Search Results (15)

The upcoming wave of personalized medicine, driven by genomic diagnostics and artificial intelligence, demands clearly defined pre-laboratory and laboratory procedures to ensure the acquisition of DNA and RNA of sufficient quantity and quality. In prostate cancer oncogenetics, diagnostic and prognostic assessments increasingly rely on personalized approaches, including Comprehensive Genomic Profiling (CGP). In this pilot study, we aimed to establish optimal pre-analytical and analytical conditions for selected genetic diagnostic methods using tissue samples acquired through multiparametric MRI-guided biopsy. Tissue specimens from thirteen patients were processed for DNA isolation, fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS). Comparative analyses were performed on DNA derived from both fresh and formalin-fixed, paraffin-embedded (FFPE) samples. Sequencing quality metrics demonstrated markedly superior performance in fresh tissue compared to FFPE. These results highlight the importance of standardized tissue collection and processing protocols to enable reliable molecular diagnostics in prostate cancer. Our findings support the feasibility of integrating high-quality genomic testing into routine biopsy workflows and emphasize the need for further large-scale validation. Full article

Soft tissue sarcomas (STSs) constitute a group of tumors with heterogeneous alterations and different biological behavior. Genetic profiling techniques have immense potential to revolutionize sarcoma classification, detection, and treatment. Cell-free DNA (cfDNA) analysis offers a minimally invasive approach to profiling tumor alterations, including tracking specific mutations or targeted panels of cancer-related genes via DNA sequencing methods. Circulating tumor DNA (ctDNA) platforms have gained popularity as a noninvasive alternative to tissue biopsies, offering a less invasive approach to tumor profiling. Nonetheless, ctDNA profiling in concordance with standard solid tumor comprehensive genomic profiling (CGP) is poorly characterized for STSs. Ultra-low-pass whole-genome sequencing and whole exome sequencing of cfDNA have yet to be fully leveraged in patients with sarcomas. This comprehensive review provides an overview of the application of ctDNA in STSs. Full article

The explosion in biomarker testing over the past two decades continues to transform cancer care in Canada and around the world. Precision medicine is supported by identifying actionable mutations that direct therapeutic choices, thus improving survival and quality of life, especially for patients with advanced/metastatic disease. In addition, our growing understanding of the genetic basis of cancer is advanced by research employing ever-expanding databases of genetic mutations, therapies and outcomes. Despite this promising progress, however, access to biomarker testing remains inequitable across Canada, to the detriment of patients. Several underlying factors contribute to this situation, including the need for investment in and standardization of laboratory medicine infrastructure and processes, and the lack of suitable methods for cost/benefit evaluations to inform funding decisions. In 2024, a Canadian conference brought together patients, clinicians, researchers, policy-makers and scientists to address “Equitable Access to Advanced Biomarker Testing for Canadian Metastatic Cancer Patients”. Two major themes arose from the conference: the urgent need to adopt comprehensive genomic profiling (CGP) as a standard of care across Canada, and the emerging role of liquid biopsy in accelerating access to biomarker testing for patients with advanced/metastatic cancer. Full article

Background: Comprehensive genomic profiling (CGP) identifies genetic alterations and patterns that are crucial for therapy selection and precise treatment development. In Colombia, limited access to CGP tests underscores the necessity of documenting the prevalence of treatable genetic alterations. This study aimed to describe the somatic genetic profile of specific cancer types in Colombian patients and assess its impact on treatment selection. Methods: A retrospective cohort study was conducted at Clínica Colsanitas S.A. from March 2023 to June 2024. Sequencing was performed on the NextSeq2000 platform with the TruSight Oncology 500 (TSO500) assay, which simultaneously evaluates 523 genes for DNA analysis and 55 for RNA; additionally, analyses were performed with the SOPHiA DDM software. The tumor mutational burden (TMB), microsatellite instability (MSI), and programmed cell death ligand 1 (PDL1) were assessed. Results: Among 111 patients, 103 were evaluated, with gastrointestinal (27.93%), respiratory (13.51%), and central nervous system cancers (10.81%) being the most prevalent. TP53 (37%), KMT2C (28%), and KRAS (21%) were frequent mutations. Actionable findings were detected in 76.7% of cases, notably in digestive (20 patients) and lung cancers (8 patients). MSI was stable at 82.52% and high at 2.91%, whilst TMB was predominantly low (91.26%). Conclusions: The test has facilitated access to targeted therapies, improving clinical outcomes in Colombian patients. This profiling test is expected to increase opportunities for personalized medicine in Colombia. Full article

Molecular profiles of thymomas and recurrent thymomas are far from being defined. Herein, we report an analysis of a comprehensive genetic profile (CGP) in a highly selected cohort of recurrent thymomas. Among a cohort of 426 thymomas, the tissue was available in 23 recurrent tumors for matching the biomolecular results obtained from primary and relapse samples. A control group composed of non-recurrent thymoma patients was selected through a propensity score match analysis. CGP was performed using the NGS Tru-SightOncology assay to evaluate TMB, MSI, and molecular alterations in 523 genes. CGP does not differ when comparing initial tumor with tumor relapse. A significantly higher frequency of cell cycle control genes alterations (100.0% vs. 57.1%, p = 0.022) is detected in patients with early recurrence (<32 months) compared to late recurrent cases. The CGPs were similar in recurrent thymomas and non-recurrent thymomas. Finally, based on NGS results, an off-label treatment or clinical trial could be potentially proposed in >50% of cases (oncogenic Tier-IIC variants). In conclusion, CGPs do not substantially differ between initial tumor vs. tumor recurrence and recurrent thymomas vs. non-recurrent thymomas. Cell cycle control gene alterations are associated with an early recurrence after thymectomy. Multiple target therapies are potentially available by performing a comprehensive CGP, suggesting that a precision medicine approach on these patients could be further explored. Full article

Background: Advanced non-small-cell lung cancer (NSCLC) can be treated with novel targeted therapies that are tailored to the genetic characteristics of malignancy. While tissue-based genomic testing is considered the gold standard for the detection of oncogenic driver mutations, several challenges like inadequate tissue availability, the invasiveness of procuring tumors, and prolonged turnaround time of analysis are encountered. Considering these limitations, guidelines have recognized liquid biopsies using circulating cell-free DNA (cfDNA) as a useful tool to complement conventional tissue testing. Even though cfDNA next-generation sequencing (NGS) can have high sensitivity and specificity, optimal patient benefit requires the interpretation of the molecular profiling results in the context of clinical and diagnostic features to achieve the best outcomes. Case Descriptions: In this case series, we present six patients with advanced NSCLC whose plasma or tissue biopsy samples were analyzed with commercially available comprehensive NGS assays that elucidate the role of testing at various time points in the treatment journey. In all six cases, comprehensive genomic profiling (CGP) provided clinically useful information to guide treatment decisions. Conclusion: Adding to the existing real-world evidence, this case series reinforces that CGP-driven treatment strategies in advanced NSCLC, coupled with other available clinical information, can optimize treatment decisions. Full article

Although comprehensive genomic profiling (CGP) tests have been covered under the Japanese national health insurance program since 2018, the utility and issues of CGP tests have not been clarified. We retrospectively reviewed 115 patients with incurable pancreatic cancer (IPC) who underwent CGP tests in a Japanese cancer referral center from November 2019 to August 2021. We evaluated the results of CGP tests, treatments based on CGP tests, and survival time. Eight cases (6.9%) were diagnosed as tumor mutation burden-high (TMB-H) and/or microsatellite instability-high (MSI-H). The gene mutation rates of KRAS/TP53/CDKN2A/SMAD4 were 93.0/83.0/53.0/25.2%, respectively. Twenty-five patients (21.7%) had homologous recombination deficiency (HRD)-related genetic mutations. Four patients (3.5%) having TMB-H and/or MSI-H were treated with pembrolizumab, and only two patients (1.7%) participated in the clinical trials. Patient characteristics were not significantly different between patients with and without HRD-related gene mutations. The median OS was significantly longer in the HRD (+) group than in the HRD (−) group (749 days vs. 519 days, p = 0.047). In multivariate analysis, HRD-related gene mutation was an independent prognostic factor associated with favorable OS. CGP tests for patients with IPC have the potential utility of detecting HRD-related gene mutations as prognostic factors as well as a therapeutic search. Full article

Comprehensive genomic profiling examinations (CGPs) have recently been developed, and a variety of tumor-agnostic mutations have been detected, leading to the development of new molecular-targetable therapies across solid tumors. In addition, the elucidation of hereditary tumors, such as breast and ovarian cancer, has pioneered a new age marked by the development of new treatments and lifetime management strategies required for patients with potential or presented hereditary cancers. In acute myeloid leukemia (AML), however, few tumor-agnostic or hereditary mutations have been the focus of investigation, with associated molecular-targeted therapies remaining poorly developed. We focused on representative tumor-agnostic mutations such as the TP53, KIT, KRAS, BRCA1, ATM, JAK2, NTRK3, FGFR3 and EGFR genes, referring to a CGP study conducted in Japan, and we considered the possibility of developing molecular-targeted therapies for AML with tumor-agnostic mutations. We summarized the frequency, the prognosis, the structure and the function of these mutations as well as the current treatment strategies in solid tumors, revealed the genetical relationships between solid tumors and AML and developed tumor-agnostic molecular-targeted therapies and lifetime management strategies in AML. Full article

Comprehensive genomic profiling (CGP) provides information regarding cancer-related genetic aberrations. However, its clinical utility in recurrent/metastatic head and neck cancer (R/M HNC) remains unknown. Additionally, predictive biomarkers for immune checkpoint inhibitors (ICIs) should be fully elucidated because of their low response rate. Here, we analyzed the clinical utility of CGP and identified predictive biomarkers that respond to ICIs in R/M HNC. We evaluated over 1100 cases of HNC using the nationwide genetic clinical database established by the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) and 54 cases in an institution-based study. The C-CAT database revealed that 23% of the cases were candidates for clinical trials, and 5% received biomarker-matched therapy, including NTRK fusion. Our institution-based study showed that 9% of SCC cases and 25% of salivary gland cancer cases received targeted agents. In SCC cases, the tumor mutational burden (TMB) high (≥10 Mut/Mb) group showed long-term survival (>2 years) in response to ICI therapy, whereas the PD-L1 combined positive score showed no significant difference in progression-free survival. In multivariate analysis, CCND1 amplification was associated with a lower response to ICIs. Our results indicate that CGP may be useful in identifying prognostic biomarkers for immunotherapy in patients with HNC. Full article

Precision (personalised) medicine for non-small cell lung cancer (NSCLC) adopts a molecularly guided approach. Standard-of-care testing in Australia is via sequential single-gene testing which is inefficient and leads to tissue exhaustion. The purpose of this study was to understand preferences around genetic and genomic testing in locally advanced or metastatic NSCLC. A discrete choice experiment (DCE) was conducted in patients with NSCLC (n = 45) and physicians (n = 44). Attributes for the DCE were developed based on qualitative interviews, literature reviews and expert opinion. DCE data were modelled using a mixed multinomial logit model (MMNL). The results showed that the most important attribute for patients and clinicians was the likelihood of an actionable test, followed by the cost. Patients significantly preferred tests with a possibility for reporting on germline findings over those without (β = 0.4626) and those that required no further procedures over tests that required re-biopsy (β = 0.5523). Physician preferences were similar (β = 0.2758 and β = 0.857, respectively). Overall, there was a strong preference for genomic tests that have attribute profiles reflective of comprehensive genomic profiling (CGP) and whole exome sequencing (WES)/whole genome sequencing (WGS), irrespective of high costs. Participants preferred tests that provided actionable outcomes, were affordable, timely, and negated the need for additional biopsy. Full article

BACKGROUND AND OBJECTIVES: Molecular genetic testing using tissue biopsies can be challenging for patients due to unfavorable tumor sites, the invasive nature of a tissue biopsy, and the added time of booking a repeat biopsy (re-biopsy). Centers in Canada have found insufficient tissue rates to be approximately 10%, and even among successful biopsies, insufficient DNA in tissue samples is approximately 16%, triggering the lengthy process of re-biopsies. Using aNSCLC as an example, this study sought to characterize the health and budget impact of alternative liquid-biopsy(LBx)-based comprehensive genomic profile (CGP) testing in tissue-limited patients (TL-LBx-CGP) from a Canadian publicly funded healthcare perspective. MATERIAL AND METHODS: An economic model was developed to estimate the incremental cost and life-years gained as a population associated with adopting TL-LBx-CGP. The eligible patient population was modeled using a top-down epidemiological approach based on the published literature and expert clinician input. Treatment allocation was modeled based on biomarker prevalence in the published literature, and the availability of funded therapies. Costs included molecular testing, as well as drug, administrative, and supportive costs, and relevant health data included median overall survival and median progression-free survival data. RESULTS: Incorporation of TL-LBx-CGP demonstrated an overall impact of $14.7 million with 168 life-years gained to the Canadian publicly funded healthcare system in the 3-year time horizon. Full article

Primary pulmonary artery sarcoma (PPAS) is a rare malignancy arising from mesenchymal pulmonary artery cells and mimics pulmonary embolism. Palliative chemotherapy such as anthracycline- or ifosfamide-based regimens and targeted therapy are the only options. However, the evidence of clinically beneficial systemic treatment is scarce. Here, we report a case of disseminated PPAS achieving clinical tumor response to olaparib based on comprehensive genetic profiling (CGP) showing genetic alterations involving DNA repair pathway. This provides supportive evidence that olaparib could be a promising therapeutic agent for patients with disseminated PPAS harboring actionable haploinsufficiency of DNA damage repair (DDR). Full article

In the precision medicine era, molecular testing in advanced cancer is foundational to patient management. Molecular tumor boards (MTBs) can be effective in processing comprehensive genomic profiling (CGP) results and providing expert recommendations. We assessed an MTB and its role in a community setting. This retrospective analysis included patients with MTB recommendations at a community-based oncology practice January 2015 to December 2018; exclusions were death within 60 days of the MTB and/or no metastatic disease. Potentially actionable genomic alterations from CGP (immunohistochemistry, in-situ hybridization, next-generation sequencing) were reviewed bi-weekly by MTB practice experts, pathologists, genetic counselors, and other support staff, and clinical care recommendations were provided. Subsequent chart reviews determined implementation rates of recommendations. In 613 patients, the most common cancers were lung (23%), breast (19%), and colorectal (17%); others included ovarian, endometrial, bladder, and melanoma. Patients received 837 actionable recommendations: standard therapy (37%), clinical trial (31%), germline testing and genetic counseling (17%), off-label therapy (10%), subspecialty multidisciplinary tumor board review (2%), and advice for classifying tumor of unknown origin (2%). Of these recommendations, 36% to 78% were followed by the treating physician. For clinical trial recommendations (n = 262), 13% of patients enrolled in a clinical trial. The median time between CPG result availability and MTB presentation was 12 days. A community oncology-based comprehensive and high-throughput MTB provided useful clinical guidance in various treatment domains within an acceptable timeframe for patients with cancer in a large community setting. Full article

The identification of the optimal cancer treatment has become progressively more intricate for non-small-cell lung cancer (NSCLC) patients due to the multitude of options available. The testing of biomarkers to predict clinical responses to therapies is pivotal to stratify the patients based on the molecular features of their tumors. The number of actionable genetic alterations to be tested is increasing together with the comprehension of the molecular mechanisms underlying tumor growth and development. The possibility of using next generation sequencing-based approaches enhanced the acquisition of genetic data with potential clinical usefulness, and favored the integration of precision medicine in clinical practice. The availability of targeted sequencing panels that cover genetic alterations in hundreds of genes allows the performance of a comprehensive genomic profiling (CGP) of lung tumors. However, different issues still need to be solved, from the tissue needed for next generation sequencing analysis, to the choice of the test and its interpretation in the clinical context. This position paper from the Italian Association of Thoracic Oncology (AIOT) summarizes the results of a discussion from a Precision Medicine Panel meeting on the challenges to bringing CGP and, therefore, precision medicine into the daily clinical practice. Full article

Down’s syndrome (DS), the most common genetic cause of significant intellectual disability in children and adults is caused by the trisomy of either all or a part of human chromosome 21 (HSA21). Patients with DS mostly suffer from characteristic tumor types. Although individual patients of DS are at a higher risk for acute leukemia and testicular cancers, other types of solid tumors including breast cancers are mostly uncommon and have significantly lower-than-expected age-adjusted incidence rates. Except for an increased risk of retinoblastomas, and lymphomas, the risk of developing solid tumors has been found to be lower in both children and adults, and breast cancer was found to be almost absent (Hasle H., The Lancet Oncology, 2001). A study conducted in the United States found only one death when 11.65 were expected (Scholl T et al., Dev Med Child Neurol. 1982). A recent study examined mammogram reports of women with DS treated in the largest medical facility specifically serving adults with DS in the United States. It was found that only 0.7% women with DS had been diagnosed with breast cancers (Chicoine B et al., Intellect Dev Disabil. 2015). Here we describe a case of breast cancer in a 25-year-old patient with DS. The disease was presented as lymph node positive carcinoma with alterations of tumor suppressor genes characteristic to the triple negative breast cancer subtype. Comprehensive Genomic Profiling (CGP) revealed a wild-type status for BRCA1. The CGP report showed a frameshift mutation, A359fs*10 of the tumor suppressor gene INPP4B and another frameshift mutation, R282fs*63 of tumor suppressor gene TP53 in the tumor biopsy as characteristically found in triple-negative breast cancers. The VUS (Variance of Unknown Significance) alteration(s) were identified in ASXL1 (L1395V), NTRK1 (G18E), DDR2 (I159T), RUNX1 (amplification), ERG (amplification), SOX2 (T26A), FAM123B (G1031D), and HNF1A (A301T). Bonafide cancer-related genes of chromosome 21 amplified in the patient’s tumor are RUNX1 and ERG genes. After the completion of the radiation, the patient was placed on everolimus which was based on the result of her CGP report. Thus, post-mastectomy radiation therapy was completed with a recommendation for everolimus for one year. During the time of writing of this report, no metastatic lesions were identified. The patient currently has no evidence of disease. Full article