Precision medicine is certainly here to stay in the diagnosis and management of patients with a cancer diagnosis. The last two decades have witnessed an amazing evolution to the point that today a broad range of molecular and other biomarker tests are commonplace to assist the diagnostician and the treating physician in proper diagnosis/classification of cancer types, to offer more accurate prognostic information and more recently to also tailor therapy based on specific molecular as well as immune characteristics of the tumor. Targeted therapies based on the presence or absence of key biomarkers, such as EGFR/K-Ras/ErbB2 etc provide key information to define patient populations of great or very limited benefit improving outcomes, avoiding unnecessary side effects and offer better value-based care by matching expensive therapies with the precise patient subset deriving the most benefit. Besides such single gene alterations, an expansion of more complex tests now offer insights into the basic underpinnings of DNA repair deficiencies, such as microsatellite instability or DNA damage response yielding enrichment strategies for immunotherapeutics or PARP inhibitors. Due to the increasing need for more complex molecular information, single gene testing is rapidly being abandoned in favor of more comprehensive platforms, such as DNA or RNA based next generation sequencing based assays. In addition, tests reflecting the expression of checkpoint molecules, immune activation signatures and tumor microenvironment offer hope for further leveraging the treatment benefit with immune-modulating agents. Lastly, a revolution in circulating tumor (ct) DNA detection now offers minimally invasive and dynamic insights into tumor molecular features including primary sensitivity and acquired resistance. Longitudinal evaluation of ctDNA provides new avenues towards patient selection strategies and therapeutic modulation based on minimal residual disease.

It is in this context that the manuscript of Pruis et al. [1] attempts to break down some new barriers with the utilization of the most comprehensive DNA-based strategy- whole genome sequencing [2] for the management of patients with advanced malignancy being evaluated for early phase treatment studies within the framework of a national study in the Netherlands. Over a period of 18 months, 31 patients were enrolled in this study and underwent a fresh on-study tissue biopsy yielding fresh frozen tissue, with paired samples submitted for routine pathologic analysis and to confirm tumor adequacy. Fresh tissue was submitted for WGS, along with a matching blood sample to filter out germline alterations. Other biopsy samples were allocated for immune profiling and trial-specific assays as required. A very laudable turnaround time of 15 days was accomplished providing information about somatic gene alterations, tumor mutational burden as well as immune profiling results. The interpretation of variants derived from whole exome/WGS testing has in the past proven to be a major bottleneck [3] delaying result delivery and limiting introduction of these tests into routine clinical practice. Thus, the TAT reported here represents a significant step towards clinical applicability. WGS results could be obtained ultimately for 29/31 for patients for a yield of more than 90% and 26/31 patients were identified with actionable alterations as defined by the authors including 9 patients with high TMB, 2 with MSI, and 1 with HRD, while 5 tumors harbored potentially actionable fusions and 3 were noted to harbor viral DNA. All in all, 18/26 (69%) of the patients had a matching treatment available and 11/31 (35%) actually received matched experimental therapy- 5 of these involved immunotherapy for TMB-high status (of note TMB based approval of checkpoint inhibitors is lacking in EU). Other matched therapies included treatments based upon CDK4, ARID1A, NRAS and ATR alterations. Overall, the study appeared to meet its key endpoints- WGS based molecular testing was feasible with a practical turnaround time for the majority of patients, offering biomarker-guided treatment choices for one-third of all participants.

However, some notable shortcomings of this otherwise pioneering approach should be highlighted. First of all, this report does not provide insights into actual treatment benefit and it is also not clear how many patients had prior biomarker testing to allow gauging the added benefit of WGS. Furthermore, the incremental yield over standard panel-based NGS testing is not readily apparent as many of the findings encompass alterations that current, more readily available large NGS panels have been validated to obtain (e.g. TMB, MSI, HRD). Panel tests also offer the advantage of increased technical sensitivity, particularly for clinical samples that, more often than not, are heavily contaminated by benign stromal cells. In addition, the immune biomarker tests included in this study are largely unvalidated with limited clinical utility at present. Also, with the emergence of RNA-based panels providing higher yield for certain key actionable fusion events and offering additional insights into expression of genes, the limitations of purely DNA-based technologies - as comprehensive as they might be - do need to be recognized. Lastly, the significant investment into bioinformatics and the subsequent challenges as to data interpretation for WGS based platforms might be hard to replicate beyond very large academic/commercial collaborations and efforts to enable ready utilization in everyday clinical practice (Table 1).

Table 1 Summarizes pros/cons of different molecular testing platforms for cancer biomarker detection.

However, as far-fetched as the idea of whole genome sequencing for each patient with advanced malignancy might seem on the surface, the revolution in technology might indeed allow such to enter clinical practice. Similar to the outstanding effort of Pruis et al. [1], recently we have seen outstanding examples of massive genomic-based sequencing efforts- such as combined whole genome and transcriptome sequencing to be introduced in a timely and effective manner into the management of patients with acute myeloid leukemia [4] and pediatric malignancies enhancing the rate of detection of novel actionable alterations [5] providing a path of the discovery to actionability model in clinical practice. Furthermore, efforts such as Tracer-X [6] demonstrate the amazing power of genomic technologies for dynamic tracing of the clonal evolution of malignancies allowing major insights now readily used in clinical practice, for example for MRD detection in the management of colorectal cancer. A recent stunning case report highlighted the ability to complete rapid whole genome sequencing to expeditiously (within 16 h!) obtain genetic information key in the management of a critically ill pediatric patient [7]. WGS has yielded pivotal insights regarding intra-tumor heterogeneity and molecular changes yielding metastasizing cancers [8, 9] and comprehensive approaches including WGS have also been shown to define a broad range of actionable alterations in an efficient manner for pediatric malignancies, such as in the context of the Zero Childhood Cancer Program [10] and also has been utilized successfully for broad definition of germline syndromes amongst pediatric cancer patients [11]. So the future is here to stay and dreaming big is the successful motto of the progress we have witnessed over the last few decades in tumor biomarker testing and cancer management. While WGS likely might not be the one size fits all for all cancer patients, such excellent efforts pushing the boundaries of biomarker testing to optimize patient management are to be applauded.