TEST:

MSK-IMPACT

GNH defines an aggressive subtype of mainly biphasic DPMs in younger patients with recurrent alterations in SETDB1 and TP53. The enrichment in biphasic histology and TILs, together with our preliminary ICB response data and anecdotal clinical trial data, suggests that further evaluation of immunotherapy may be warranted in this subset.

P=N/A, N=27, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P2, N=35, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Aug 2024 --> Apr 2024 | Trial primary completion date: Aug 2024 --> Apr 2024

We identified MYC amplification and ERBB3 as possible predictors of disease metastases and recurrence. Additional research regarding targetable MYC and ERBB3 therapies are warranted.

Mainstreaming increased the likelihood of GT in patients with EOC. We found lower testing rates in patients without partners/spouses, non-high-grade serous histology, and early-stage disease, representing potential areas for future interventions.

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

Presence of high-risk states may be enriched in certain groups such as those with East Asian ancestry. Future research is needed to understand the pathophysiology driving such differences and potential impact on disparities in outcomes.

This is the largest retrospective review to date investigating the feasibility of EUS-FNA/B for NGS. In this series, EUS-FNA/B reliably provided sufficient tissue for NGS with improved success rates over time. Certain clinical features and procedural factors did not have a significant effect on NGS success.

We predict that the diversity of response to FGFR inhibitors in FGFR3-altered NMIBC will be dependent on co-mutational patterns, and identified three co-alterations (CDKN1A, CDKN2A, TP53) that affect the HG-RFS and C-PFS of patients with FGFR3-altered tumors.

Delayed cytoreductive nephrectomy in selected patients is associated with favorable outcomes and offers unique opportunities for tissue and peripheral based biomarkers for long term clinical responses in metastatic RCC. Patients who demonstrate an exceptional pathologic response may have a favorable prognosis.

Within our analysis, we did not identify an ancestry-smoking interaction in bladder urothelial carcinoma. However, we plan to evaluate additional genes of interest, explore different classifiers of smoking intensity, and this relationship in larger and more ethnically diverse datasets.

uRCC demonstrates an aggressive disease course with 55% of patients recurring. We identified genomic alterations correlating with recurrence, which may help select patients for treatment intensification, though confirmatory studies are required.

P2; Active, not recruiting --> Completed | Trial completion date: Feb 2025 --> Mar 2024 | Trial primary completion date: Feb 2025 --> Mar 2024

Investor Presentation

However, following the breast cancer-specific FDA approvals of alpelisib+fulvestrant for PIK3CA-mutant disease in 2019 and elacestrant for ESR1-mutant disease in 2023, a significant shift in Level 1 actionability was observed between EUR (45%) and AFR (34%) attributed in part to the paucity of PIK3CA (26.3% vs. 36.2% in EUR) and ESR1 (4.1% vs. 7.5% in EUR) oncogenic alterations in AFR.We further observed AFR with CRC to have lower prevalence of MSI-H (5.8% vs.10.7% in EUR), TMB (12.5% vs. 18.8% in EUR) and BRAF V600E (5.1% vs. 9% in EUR). Correspondingly, in 2023, 16.4% of AFR with CRC have Level 1 alterations compared to 25.4% of EUR. Moreover, while AFR have higher rates of KRAS mutations (57.2% vs. 42.6% in EUR), they have a lower prevalence of the standard care biomarker KRAS G12C (3.4% vs. 7% of KRAS-mutant CRC in EUR) further exacerbating the disparities in CRC clinical actionability.Taken together, here we demonstrate that a significant disparity exists in the clinical actionability landscape of AFR with cancer compared to EUR, largely due to differences in relative mutational frequencies of Level 1 genomic alterations.

MSK-IMPACT successfully determined class I HLA genotypes in a large, multi-ethnic population of patients. A substantial proportion of patients were identified as potential candidates for HLA-matched trials, supporting local trial enrollment.

The association between AL and clinically actionable mutations highlights the importance of understanding the relationship between somatic alterations and social/environmental factors. The study underscores the utility of AL as a powerful prognostic tool that can be routinely collected in a clinical setting.

Overall, tumors have mutations mainly in TP53 (42.4%), PIK3CA (12.5%), KRAS (9.6%), PTEN (4.7%), BRCA1/2 (9%). Driver mutations were present in TP53 (42%), PIK3CA (16%), KRAS (10%), ERBB2 (7%), PTEN (7%), BRCA1/2 (8%), ATM (7%), among others. Accionable mutations were found primarily in PIK3CA (17%), KRAS (10%), ERBB2 (9%), and NTRK1/2/3 (4.8%).

BALVERSA (erdafitinib), a selective pan-FGFR kinase inhibitor, has shown clinical activity against FGFR altered solid tumors in pts who exhausted standard treatment options... The large Chinese solid tumor cohort analysis showed comparable FGFR alts prevalence between Chinese and Western population. Differences in relationship between FGFR alts and PD-L1 expression across tumor types reflect the differential role of predominant FGFR types in each tumor type.

Due to the above 0.9 calculated accuracy this NLP model is successful in replicating the curated results of cancer status and the next steps will be to run this model on a new cohort of patients not yet curated.

WGS of human CRC organoids co-cultured for three months with pks+ and delta-pks E. coli NC101 confirmed induction of pks+ specific SBS-pks signatures, validating the model. Leveraging this model and a biobank of normal colon organoids from donors aged 50 years, we are investigating the molecular mechanisms underlying the association of SBS-pks with younger age of onset CRC.

The results demonstrate that detection of ecDNA using clinical-grade NGS assays is feasible and that key oncogene FH-amp on ecDNA (e.g., EGFR, FGFR2) are common in select tumor types. ECHO may be developed as a clinical trial device to prospectively identify patients with oncogene ecDNA+ FH-amp for clinical testing of ecDNA-directed therapies.

Our analysis between genomic markers and clinical outcomes in melanoma BM reveals genomic features which may improve prediction and treatment strategies.

The risk of developing metastatic disease and organ-specific dissemination might be linked to genomic abnormalities detectable at the localized stage. No significant difference in the frequency of actionable alterations was observed between primary and metastatic CRC samples.

Specifically, the presence of enhancing disease and contact of the tumor with the ventricular space were positively associated with detection of CSF ctDNA. Additionally, CSF ctDNA was associated with positive cytology in 21/21 cases (100%).With our improved bioinformatics pipeline we hypothesize ctDNA from CSF may be used as a prognostic biomarker for survival, but confirmation requires further validation in a prospective study.

The scIMPACT assay has been successfully adapted to analyze samples at the single-cell level. Therefore, our method can be applied for the genomic profiling of patient-derived CTCs.

Using a robust measure to detect HRD scars from MSK-IMPACT panel data, we demonstrate evidence for BRCA-mediated tumorigenesis in an expanded spectrum of cancers with potential therapeutic relevance.

RNA sequencing gene expression analysis based on 22qDEL status revealed downregulation of most genes residing on chromosome 22q and significant differential expression activity of immune-related genes, further implicating a role of immune dysregulation in PTC. Our study suggests that 22qDEL may not act as a primary driver of PTC but plays an important role as a co-factor of RAS point mutations, which could further drive PTC development.

In LUAD, metastatic specimens exhibit increased chromosomal instability in relation to their matched primaries. This translates into unique copy number alterations detected only in the metastasis. By contrast, driver mutations - which account for most of the clinically targetable alterations with currently approved FDA drugs - are more often shared between paired samples from the same patient.

Finally, VUSs reclassified as oncogenic by AlphaMissense in genes within the RTK/RAS and NRF2 pathways followed expected patterns of mutual exclusivity, further suggesting biological validity.Despite not being trained to predict somatic effects in cancer, AI-derived mutation annotations can broaden the subset of annotated pathogenic variants in cancer and contribute to a more complete understanding of cancer genetics. Real-world outcomes and alteration patterns are additional benchmarks to consider when assessing the utility of VEPs in cancer.

A PDXT-based population trial with the clinically approved anti-EGFR antibody cetuximab was performed in 116 PDXTs, revealing variable sensitivities that were consistent with clinical response biomarkers and with tumor growth changes in 79 matched PDXs...Results were finally validated in PDXs.To our knowledge, this is the first large-scale study in which a systematic comparison of molecular and therapeutic profiles between PDXT-PDX pairs was attempted. As a publicly available resource, XENTURION will offer a knowledge base of disseminatable methods, resources and information to streamline preclinical studies and accelerate new treatments for patients with mCRC.

Our analysis provides insights into the complex interplay of sex and racial factors in shaping CHIP mutation frequencies. As CHIP continues to gain recognition as a critical precursor to malignancies, understanding these variations contributes to refining our understanding of its underlying mechanisms and clinical implications.

In summary, the results showed that all the acceptance criteria were met and the TSO500 assay can be utilized for genomic profiling of FFPE tumor samples. The study also identified a few limitations of the Illumina LRM software e.g. potential false positive SNV within a indel background, potential false negative of complex indel, and the challenge of long indel detection.

Underweight patients by BMI at presentation were most likely to have cachexia symptoms.These results reciprocate well-established information about cancer cachexia, demonstrating that our text classification NLP model can be reliably used to predict AWL from free-text medical notes. AWL may thus be a viable means of studying correlates of cachexia at scale in real-world cohorts.

Hypermutation-associated signatures, including POLE, temozolomide, and mismatch repair deficiency could be detected robustly using targeted sequencing data. In summary, WES had limited clinical value over targeted sequencing panels and future clinical diagnostic development should focus on transcriptome and WGS that can detect additional signatures and gene fusions.

P1/2; Completed --> Terminated; Sponsor terminated study agreement

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

CNA burden was associated with poor overall survival in patients receiving ICB and could improve patient stratification when incorporated with TMB. These findings may guide patient selection for immunotherapy or alternative strategies.

Measures of CIN yield phenotypic features that can be robustly identified by AI analysis of H&E WSI in primary and metastatic BCs. Subtype stratification of BC was robust with respect to AUC and more readily detectable in primary than in metastatic BC. This study provides the basis for development of AI-based tools to detect CIN not only in breast cancer but across cancer types, and a means to test CIN broadly within clinical trials.

FLCN alterations are exceedingly rare in TCa with an incidence of pathogenic changes below 1%. However, FLCN may exceptionally serve as a key driver mutation in TCa, based on our index patient. Identification of FLCN mutations may be clinically important due to possible presence of a germline mutation predisposing to renal tumors and potential responsiveness to immune checkpoint inhibitors.

We developed an effective AI system for detecting phenotypes associated with FGFR3 abnormalities that may be targetable by FGFR inhibitors. This system may allow cost and time savings in comparison to existing assays to screen bladder carcinomas for additional diagnostic testing.

The majority of IHC with high homology to HCC by hidden-genomic classifier are histologically adenocarcinoma. There is strong correlation between genotype and certain histologic features. Features such as small duct, large duct, and intracellular mucin strongly correlate with one class over other.