Personalised selection of experimental treatment in patients with advanced solid cancer is feasible using whole-genome sequencing

Abstract

Background: Biomarker-guided therapy in an experimental setting has been suggested to improve patient outcomes. However, trial-specific pre-screening tests are time and tissue consuming and complicate the personalised treatment of patients eligible for early-phase clinical trials. In this study the feasibility of whole-genome sequencing (WGS) as a one-test-for-all for guided inclusion in early-phase trials was investigated.

Methods: Phase I Molecular Tumor Board (MTB) at the Erasmus MC Cancer Institute reviewed patients with advanced cancer without standard-of-care treatment (SOC) options for a 'fresh-frozen' (FF) tumour biopsy for WGS based on clinical-pathological features. Clinical grade WGS was performed by Hartwig Medical Foundation. MTB matched the patient with a trial, if available.

Results: From September 2019-March 2021, 31 patients with highly diverse tumour types underwent a tumour biopsy for WGS. The median turnaround time (TAT) was 15 days [10-42 days]. At least one actionable event was found in 84% of the patients (26/31). One-third of the patients (11/31) received matched experimental treatment.

Conclusions: WGS on fresh FF biopsies is a feasible tool for the selection of personalised experimental therapy in patients with advanced cancer without SOC options. WGS is now possible in an acceptable TAT and thus could fulfil the role of a universal genomic pre-screening test.

Fig. 1. Illustration of level of actionability of molecular alterations per patient.

Some tumours harboured multiple actionable alterations. Actionability of microsatellite instability and high tumour mutational burden/load are expressed in OncoKb level of evidence, since these are no biomarkers for targeted therapy. The CDKN2A mutations entail homozygous deletions. In Table 2 the exact mutations and therapy consequences are specified. AMP amplification, ESCAT ESMO Scale of Clinical Actionability for molecular Targets, HRD homologous recombinant deficient, HZD homozygous deletion, MSI microsatellite instability.

Fig. 2. Summary of multiplex immunofluorescent staining (IF) performed on the parallel FFPE tumour biopsies (n = 29).

a Boxplot of CD8-positive, PD-L1-positive and FOXP3-positive cells per mm² tumour tissue according to TMB high or low. No significant differences were found in median cell count between TMB high and low. Ns not significant, TMB tumour mutational burden. b Boxplot of CD68/PD-L1 double-positive and -negative tumours plotted against CD8/PD-L1 double-positive cell count. The CD8/PD-L1 double-positive cell count was significantly higher in the CD68/PD-L1 double-positive sample than in the negative sample (p = 0.000).***p < 0.001. c Illustrative example of the multiplex immunofluorescent staining of one patient and corresponding cell counts.