While there is great potential for unbiased next-generation sequencing (NGS) approaches-eg, whole transcriptome sequencing (WTS)-for exploration, discovery, and clinical application in the realm of oncology, there are limitations that should be considered when relying on these methodologies for clinical decision making. When using WTS for the detection of clinically relevant gene fusions in tumor specimens, a key consideration is whether a limited coverage depth (approximately 30-50X) is sufficient for detecting these events, especially in samples with low tumor purity. We demonstrate the reduced sensitivity of both a commercial WTS assay for the detection of clinically relevant fusions in analytical validation control samples and of a research use only (RUO) WTS assay for the detection of clinically relevant fusions in real-world clinical samples compared to RNA comprehensive genomic profiling (CGP). Notably, the RUO WTS assay would not have reported 30% (6/20) of fusions detected using RNA CGP assays in fusion-positive tumor samples, highlighting a potential disadvantage of broader sequencing.

The Victorian Precision Oncology Summit, convened in 2023, was a joint initiative between the Victorian Comprehensive Cancer Centre Alliance (VCCC Alliance) and the Monash Partners Comprehensive Cancer Consortium (MPCCC) and was proposed to guide a coordinated state-wide conversation about how the oncology sector can overcome some of the current obstacles in achieving equity of access to clinical cancer genomics for Victorian patients. Themes that emerged from discussion groups at the Summit include standardisation, centralisation, funding, education and communication and insights across those themes are outlined in this manuscript. The event served as a large consultation piece for the development of a broader precision oncology roadmap, which explores equitable access to molecular testing for Victorian patients, currently in development by the VCCC Alliance and MPCCC in collaboration with other key Victorian and national stakeholders. While this symposium was a Victorian initiative, it is felt that the insights garnered from this consultation piece will be of interest to consumer groups, clinicians, researchers, educators, policy makers and other key stakeholders in other states of Australia as well as in other countries implementing comprehensive genomic profiling within complex health systems.

EUS-TA in unresectable pancreatic cancer requires not only a tissue diagnosis but also tissue collection in anticipation of comprehensive genomic profiling. However, the optimal puncture target remains controversial. Therefore, the Primary and Metastatic Lesions in Pancreatic Cancer (PRIMATE) study was designed to clarify the optimal target by comparing the success rates for meeting OncoGuide NCC Oncopanel (NOP) analysis criteria on pre-check primary and metastatic lesion specimens obtained during the same EUS-TA session in patients with invasive pancreatic ductal adenocarcinoma. In this ongoing prospective study, two specimens, each from primary and metastatic lesions, are obtained by EUS-TA (typically using a 19G fine-needle biopsy needle) in patients with invasive pancreatic ductal adenocarcinoma. The primary endpoint is the proportion of EUS-TA specimens that meet NOP analysis criteria during pre-check (i.e., tumor cellularity of ≥20% and a tissue area of ≥4 mm2), which are then compared between primary and metastatic lesions. This study has been approved by the National Cancer Center Institutional Review Board (Research No. 2022-168). The results of this study will be reported at an international conference and published in an international peer-reviewed journal. The trial registration number is UMIN 000048966.

Recent studies show increased expression of human epidermal growth factor receptor 2 (HER2) in cervical cancer, but the efficacy of anti-HER2 therapy remains under-researched. Here, we present a case of recurrent HER2-positive serous carcinoma, presumably arising in the cervix, diagnosed by comprehensive genomic profiling, which responded to trastuzumab. The patient underwent a radical hysterectomy with concurrent adjuvant chemoradiotherapy. One year after surgery, the patient experienced recurrence (multiple lymph node metastases). She underwent chemotherapy and subsequent comprehensive genomic profiling, which revealed HER2 positivity. Despite treatment, the lymph node and peritoneal metastases progressed. Therefore, combination chemotherapy with paclitaxel and trastuzumab was initiated. Subsequently, the patient\'s clinical symptoms improved considerably, and good health was maintained for 8 months. This report highlights the importance of comprehensive genomic profiling and targeted therapies when standard treatments fail.

BACKGROUND: Comprehensive cancer genomic profiling tests have recently been used clinically to guide optimal treatment. Currently approved tests use DNA from tissue or plasma samples to analyze a few hundred genes. RNA panels complement DNA panels to detect fusion and exon skipping.
METHODS: Between April 2017 and March 2022, we analyzed non-small cell lung cancer samples using Todai OncoPanel, a matched tumor/normal pair panel targeting both DNA and RNA. Publicly available genomic data was downloaded from the Center for Cancer Genomics and Advanced Therapeutics database on 2022/11/3.
RESULTS: Sixty non-small cell lung cancer (NSCLC) samples were analyzed. With the DNA panel, 32 samples (53%) had TP53 loss-of-function mutations. Among adenocarcinoma, 17 (33%) had EGFR activating mutations, and 6 (12%) had ERBB2 activating mutations. One BRCA1 and one BRCA2 pathogenic germline variant were also detected. With the RNA panel, 11 fusion genes were detected, all in adenocarcinoma. Specifically, EML4-ALK and KIF5B-RET were detected from one sample each, and 9 others were all novel fusions with unknown pathogenicity. In addition, 4 of 60 (7%) NSCLC samples harbored MET exon 14 skipping. Analysis of the Center for Cancer Genomics and Advanced Therapeutics database found 37 MET exon 14 splice site mutations in 1514 NSCLC samples (2%, p = 0.039).
CONCLUSIONS: Analysis of NSCLC with Todai OncoPanel detected many druggable targets. Its RNA panel may detect MET exon 14 skipping with high sensitivity.

Some genomic alterations in non-small cell lung cancer (NSCLC) are known to differ according to race, sex, or age. These studies have been limited in sample size and thus they cannot detect the differences precisely and comprehensively.
Tissue-based comprehensive genomic profiling was performed on 75,362 patients with NSCLC from the United States during routine clinical care. Additionally, we examined data of a Japanese NSCLC cohort with 1,019 patients. In the US cohort, 296 genes were examined for pathogenic alterations. Predominant genetic ancestry was inferred using a SNP-based approach, and patients were categorized into European (EUR), African (AFR), East Asian (EAS), Admixed American (AMR), and South Asian (SAS) ancestry groups. Patients were additionally stratified by histologic type, age (<40/≥40 years, <75/≥75 years), and sex. The prevalence of high tumor mutational burden (TMB-High) and microsatellite instability status was also calculated.
Stratified by ancestry, EGFR alterations were significantly enriched in EAS versus other ancestry groups. The prevalence of ALK was significantly higher in the AMR, EAS, and SAS patients than in AFR and EUR patients. KRAS and STK11 were enriched in EUR and AFR patients versus other groups. TMB-High was significantly enriched in AFR patients versus all other groups. An analysis based on sex revealed differences in prevalence of alterations in 80 genes and TMB-High status. For example, EGFR, ALK, BRAF, and KRAS alterations were significantly enriched in females, whereas TP53, STK11, KEAP1, and TMB-High were significantly enriched in males. With respect to age, the prevalence of alterations in 41 genes, including ALK, RET, MET, EGFR, STK11, KEAP1, BRAF, and KRAS, as well as TMB-High, were significantly different between patients aged <40 years and those aged ≥40 years.
Comprehensive analysis from a large real-world dataset revealed ancestry-associated differences in genomic alterations in NSCLC. Age- and sex-related differences in prevalence of genomic alterations and TMB-High status were also observed.

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Precision oncology has a significant role to play in delivering optimal patient care. Biomarkers are critical enablers for precision oncology across the continuum of cancer diagnosis, in defining patient prognosis, and in predicting the response to treatments and their potential toxicities, as well as delineating the risk of hereditary cancer syndromes. Biomarkers also potentiate cancer drug development, accelerating patient access to safe and effective therapies. However, despite an accurate and timely diagnosis being critical to patient survival, advances in genomic testing are not being fully exploited in daily clinical practice, leading to missed opportunities to deliver the most effective treatments for patients. Biomarker testing availability and implementation often lag behind approvals of respective biomarker-informed therapies, limiting prompt patient access to these life-saving drugs. Multiple factors currently impede the routine adoption of biomarker testing including, but not limited to, cost, lack of test reimbursement, limited access, regulatory hurdles, lack of knowledge, insufficient cooperation on assay development, and the urgent need to harmonize and validate testing assays, all leading to inefficient diagnostic pathways. Clinical guidelines increasingly include genomic profiling, and recent evidence suggests that precision oncology can be delivered in a cost-effective way for financially-challenged health systems. Therefore, precision genomic testing for cancer biomarkers must be embedded into the clinical practice of oncology care delivery going forward. We articulate a series of recommendations and a call to action to underpin the mainstreaming of a biomarker-informed precision oncology approach to enhance patient outcomes and deliver cost effective 21st century cancer care.

Comprehensive Genomic Profiling (CGP) allows for the identification of many targets. Reimbursement decision-making is, however, challenging because besides the health benefits of on-label treatments and costs, other factors related to diagnostic and treatment pathways may also play a role. The aim of this study was to identify which other factors are relevant for the technology assessment of CGP and to summarize the available evidence for these factors. After a scoping search and two expert sessions, five factors were identified: feasibility, test journey, wider implications of diagnostic results, organisation of laboratories, and \"scientific spillover\". Subsequently, a systematic search identified 83 studies collecting mainly evidence for the factors \"test journey\" and \"wider implications of diagnostic results\". Its nature was, however, of limited value for decision-making. We recommend the use of comparative strategies, uniformity in outcome definitions, and the inclusion of a comprehensive set of factors in future evidence generation.

Thyroid-like follicular renal cell carcinoma (TLFRCC), an emerging subtype of renal cell carcinoma, presents diagnostic challenges due to its resemblance to normal thyroid tissue. Here, we report a rare case of TLFRCC in a pediatric patient, a demographic rarely affected by this subtype. Histologically resembling a typical TLFRCC, our case exhibited unique features including post-neuroblastoma development, occurrence in a male teenager, and diffuse MelanA expression, which has not been previously reported in TLFRCC. Comprehensive genomic profiling revealed the EWSR1::PATZ1 fusion, confirming its genetic basis. Due to the advanced tumor stage, the patient received combined immunotherapy, and after a 9-month follow-up, remains tumor-free. Our case broadens the diagnostic spectrum of pediatric renal cell carcinomas, highlighting the importance of comprehensive molecular profiling in rare subtypes such as TLFRCC. Further research is needed to better understand TLFRCC\'s genetic landscape and optimize therapeutic strategies, especially in pediatric populations with evolving treatment protocols.