Comprehensive genomic profiling of over 10,000 advanced solid tumors

Abstract

Purpose: To summarize clinically relevant genomic alterations in solid tumor samples from over 10,000 patients.

Methods: Descriptive statistics were used to summarize findings of retrospectively analyzed OncoExTra assay data from solid tumor samples.

Results: The analysis cohort included 11,091 solid tumor samples from 10,768 patients. Therapeutically actionable alterations were present in 92.0% of patient samples. Biomarkers associated with on- or off-label FDA-approved therapies were detected in 29.2% and 28.0% of samples, respectively. The prevalence of hotspot alterations detected at variant allele frequency (VAF) <5% was analyzed among 7,481 samples (67.5%) harboring ≥1 of these events: 13.7% (1,022 of 7,481) had ≥1 alteration detected at VAF <5%, and 9.8% (558 of 5,690) of hotspot alterations associated with an on- or off-label FDA-approved therapy were detected at VAF <5%. Common and rare mutations in the TERT promoter were found in 8.4% (933) of samples. Whole transcriptome sequencing detected clinically relevant fusions in 7.5% of samples, with highest frequencies in prostate cancer (42.0%). The METe14 transcript was found in 14 NSCLC samples (2.7%).

Conclusions: The broad capabilities of the OncoExTra assay detected therapeutically actionable and other clinically relevant genomic events that can inform clinical decision-making for patients with advanced solid tumors.

Keywords: comprehensive genomic profiling; gene fusions; limit of detection; matched therapy; solid tumors.

Figure 1. Distribution of samples by tumor type.

Figure 2. Distribution of samples with therapeutically actionable alterations in the OncoExTra analysis cohort.

(A, B) Distribution of samples with therapeutically actionable alterations (A) by alteration type, overall and for the five most common cancer types in the cohort and (B) by alteration type for 61 genes detected in >100 samples. (C, D) Distribution of samples with biomarkers associated with on-label and off-label therapies (C) overall and by tumor type and (D) by biomarker. CNS* = grade II astrocytoma and oligodendroglioma; CNS** = low-grade glioma (E) Distribution of samples characterized by composite biomarkers TMB-high and MSI-high, overall and by tumor type. Data labels indicate the percentage of samples with TMB-high and MSI-high in each cancer type. For (A–D), samples can have >1 alteration as well as >1 alteration within the same gene.

Figure 3. Hotspot alterations detected at low VAF.

(A) Distribution of samples with at least one hotspot alteration detected at a VAF <5%, overall and by cancer type. (B) Distribution of hotspot biomarker alterations associated with on- and off-label matched therapies detected at a VAF <5% by biomarker. (C) Distribution of hotspot biomarker alterations associated with on-label matched therapies detected at a VAF <5% for HR+/HER2- breast cancer, CRC, and NSCLC.

Figure 4. Characterization of clinically relevant fusions detected by WTS in solid tumor samples.

(A) Frequency of clinically relevant fusion drivers detected in samples, overall, by tumor type and by partner genes forming fusions. (B) Frequency of fusions and partner genes detected in sarcoma subtypes. Number of fusions with indicated oncogenic driver gene in each tumor type.

Figure 5. Distribution of cancer-relevant pathways, overall and by tumor type.

Top: Co-occurrence matrix of cancer-relevant pathways. Data labels indicate frequency of alterations in a gene within the indicated pathway that is associated with matched therapy. Bottom: Heatmap displaying frequency of alterations in a gene within the indicated pathway that is associated with a matched therapy by cancer type.

Figure 6. TERT promoter mutations.

(A) Distribution of TERT promoter mutations, overall and by tumor type. (B) Location and frequency of TERT promoter mutations across all tumor types. In addition to alterations at the sites shown, seven TERT fusions and eight TERT amplifications were also observed.