Feasibility of Large-Scale Genomic Testing to Facilitate Enrollment Onto Genomically Matched Clinical Trials

Abstract

Purpose: We report the experience with 2,000 consecutive patients with advanced cancer who underwent testing on a genomic testing protocol, including the frequency of actionable alterations across tumor types, subsequent enrollment onto clinical trials, and the challenges for trial enrollment.

Patients and methods: Standardized hotspot mutation analysis was performed in 2,000 patients, using either an 11-gene (251 patients) or a 46- or 50-gene (1,749 patients) multiplex platform. Thirty-five genes were considered potentially actionable based on their potential to be targeted with approved or investigational therapies.

Results: Seven hundred eighty-nine patients (39%) had at least one mutation in potentially actionable genes. Eighty-three patients (11%) with potentially actionable mutations went on genotype-matched trials targeting these alterations. Of 230 patients with PIK3CA/AKT1/PTEN/BRAF mutations that returned for therapy, 116 (50%) received a genotype-matched drug. Forty patients (17%) were treated on a genotype-selected trial requiring a mutation for eligibility, 16 (7%) were treated on a genotype-relevant trial targeting a genomic alteration without biomarker selection, and 40 (17%) received a genotype-relevant drug off trial. Challenges to trial accrual included patient preference of noninvestigational treatment or local treatment, poor performance status or other reasons for trial ineligibility, lack of trials/slots, and insurance denial.

Conclusion: Broad implementation of multiplex hotspot testing is feasible; however, only a small portion of patients with actionable alterations were actually enrolled onto genotype-matched trials. Increased awareness of therapeutic implications and access to novel therapeutics are needed to optimally leverage results from broad-based genomic testing.

Fig 1.

(A) The most common cancer diagnosis for patients who underwent genomic testing. Each diagnosis consisted of a variety of different histologic subtypes. (B) The most common (likely somatic) mutations observed in the overall cohort.

Fig 2.

Frequency of actionable alterations. (A) Frequency of potentially actionable alterations among the 2,000 patients tested (left panel). For this analysis, patients were classified into mutually exclusive categories based on the highest category of alteration (actionable somatic mutation > nonactionable somatic mutation > germline variant; reporting each patient once). For the analysis, TP53, IDH1, and IDH2 were considered not actionable, and KRAS was considered actionable. Frequency of potentially actionable alterations by tumor type among tumor types with 10 or more patients tested (right panel). (B) Frequency of potentially actionable alterations with KRAS as well as TP53, IDH1, and IDH2 considered not actionable (left panel). Frequency of potentially actionable alterations by tumor type with this classification (right panel). (C) Frequency of potentially actionable alterations considering KRAS, TP53, IDH1, and IDH2 actionable (left panel). Frequency of potentially actionable alterations by tumor type with this classification (right panel).

Fig 3.

Frequency of selected alterations in different tumor types. Frequency of (A) AKT1, (B) KRAS, (C) BRAF, (D) NRAS, (E) EGFR, (F) PIK3CA, (G) ERBB2, and (H) PTEN mutations in breast cancer, colorectal cancer, melanoma, brain tumors, sarcoma, ovarian cancer, lung cancer, head and neck cancer, esophageal cancer, endometrial cancer, and kidney tumors.

Fig 4.

Clinical trial enrollment. (A) Proportion of patients enrolled onto a therapeutic clinical trial after results of genomic testing were available. (B) Proportion of patients enrolled onto a therapeutic clinical trial among patients with actionable mutations and those without actionable alterations (28.4% v 24.4%, respectively; P = .0445). (C) CONSORT diagram of patients who went on genotype-matched trials. (D) Key genomic alterations of patients who were enrolled onto genotype-matched trials (left panel). The right panel depicts the key genomic alterations of patients who were enrolled onto genotype-matched trials excluding alterations detectable by standard-of-care assays (EGFR, n = 5; BRAF, n = 16; and KRAS mutant, n = 3).

Fig 5.

Genotype-matched trial enrollment in patients who had tumors with PIK3CA/AKT1/PTEN/BRAF mutations. (A) Subsequent treatment of 429 patients who had tumors with PIK3CA/AKT1/PTEN/BRAF mutations. (B) Treatments given to the 230 patients with PIK3CA/AKT1/PTEN/BRAF–mutant tumors who received a subsequent new treatment regimen at The University of Texas MD Anderson Cancer Center. (C) Reasons patients who had tumors with PIK3CA/AKT1/PTEN/BRAF mutations were not enrolled onto trials. PS, performance status.