Insights of Clinical Significance From 109 695 Solid Tumor Tissue-Based Comprehensive Genomic Profiles

Abstract

Background: FoundationOneCDx is approved in the US and Japan as a companion diagnostic test to identify patients with cancer who may benefit from treatment with 30 drug therapies in the US and 23 in Japan. Tumor profiling with FoundationOneCDx also detects genomic findings with evidence of clinical significance that may inform clinical care decisions beyond companion diagnostic claims. This observational study reports the breadth and impact of clinical decision insights from FoundationOneCDx solid tumor profiles.

Materials and methods: Consecutive test result reports for patients with solid tumor diagnoses (n = 109 695) were retrospectively analyzed for clinically significant predictive, prognostic, and diagnostic genomic alterations and signatures, determined in accordance with professional guidelines. Interventional clinical trials with targeted therapies or immune checkpoint inhibitors were matched to tumor profiles based on evidence that the genomic finding may be an actionable, investigational, or hypothetical target in the patient's tumor type.

Results: In 14 predefined cancer types (80.7% of analyzed solid tumors), predictive, prognostic, and diagnostic markers were reported in 47.6%, 13.2%, and 4.5% of samples, respectively, accounting for a total of 51.2% of tumor profiles. Pan-cancer predictive markers of tumor mutational burden (TMB) of 10 or more mutations per megabase, high microsatellite instability (MSI), or NTRK1/2/3 fusions were observed in 15.6%, 2.0%, and 0.1% of solid tumors, respectively. Most solid tumor profiles (89.2%) had genomic results that could theoretically inform decisions on the selection of immunotherapy and targeted therapy clinical trials.

Conclusion: For this real-world population of patients with FoundationOneCDx solid tumor profiles in the routine course of clinical care, clinically significant findings were reported for approximately half of patients with genomic results.

Keywords: comprehensive genomic profiling; in vitro diagnostic; next generation sequencing; oncology; precision medicine; solid tumors.

Figure 1.

Criteria for the markers with evidence of clinical significance and the matching of clinical trials to tumor profiles with actionable, investigational, or hypothetical therapeutic markers. Categories and tiers for the interpretation of the clinical significance of genomic alterations and signatures in tumor profiles were adapted from the Association for Molecular Pathology/American Society of Clinical Oncology/College of American Pathologists Guidelines. The criteria for evidence of therapeutic significance were modified to include predictive markers in drug labels (US FDA, EMA, Swissmedic; eg, BRAF V600E mutation in non-small cell lung cancer, colorectal cancer, or melanoma) or professional guidelines (NCCN and ESMO Guidelines; eg, ERBB2 amplification in colorectal cancer) that are used to select treatments in the patient’s tumor type, with ESCAT levels of evidence tiers I and II being considered actionable. These therapeutic markers are detailed in Tables 1-4. Diagnostic markers inform the diagnosis, and prognostic markers inform the prognosis, for the patient’s tumor type based on evidence in professional guidelines or from well-powered significant clinical studies with consensus in the literature. The prognostic (eg, KRAS G12V mutation in non-small cell lung cancer) or diagnostic markers (eg, IDH1 R132C mutation in glioma) are listed in Supplementary Tables S2 and S3, respectively. The frequency of the tumor profiling results with evidence of clinical significance is summarized by cancer type and marker category in Fig. 2. Therapeutic markers with evidence of clinical significance or of potential significance were matched to interventional trials for the patient’s tumor type and profile and ranked as described in the Methods section. The targets of the therapies in the matched and ranked trials on the tumor profiling reports are analyzed in Fig. 3. The frequency of tumor profiles with trial matches is provided by cancer type in Supplementary Table S4.

Figure 2.

Relative frequency of clinically significant predictive, prognostic, and diagnostic markers and their combination in the profiled solid tumors. All 14 analyzed cancer types (n = 88 569) include non-small cell lung cancer (n = 22 152), colorectal cancer (n = 13 193), breast cancer (n = 11 016), ovarian cancer (n = 6999), prostate cancer (n = 6513), pancreatic adenocarcinoma (n = 6168), gastroesophageal adenocarcinoma (n = 4762), unknown primary carcinoma (n = 4607), urothelial carcinoma (n = 3236), cholangiocarcinoma (n = 2901), melanoma (n = 2743), glioma (n = 2350), head and neck squamous cell carcinoma (n = 1787), and uveal melanoma (n = 142). Note that the markers in unknown primary carcinoma are predictive pan-cancer markers (TMB ≥ 10 mut/Mb, MSI-high, and NTRK1/2/3 fusion) as well as investigational targets that are associated with therapy approvals in other tumor types.

Figure 3.

Relative frequency of the targets of therapies in interventional clinical trials matched to 109 695 clinical reports based on the patient’s tumor type, age, and evidence that the genomic finding is an actionable, investigational, or hypothetical marker (criteria in Fig. 1). The figure describes the landscape of therapy targets accounting for at least 1% of the targets in matched trials by ranking their relative frequency across all reports and showing their frequency in 10 select cancer types. For example, PD-1, PD-L1, or CTLA-4 indicate how many of the matched clinical trials evaluate immunotherapies against these targets, whereas aromatase, ER, LHRH, or AR point to hormonal agents under clinical investigation. Color shading indicates frequency in each column, with red being more and blue less frequent. The frequency of a target can depend on various distinct genomic markers; for example, trials targeting PARP are matched to alterations in different homologous recombination repair genes, such as BRCA1, BRCA2, ATM, BRIP1, CHEK2, etc. Targets of therapies approved in the cancer types are underlined, irrespective of genomic alterations or biomarkers in the drug label (eg, PD-1 and CTLA-4 are approved targets due to the nivolumab plus ipilimumab indication in MSI-high or mismatch repair-deficient colorectal cancer).