Journal
Annals of Oncology
Authors
Pleasance E, Bohm A, Williamson LM, Nelson JMT, Shen Y, Bonakdar M, Titmuss E, Csizmok V, Wee K, Hosseinzadeh S, Grisdale CJ, Reisle C, Taylor GA, Lewis E, Jones MR, Bleile D, Sadeghi S, Zhang W, Davies A, Pellegrini B, Wong T, Bowlby R, Chan SK, Mungall KL, Chuah E, Mungall AJ, Moore RA, Zhao Y, Deol B, Fisic A, Fok A, Regier DA, Weymann D, Schaeffer DF, Young S, Yip S, Schrader K, Levasseur N, Taylor SK, Feng X, Tinker A, Savage KJ, Chia S, Gelmon K, Sun S, Lim H, Renouf DJ, Jones SJM, Marra MA, Laskin J.

Background: Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data provided by whole genome and transcriptome sequencing and analysis (WGTA) presents an opportunity to align a much larger proportion of patients to therapies.

Patients and methods: Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number, and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected.

Results: Clinically actionable targets were identified for 83% of patients, 37% of whom received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, PARP inhibitors, and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%), and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies.

Conclusions: Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.

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