The global cancer landscape is characterized by a burgeoning clinical burden and the escalating costs of oncological therapies. In 2020, the global reports were approximately 19.3 million new cancer diagnoses (18.1 million when nonmelanoma skin cancers are excluded) and close to 10 million cancer-related fatalities (9.9 million excluding nonmelanoma skin cancers)[1]. By 2023, the United States alone anticipated around 2 million new cancer diagnoses and 610,000 cancer-related deaths [2]. This growing prevalence underscores the urgent need for advanced genomic testing to enable healthcare providers to deliver precise, personalized patient care informed by comprehensive analysis. Personalized medicine, particularly in oncology, hinges on the molecular profiling of tumors [3]. Large-scale projects like The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) have revealed a wide array of genomic alterations opening up the clinical actionability of genomic information informing patient care [4–6].
In the pursuit of personalized oncology, next-generation sequencing (NGS) has surfaced as a pivotal clinical instrument. Years of genomic research have conclusively shown that cancer is largely governed by genetic elements [6]. The condition emerges from a sophisticated interaction between inherited germline mutations and newly acquired somatic mutations, endowing cancer cells with the ability to thrive and circumvent immune detection [7]. The integration of personalized medicine into oncology through the adoption of genomic and molecular profiling technologies for customized treatment plans has been validated by its inclusion in the European Society for Medical Oncology (ESMO) guidelines. ESMO's structured recommendation framework endorses NGS for evaluating tumors in specific conditions, such as advanced non-squamous non-small cell lung cancer (NSCLC), prostate, ovarian, and cholangiocarcinoma, and positions NGS as a viable alternative to PCR for colon cancer diagnostics [8]. Additionally, in light of pembrolizumab's efficacy in certain cancer types, ESMO advocates for the evaluation of tumor mutational burden (TMB) in cancers like cervical, certain neuroendocrine, salivary, thyroid, and vulvar [8], underscoring the critical role of molecular insights in guiding therapeutic decisions.
Despite the significant potential of genomic testing, its integration into clinical practice has been modest, with only a select group of patients currently reaping its benefits [9, 10]. This limited utilization may stem from the limitations inherent in conventional testing methods, such as targeted panel sequencing (TPS) that focuses on specific exons and introns within a select group of 50–500 recognized cancer-related genes (typically representing 0.01%-0.1% of the genome). A notable limitation of TPS is its diminished ability to detect off-target driver mutations, intricate genomic rearrangements, and distinct mutational signatures, which are critical for a comprehensive understanding of cancer genomics [11, 12]. Additionally, these platforms often necessitate predefined diagnostic hypotheses based on prior clinical or genomic information, constraining their utility [7, 13]. Moreover, the need for periodic updates to incorporate new biomarkers, coupled with lengthy validation processes, hampers their ability to swiftly adapt to emerging genomic discoveries [10]. The limitations of current genomic testing methodologies underscore the unmet need for a nuanced and comprehensive approach to genomic analysis. Whole-genome sequencing (WGS) platforms emerge as the solution, offering a holistic view of the genome.
The clinical relevance of WGS platforms has escalated with the rapid advances in sequencing technologies and significant reductions in associated costs. WGS distinguishes itself from targeted panel or exome sequencing by circumventing the biases linked to sequence capture techniques, thereby offering a more exhaustive overview of the genomic landscape. WGS, when paired with a tumor-normal matched approach, facilitates a refined assessment of both somatic and germline genomic changes. Tumor-only tests have been reported to have higher false-positive rates, especially in non-European patients, due to the reliance on SNP databases that mainly represent European genetics, limiting their utility across diverse populations [14, 15] [14, 15].
A critical consideration for WGS lies in its feasibility for everyday clinical use. The analysis reported here assesses the real-world clinical utility of the Targeted Enhanced Whole Genome Sequencing (TE-WGS) assay, CancerVision™ (Genome Insight Inc. in San Diego, CA, USA). TE-WGS combines a tumor-normal paired whole-genome analysis with targeted scrutiny of key biomarker genes, providing a holistic genomic profiling method. The assay's clinical utility was evaluated across several domains of the likely impact of genomic insights: targeted therapy selection, clinical trial opportunities, the exclusion of non-beneficial therapies, and diagnostic clarity.