Bridging the gap: Implementation of whole genome sequencing in routine clinical care

Abstract

Over the past years, the druggable genome has expanded rapidly which has led to an increase in the number and complexity of biomarkers that need to be assessed in each single patient. The current increase in numbers and complexity of biomarkers puts the logistics and sustainability of molecular diagnostics under constant pressure. Consequently, uptake of newly discovered biomarkers is often delayed resulting in less than optimal access to rational treatment options and ultimately inequality of care. In addition, targeted drugs are increasingly used for tumor-agnostic approaches which renders a tumortype specific molecular diagnostic approach less suitable. Hence there is a strong need for one technique which captures all DNA aberrations of the tumour. A comprehensive technique, Whole Genome Sequencing (WGS), has become accessible for implementation into routine diagnostics as the costs have been decreasing. This thesis investigated i.a. the feasibility of WGS in routine care and the use of (whole) genome sequencing in rare tumour types such as cancer of unknown primary (CUP) and neuroendocrine tumours (NETs). The results of the WIDE (WGS Implementation in standerd Diagnostics for Every cancer patient) study show that WGS is feasible for 71% of patients with metastatic cancer. Additionally, it is a clinically valid test with an acceptable turn around times (median 11 working days). For 71% of patients a genetic biomarker was identified, which renders them eligible for a treatment (possibly in study setting). Consequently, 24% of patients started a biomarker based therapy after a median follow-up of 14 months. WGS proved its additional diagnostic value in germline diagnostics, with previously 49 unrecognized germline mutations being identified by WGS. Rare cancers have a more dismal prognosis than common cancers, potentially due to poor elucidation of the genomic alterations underlying tumorigenesis and lack of effective therapeutic options. WGS has added value by solving differential diagnosis in patients with a CUP. CUP is a heterogeneous group of cancers defined by the presence of metastatic disease without an identified primary tumour site despite modern imaging and extensive pathology work-up. CUP accounts for 3-5% of all metastatic cancers. A WGS-based 'cancer of unknown primary algorithm' (CUPPA) was developed based on tumour specific drivers, regional mutational density and mutational profile characteristics. CUPPA could identify primary tumour type in 68% (n=49) and detect actionable events in 47% of patients. Small intestinal neuroendocrine tumours (SI-NETs) are rare neoplasms arising from neuroendocrine cells of the bowel. Driver mutations were identified in approximately 50% of SI-NETs and potential targetable mutations in 21% SI-NETs. In conclusion, WGS-based diagnostics is feasible in routine pathology practice. The required adjustments to multiple logistic processes were perceived as manageable tot the health care professionals involved, indicating that implementation hurdles in adopting WGS in routine clinical care be overcome. As the costs of WGS will steadily decrease in the foreseeable future, the path is smoothed for implementation of WGS in routine clinical care, thereby optimally deploying precision oncology and supporting learning health care systems.