TEST:

OncoPanel™ Assay

The performance of indel calling can further be improved by restricting the calls within high confidence intervals (HCIs) and coding regions, and by excluding low complexity regions (LCR) regions. Certain VAF cut-offs could be applied according to the applications.

P2, N=12, Terminated, Dana-Farber Cancer Institute | Trial completion date: Mar 2024 --> Oct 2023 | Active, not recruiting --> Terminated; Funding was pulled

Overall, having similar categories of criteria across trials suggests that common clinical data could be used for many different PM trials. Currently, we are investigating which categories are most relevant for trial matching and the use of AI for structuring unstructured clinical data.

Our studies have elaborated the mechanism of AUS_001 as an inhibitor of tubulin polymerization. The favorable safety profile of AUS_001, along with its ability to circumvent Pgp-mediated multidrug resistance, provides potential for efficacy against multiple cancers where microtubule destabilization is proven to be an effective target.

Interestingly, in three cases there was emergence of a new variant activating the RAF/MAPK or AKT pathway.Conclusion Pediatric sarcomas display a range of genomic changes over time. Given the observed changes in oncogenic alterations, there may be utility to repeat sequencing of relapsed tumor biopsies to understand these changes.

Furthermore, CD4+ T-cells isolated from fresh PBMCs demonstrated proliferative responses following stimulation (ImmunoCultâ„¢) in the presence of PIC eIF4E regulators. The impact on key oncogenic drivers and potent antiproliferative activity in multiple myeloma models with minimal effects on normal immune cell populations suggests that targeting eIF4E activity with PIC allosteric eIF4E regulators could offer an attractive therapeutic strategy in multiple myeloma.

Our results suggest that primary low-grade mucinous neoplasms of the seminal vesicle may represent a distinct entity equivalent to appendiceal counterparts, driven by gain-of-function variants of RAS GTPases. The remaining tumours showed genomic features that closely resembled those of neoplasms with comparable phenotypes and/or biological characteristics arising in other sites, suggesting that they could be managed similarly, with special considerations related to their anatomical location.

The presence of a PRKACA/B fusion appears to contribute to oncocytic morphology, but 71% of fusion-positive cases had mixed epithelial subtypes. Rare cases harbored concurrent fusion and driver mutation associated with IPMN. Though fusion-positive lesions were more commonly seen in the non-recurrence group, they also comprised >50% of cases with disease recurrence.

P2; Trial primary completion date: Jun 2024 --> Dec 2024

P3; These data highlight the presence of underlying biological differences able to predict survival and response following treatment with immunotherapy in platinum-refractory R/M HNSCC that could have translational implications improving treatment selection.

We identified recurrent germline variants in 42 (75%) patients occurring mainly in JAK/STAT, Hypoxia and Iron metabolism pathways, among them: JAK3-V722I and HIF1A-P582S; a high fraction of patients (48.2%) resulted also mutated in homeostatic iron regulatory gene HFE-H63D or C282Y. By generating cellular models, we showed that JAK3-V722I causes activation of the JAK-STAT5 axis and upregulation of EPAS1/HIF2A, while HIF1A-P582S causes suppression of hepcidin mRNA synthesis, suggesting a major role for these variants in the onset of IE.

Genomic biomarkers based on functional variant analysis of a routine clinical panel may help identify adverse events in GBM, particularly seizures. Identifying these risk factors could improve the management of patients through better supportive care and consideration of prophylactic therapies.

P2; N=15 --> 0 | Recruiting --> Withdrawn

P1/2; Recruiting --> Suspended

By implementing next-generation sequencing into the diagnostic pipeline for breast cancer, we can identify more patients with hereditary breast cancer and expedite familial screening for breast cancer prevention. This pilot program will offer valuable insights for future implementation of tumour genetic testing on a larger scale in the province. Additionally, the results will provide evidence supporting the adoption of POAga as an alternative cascade genetic testing approach, leading to a 50% increase in efficiency, reduced financial burden, and emotional benefits for patients and their families.

High level ERBB2 amplification reliably predicts HER2 amplification in NSCLC patients and HER2 ADC is effective therapy in this population.

P2; Trial completion date: Oct 2023 --> Jun 2024

After January 2022, the addition of standard of care abiraterone/prednisone was allowed after 7 months of study treatment at investigator discretion. Clinical trial information: NCT04126070.PD-L1 Combined Positive Score (CPS) ≥ 1 and/or CD T cell density ≥ 200. Homozygous deletions and/or deleterious mutations in a DDR gene, including and not limited to BRCA2, ATM, CHECK2, BRCA1, PALB2, RAD51D, ATR, NBN, PMS2, GEN1, MLH1, MSH2, MSH6, RAD51C, MRE11A, BRIP1, FAM175A, and CDK12.

In 2022, 151,030 new CRC and 65,950 new EC cases were diagnosed in the USA. Extrapolating our findings to this larger population, use of NGS mutational signature analysis instead of IHC would amount to about 1510 additional MMR-D CRC cases and 3297 additional MMR-D endometrial cases identified each year for whom first-line ICI therapy is preferred. Our findings support revisiting guideline recommendations for diagnostic testing of MMR to incorporate both IHC and targeted NGS tumor panel testing using sensitive and specific mutation signature calling algorithms.

P1/2; Trial completion date: Nov 2023 --> Nov 2024 | Trial primary completion date: Nov 2023 --> Nov 2024

GP-2250 demonstrated cytotoxic activity in vitro and reduced the tumor volume in a variety of human cancer cell lines in a xenograft mouse model. Given these results, as well as evidence of synergism with other anticancer drugs, GP-2250 shows promise as a new therapeutic agent for treating human cancers and is being evaluated in a phase 1 dose-escalation study (NCT03854100).

In summary, there is no significant association between TMB at baseline and poor survival outcomes in IDH-wildtype GBM. Further research is needed to explore the potential implications of TMB as a prognostic marker and its relevance for personalized treatment strategies in GBM patients.

Cox multivariate regression analysis of 341 GBM patients (median survival=15.9 months) revealed that older age, lack of MGMT promoter methylation, and impaired performance status (Karnofsky performance scale < 80) were significantly associated with survival outcome (HRage=1.40, Page=7.64×10-3, HRMGMT=1.43, PMGMT=6.98×10-3, and HRKPS=1.79, PKPS=3.05×10-6). In summary, by utilizing the AMC OncoPanel and the 2021 WHO criteria, we successfully classified diffuse glioma into three distinct.

Finally, we have also identified group-specific therapeutic strategies combining repositioned FDA-approved drugs with the inhibition of crucial DDR factors. Our long-term goals are i) to understand the molecular basis behind the differential response to DNA damage and replication stress developed by G1 and G3 cells and ii) to propose group-specific, DDR-based combination therapies that prevent treatment resistance and promote long-lasting treatment.

Taken together, this study provides a comprehensive landscape of somatic alterations in a large cohort of patients with metastatic IBC and non-IBC. Our data support a lack of major genomic differences other than enrichments in TP53 mutations and an associated LumB-like histopathology. These results both reinforce the importance of TP53 mutations in IBC biology and suggest additional analyses beyond somatic DNA-level changes are warranted.

These data highlight the utility of evaluation of SNP performance in targeted NGS assays using exclusively tumor-only data. Identification of high-quality informative SNP loci can aid in tumor purity estimation and in the interpretation of ASCN variants, as well as provide informative inputs for machine learning-based algorithms trained on a ground truth of CMA data.

Somatic databases such as COSMIC and polymorphism databases such as gnomAD provide convenient means to distinguish somatic versus germline mutations in Tonly tests without a matched germline sample. Careful validation of the data from these databases was essential to ensure that the results were accurate and specific. By using data from the T/G pipeline, we recalibrated the COSMIC and gnomAD cut-offs in our T-only pipeline to ≥10 instances and ≥1%, respectively.

Matched T/G sequencing enables definitive reporting of tumor-specific variants, more accurate TMB calculation, and appropriate classification of germline pathogenic/likely pathogenic findings. These improved genomic results enable more specific targeted and immunotherapy recommendations for patients and inform inherited cancer risk. Operationally, implementation of matched T/G sequencing can enable expansion of panel testing to whole-exome or whole-genome approaches.

These data highlight the stability of cfDNA in CSF, which allows for cytopathologic evaluation before triage for next-generation sequencing assays. For a subset of cases in which clinical suspicion is high but cytologic or radiographic studies are inconclusive, the detection of pathogenic somatic variants in CSF cfDNA may aid in the diagnosis of leptomeningeal metastases.

Utilizing a targeted panel of genes with a known role in cancer pathogenesis, we developed a genomic score that can be calculated from an extracranial or intracranial site to quantify local recurrence risk following brain-directed radiation. Prior attempts to develop a biomarker-based radiation response signature have not focused on patients with BrM and have primarily relied on RNA-based measures of radiosensitivity, limiting their utility in real-world clinical practice for this patient population. To our knowledge, this represents the first study to systemically correlate DNA-based alterations with radiation-based outcomes among patients with BrM. If validated, Brain-RPS has potential to facilitate clinical trials aimed at genome-based personalization of radiation treatment among patients with BrM.

Utilizing a targeted panel of genes with a known role in cancer pathogenesis, we identified genomic alterations in three genes as being predictive of LMD development. If validated in independent datasets, development of clinical trials exploring inhibition of pathways affected by these genomic alterations may be warranted with the goal of LMD prevention and targeted treatment among particularly high-risk cohorts. To our knowledge, this represents the first study to identify potentially actionable alterations as predictive of leptomeningeal disease development among patients with brain metastases.

Conclusions Our analysis identified several risk factors for ICI-DM that may identify patients at higher risk for ICI-DM. The results from our multi-modal strategy – combining clinical, genetic and translational approaches – to dissecting ICI-DM pathogenesis provides a roadmap on how to dissect the mechanistic determinants of ICI toxicities more broadly.

Utilizing a targeted panel of genes with a known role in cancer pathogenesis, we identified genomic alterations in three genes as being predictive of LMD development. If validated in independent datasets, development of clinical trials exploring inhibition of pathways affected by these genomic alterations may be warranted with the goal of LMD prevention and targeted treatment among particularly high-risk cohorts. To our knowledge, this represents the first study to identify potentially actionable alterations as predictive of leptomeningeal disease development among patients with brain metastases.

Utilizing a targeted panel of genes with a known role in cancer pathogenesis, we developed a genomic score that can be calculated from an extracranial or intracranial site to quantify local recurrence risk following brain-directed radiation. Prior attempts to develop a biomarker-based radiation response signature have not focused on patients with BrM and have primarily relied on RNA-based measures of radiosensitivity, limiting their utility in real-world clinical practice for this patient population. To our knowledge, this represents the first study to systemically correlate DNA-based alterations with radiation-based outcomes among patients with BrM.

Our findings expand the spectrum of tumors with underlying WNT/β-catenin pathway and highlight the histologic, clinical, and genetic differences of SNM compared with desmoid fibromatosis. APC deletion raises the possibility of underlying germline alteration and familial adenomatous polyposis.

In EWS we observed a predominant pattern of emergence of new biological and/or actionable variants over time with emergence of new STAG2 or TP53 mutations occurring in 26% of patients, confirming the importance of these genes in resistant disease. In OS, we observed mixed patterns of change including persistence, emergence and disappearance of variants, suggesting the previously described unstable genome in OS impacts key oncogenes and potentially targetable genes. Given the observed patterns of genomic change in OS and EWS, there may be utility to repeat sequencing of relapsed tumor biopsies.

Of note, next-generation thyroid oncopanel sequencing was unable to distinguish the thyroid cancer histotypes in our study cohort. In summary, our data suggest that 3D nuclear architecture can be a powerful analytical tool to diagnose and guide clinical management of NIFTP.

P=N/A; Trial completion date: Jun 2023 --> Jun 2025 | Trial primary completion date: Jun 2023 --> Jun 2025

P2; Trial primary completion date: Jun 2023 --> Jun 2024

P2; Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2023 --> Jun 2024

The most common treatment received was platinum-based chemotherapy doublet [cisplatin+pemetrexed] (n=18, 56.3%). RET fusions were diagnosed in 4.3% of aNSCLC patients who underwent NGS testing at AMC; higher than reported globally but within the range reported in South Korea. The most frequently received 1st LoT (platinum-based chemotherapy doublet) was in-line with standard practice for aNSCLC. A high proportion of patients were enrolled in clinical trials for first and subsequent LoT, likely representing enrollment in ongoing selective-RET-inhibitor trials at this site.

P2; Trial primary completion date: Jun 2023 --> Jun 2024