As the number of known cancer targets and precision therapies increases, implementing whole-genome sequencing (WGS) into regular clinical practice may benefit patients with metastatic cancer.
As the number of targeted anticancer therapies grows, so does the need for a fast and accurate diagnosis to optimize treatment for each patient. Whole-genome sequencing (WGS) has potential to facilitate timely identification of relevant targets and biomarkers, and findings from a recent study suggest WGS is feasible for genomic profiling in clinical practice.
Targeted therapies have changed the treatment landscape of several cancer types in recent years, and the arsenal of both tumor-specific and tumor-agnostic targeted agents has grown. However, the discovery of novel biomarkers and development of targeted drugs also pose challenges to pathology laboratories and providers.
In laboratories, molecular diagnostic (MolDx) tools must be continuously updated and validated, which delays implementing new findings into practice. MolDx indications also are often specific to tumor types, meaning numerous specific diagnostic routings exist and can be prone to errors or becoming outdated. As research advances, somatic mutations and potentially germline mutations are important. WGS has potential to assess both types, as well as more complex biomarkers such as homologous repair deficiency (HRD) signatures, microsatellite instability (MI), and tumor mutational load.
The study, published in Journal of Pathology, highlights these challenges and emphasizes the importance of a tumor-type independent, comprehensive MolDx approach for patients with cancer, especially those with metastatic disease. To assess the feasibility, validity, and value of WGS in routine clinical care, WGS was conducted on samples from 1200 patients with 32 types of tumors over 22 months. Results from WGS were compared with standard-of-care (SOC) diagnostics. There were 1302 total samples; 95 patients underwent multiple samplings.
Of the 1302 samples, 86 did not contain tumor cells. The 1216 samples containing tumor cells included 931 biopsies, 247 resections, and 38 cytological specimens that underwent WGS. The procedure was successfully completed in 70% of tumor samples, with the main barrier to completion being low tumor purity. Nine percent of samples had a tumor cell percentage (pTCP) below 20% as determined by microscopic assessment by a pathologist, and 15% had a molecular TCP below 20% as determined by WGS data despite a pTCP of at least 20%. Poor DNA quality (technical failure), low DNA yield, and patient-specific circumstances were additional reasons for study dropout.
The median turnaround time was 11 days, and WGS identified 99.2% of the 896 biomarkers identified overall with the 2 test types. SOC MolDx identified 99.7% of these biomarkers. In 603 of the 848 patients (71%) whose testing was completed, actionable biomarkers were found. Of the 936 associated therapy options—145 regular and 791 experimental—identified with WGS, SOC MolDx identified 343 (36.6%). WGS also found 49 pathogenic germline variants that were not previously identified. At 14 months of follow-up, 147 of 603 patients with actionable events had commenced biomarker-based therapy in either a regular or clinical trial setting. With biopsies and resections, WGS was successful in 70% and 77%, respectively, while cytology specimens had a 21% success rate, due largely to low pTCP. Various biopsy sites had different success rates, as well. Liver biopsies had the highest rate, at 78%, and lung, peritoneum, and bone biopsies had the lowest rates of 49%, 52%, and 54%, respectively.
“Importantly, when WGS could not be completed, yet a clinical indication for MolDx existed, both panel sequencing and Archer fusion analysis was successful in 87% (186/214) of these cases, indicating that targeted sequencing approaches can still be performed in the majority of cases if WGS is not feasible,” the study authors noted.
Overall, the findings suggest that WGS is a feasible option for patients with metastatic cancer, although the authors note that a main consideration is the cost of routinely implementing WGS into clinical practice.
“The present prospective study has demonstrated that WGS-based diagnostics is feasible in routine pathology practice and adds value for clinical decision-making,” the authors concluded. “The required adjustments in laboratory logistics were well manageable and acceptable to the health care professionals involved, which shows implementation hurdles in adopting WGS in routine pathology practice can be overcome.”
Samsom KG, Schipper LJ, Roepman P, et al. Feasibility of whole genome sequencing based tumor diagnostics in routine pathology practice. J Pathol. Published online July 6, 2022. doi:10.1002/path.5988