with glioma cancer. The y-axis represents the distributions of patients harboring the genetic alteration.

Figure 3. Flowchart of actionability in 1,113 patients who underwent next-generation sequencing (NGS) interrogation

Of all patients harboring at least one actionable alteration (N=1054, 97.4%), 98.3% of them were actionable by an FDA-approved drug and 1.7% were actionable by an experimental drug only.