Heong V1,2, Syn NL1,2, Lee XW1, Sapari NS2, Koh XQ2, Adam Isa ZF2, Sy Lim J2, Lim D3,4, Pang B2,3,4, Thian YL5, Ng LK3, Wong AL1,2, Soo RA1,2, Yong WP1,2, Chee CE1, Lee SC1,2, Goh BC1,2,6, Soong R2,3, Tan DSP1,2,7.
1 Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
2 Cancer Science Institute of Singapore, National University of Singapore, Singapore.
3 Department of Pathology, Yong Loo Lin School of Medicine, National University Health System, Singapore.
4 Department of Pathology, National University Hospital, National University Health System, Singapore.
5 Department of Diagnostic Imaging, National University Hospital, National University Health System, Singapore.
6 Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore.
7 Department of Medicine, Yong Loo Lin School of Medicine, National University Health System, Singapore.
The value of precision oncology initiatives in Asian contexts remains unresolved. Here, we review the institutional implementation of prospective molecular screening to facilitate accrual of patients into biomarker-driven clinical trials, and to explore the mutational landscape of advanced tumors occurring in a prospective cohort of Asian patients (n = 396) with diverse cancer types. Next-generation sequencing (NGS) and routine clinicopathological assays, such as immunohistochemistry, copy number analysis and in situ hybridization tests, were performed on tumor samples. Actionable biomarker results were used to identify eligibility for early-phase, biomarker-driven clinical trials. Overall, NGS was successful in 365 of 396 patients (92%), achieving a mean depth of 1,943× and coverage uniformity of 96%. The median turnaround time from sample receipt to return of genomic results was 26.0 days (IQR, 19.0-39.0 days). Reportable mutations were found in 300 of 365 patients (82%). Ninety-one percent of patients at study enrollment indicated consent to receive incidental findings and willingness to undergo genetic counseling if required. The most commonly mutated oncogenes included KRAS (19%), PIK3CA (16%), EGFR (5%), BRAF (3%) and KIT (3%); while the most frequently mutated tumor suppressor genes included TP53 (40%), SMARCB1 (12%), APC (8%), PTEN (6%) and SMAD4 (5%). Among 23 patients enrolled in genotype-matched trials, median progression-free survival was 2.9 months (IQR, 1.5-4.0 months). Nine of 20 evaluable patients (45%; 95% CI, 23.1-68.5%) derived clinical benefit, including 3 partial responses and 6 with stable disease lasting ≥ 8 weeks.
KEYWORDS: biomarker-driven clinical trials; next-generation sequencing; precision medicine; precision oncology; targeted therapy.