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MSK-IMPACT

We observed YOGC was more common in East and South Asians, and while YOGC may be less likely to develop in the setting of precursor lesions these high-risk states may also be enriched in East Asians. Future research is needed to understand drivers behind such differences and outcome disparities given these individuals may be less amenable to endoscopic interventions.

We report a genome-wide evaluation of co-occurring mutations in MSS CRCs, and suggest that co-mutations can improve the prognostic stratification compared to single mutations alone.

"SOPHiA GENETICS...announced the global launch of MSK-IMPACT® powered with SOPHiA DDM™ today from the Association for Molecular Pathology (AMP) Annual Meeting. This innovative solution provides organizations worldwide with the opportunity to benefit from Memorial Sloan Kettering Cancer Center (MSK)’s best-in-class comprehensive genomic profiling (CGP) application on the SOPHiA DDM™ Platform with high accuracy and efficiency...The launch of MSK-IMPACT® powered with SOPHiA DDM™ is another major milestone in our journey to expand access to precision oncology globally and demonstrates our commitment to democratizing data-driven medicine"

"Precision medicine for rare tumors still poses challenges. In this Japanese cohort, 42.2 % of high-grade OSs had potentially actionable alterations per CKDB. Concurrent gene amplifications of KIT, KDR, and PDGFRA at 4q12, and VEGFA and CCND3 at 6p12-21, might offer promising therapeutic options for patients with recurrent/metastatic OS resistant to conventional chemotherapy."

Use of a novel shared variant framework can provide information to clarify the molecular relationship between compared biospecimens with minimal required input.

This database analysis showed that the main type of MET mutation is amplification in malignant melanoma. MET-amplified solid tumors might be considered for targeted therapy, as MET amplification can be regarded as a risk factor affecting the prognosis of patients with tumors treated with immunotherapy.

"Treatment of Ba/F3 or lung cells expressing MDK::ERBB2 with ERBB2 inhibitors (afatinib, poziotinib, tucatinib) blocked phosphorylation of ERBB2 and downstream effectors, and inhibited growth of both cell lines. ERBB2 fusions are rare oncogenic drivers that are candidates for targeted therapy. The subset of recurrent ERBB2 fusions with C-terminal/3' partners may represent an alternative mechanism of fusion oncogenicity."

IDH1/2 mutations are identified in a small subset of NSCLCs. Our findings suggest that >25% of these mutations are hematopoietic in origin with important implications for diagnosis and management of these patients. Among those with mutations arising from the lung neoplasm, IDH1/2 mutations were primarily seen in conjunction with another driver and were subclonal in nature, suggesting patterns of clonal heterogeneity and evolution.

P1, N=1, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Dec 2025 --> Nov 2024 | Trial primary completion date: Dec 2025 --> Nov 2024

Radiographic findings such as enhancing disease and contact of the tumor with the ventricular space were positively associated with CSF ctDNA positivity. Additionally, CSF ctDNA was associated with positive cytology in 12/12 cases (100%).With our improved pipeline, we hypothesize CSF ctDNA may be used as a prognostic biomarker for survival, but confirmation requires further validation in a prospective study.

Alterations in key driver genes are associated with initial development and progression of CRC BM. BRAF alterations are enriched in PT of patients who develop BM. SMAD4 alterations are enriched in BM compared to extracranial disease and furthermore predict early IP after BM-targeted therapy.

Clinical germline sequencing identifies a germline mutation in a high proportion of patients with CNS tumors. Biallelic inactivation was most commonly identified in tumors from patients with germline TP53 or NF1 mutations and were less common in patients with a germline MMR alteration.

ctDNA positivity corresponded with shortened overall survival after CSF collection (HR: 3.23, 95% CI: 2.58-4.05, P < 0.001).NGS of CSF cfDNA can detect clinically actionable somatic alterations in a large subset of CNS cancer patients and allows tracking of tumor evolution. Detection of somatic alterations in CSF may be a useful prognostic biomarker for survival in cancer patients.

Generalization of the model to an external test set was satisfactory, despite significant racial and socioeconomic differences between the two groups and the labelling of CAT events with different algorithms. Additional work is required to further validate and implement this methodology.

DNMT3A adversely impact outcomes, as previously reported. Our findings warrant confirmation in larger cohorts to refine understanding of nTFHL subtypes and inform management.

Deleterious DDR alterations were associated with pathologic response following NAC in S1314. Functional validation of ERCC2 and other DDR alterations is underway to help refine such alterations as biomarkers of NAC in patients with bladder cancer.

P1, N=1, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

The multimodal machine learning model integrating both clinical and genomic features, provided superior stratification and predictive power for outcomes on 1st line CDK4/6i combination compared to unimodal models. Precise risk stratification of HR+/HER2- MBC patients at the time of metastatic recurrence is key for devising therapeutic and monitoring strategies and trial design.

This study highlights the significant role of PIK3CA, AKT1 and PTEN gene alterations in Chinese BC patients. In Chinese BC patients, alterations in the PTEN/PI3K/AKT signaling pathway are common, and the frequencies of PIK3CA, AKT1 and PTEN gene are similar to that observed in Western countries. The gene alterations in this pathway are associated with clinicopathological features as well as prognosis, such as disease stage and BC subtypes, but not with primary/metastatic status or treatment.

The SUMMIT trial demonstrated meaningful activity of neratinib + fulvestrant + trastuzumab in patients with HR+, HER2 non-amplified, HER2-mutant MBC. In patients with mILC and HER2 mutation, there was a trend toward longer TTP with T-DXd. Genomic data could aid in prognostication in patients with mILC treated with T-DXd. These findings warrant confirmation in larger cohorts.

We successfully established long-term ILC organoids. Our comprehensive genomic analysis of ILC organoids and patient samples underscores the genomic heterogeneity of ILC. Advanced sequencing techniques provide a framework for understanding ILC's molecular landscape.

Upon exposure to the CDK4/6 inhibitor abemaciclib, these cells acquired APOBEC3-context truncating mutations in RB1 tumor suppressor gene, a well-characterized mechanism of resistance... Our work reveals that APOBEC3 mutational signatures predict poor treatment outcomes of HR+ mBC. We demonstrate that APOBEC3 mutagenesis, primarily through the enzymatic activity of A3A and A3B, drives resistance to endocrine and targeted therapies by causing APOBEC3-context resistance-associated changes. We further show that the presence of APOBEC3 mutagenesis can be detected before therapy exposure and may therefore represent a valuable biomarker and therapeutic target.

In this cohort of high-risk BC patients who all had a DR event, BCI remained prognostic with lower BCI scores associated with longer TTDR. Initial findings from the genomic correlative analysis suggested an association of BCI with certain genomic features. Further analyses with additional samples are ongoing to substantiate these findings.

Multimodal data can be incorporated into machine learning models for improved prediction of pCR to NACT in breast cancer. Additional work is needed to validate the clinical utility of these types of multimodal approaches, as well as to determine the most informative data modalities for each hormone receptor subtype and the subset of patients that are most likely to benefit from the use of these models. Automated workflows using DL pre-trained models may provide valuable clinical decision support, guiding escalation and de-escalation therapeutic and monitoring strategies to improve outcomes for pts with high-risk early breast cancer.

Therapies targeting mutations in this pathway approved in conjunction with endocrine therapy include alpelisib, everolimus and capivasertib...She received nab-paclitaxel/atezolizumab for 4 months, letrozole and abemaciclib for 2 months, letrozole alone for 6 months, and letrozole and ribociclib for 6 weeks. Given presence of PIK3CA mutation, 4th line treatment with fulvestrant and alpelisib was planned...After progressing on capecitabine after 2 months, alpelisib with exemestane was initiated...Due to a low ejection fraction despite work with cardiooncology, she was not a candidate for trastuzumab deruxtecan. She progressed on oral cyclophosphamide and methotrexate after 2 months and Sacituzumab govitecan after 3 months...Comprehensive biomarker assessment is needed to identify patients who may benefit from sequential therapies. There is a need for trials comparing therapies that target the PI3K pathway at distinct points, potential sequencing of these therapies, and the optimal sequence strategy.

The antitumor activity of HER3-DXd (10 mg/kg or 3 mg/kg dosed once weekly, 4 doses in total; Q1W x 4) was assessed in 30 BC PDX models (21 ER+/HER2- and 9 triple negative [TNBC]) and compared to the antitumor activity of the clinically approved TOP1 inhibitor irinotecan (50 mg/kg dosed once weekly; Q1W). HER3-DXd exerts a potent antitumor response in BC PDXs across baseline levels of HER3/ERBB3 expression in ER+/HER2- and TNBC models. Based on our data, basal-like PDX models were more likely to show long-term responses to HER3-DXd than luminal B PDX models. Results also suggest that BRCA1/2-altered PARPi-resistant tumors will show high benefit with HER3-DXd treatment.

We demonstrate that CDH1 affecting SVs act as drivers of a subset of ILCs. Most of these SVs result in loss of E-cadherin protein expression and a lobular phenotype, akin to CDH1 mutations. ILCs harboring CDH1 SVs were enriched for aggressive histologic features and display a repertoire of genetic alterations resembling that of ILCs with CDH1 mutations.

Despite the similarities between ILCs arising in the germline and sporadic settings, significant differences in their clinicopathologic and genomic features were identified, such as a higher rate of HER2-positivity and an enrichment in somatic genetic alterations in ERBB2 and in chromatin remodeling genes. These findings highlight opportunities for treatment personalization in patients with ILC who have germline predisposition.

In colon adenocarcinoma, we observe a significantly higher rate of clinical detection for TP53-positive tumors, while in lung adenocarcinoma, the same is true for EGFR-positive tumors. Compared to classical MHNs, this approach eliminates several spurious suppressive interactions and uncovers multiple promoting effects.

Our study aims to systematically evaluate how Chr13q deletion impacts the progression of PC and its susceptibility to treatment. We anticipate that our study will establish a solid foundation of knowledge that can be used to identify aggressive primary PC and the related risk of progressing to lethal CRPC. This will help develop more effective treatments for patients with aggressive and lethal PC, particularly those with Chr13q..

P2, N=63, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting

The prevalence of lithiasis seems to be higher in Chilean versus US patients with GBC. A similar prevalence of ERBB2 alterations of overall 14% and better OS suggests that a proportion of them could benefit from human epidermal growth factor receptor type 2-targeted therapies. The smaller cohort of Chile, where the disease prevalence is higher, is a reminder and invitation for the need of more robust next-generation sequencing analyses globally.

Finally, patients who died of disease in less than 24 months (n=45; 28%) showed enrichment of bordetella (21% vs. 8%; OR 3.11; p = 0.050) compared to those with more durable survival. Conclusions These findings highlight potential biomarkers in the TME, suggesting several directions for future studies to leverage large-scale genomic sequencing to identify microbial signatures that can form the basis of prognostication and targeted therapeutics.

All pts received treatment for metastatic disease, 5 received first-line (1L) ChemoIO with platinum/etoposide plus durvalumab (N=3) or atezolizumab (N=2) and 8 received 1L Chemo with platinum/etoposide. A prospective trial of first-line chemoimmunotherapy in advanced extrapulmonary NECs is ongoing NCT05058651.4 Ethics Approval MSK IRB 19-006.View this table:View inline View popup Download powerpoint Abstract 708 Table 1 Download figure Open in new tab Download powerpoint Abstract 708 Figure 1 Kaplan-Meier curves denoting Progression Free Survival (PFS) for patients treated with first-line chemoimmunotherapy vs. first-line chemotherapy. The median PFS for chemoimmunotherapy group was 17.3 months (95% CI 11.6-NR) versus 5.8 months (95% CI 2.0-NR)

Introduction Mirvetuximab soravtansine-gynx (MIRV) is an antibody-drug conjugate that binds to folate receptor alpha and delivers a microtubule inhibitor payload...Median PFS did not significantly differ based on number of prior treatment lines (for 1-3 versus >3 lines, P = 0.3) or prior PARP inhibitor ( P = 0.9) or bevacizumab ( P = 0.4) use...Conclusion/Implications MIRV confers meaningful PFS benefit for a subset of individuals. Biomarkers of response and resistance are urgently needed to optimize patient selection for treatment.

Our findings collectively provide unprecedented insights into the significance of age and ethnicity on the molecular and clinical characteristics of BC patients.

Additional immunohistochemistry for p53 in patients with LADC histology in the Tokyo Medical and Dental University cohort showed a significant correlation between TP53 mutations and abnormal IHC pattern of p53 (Cramer's correlation coefficient V = 0.67). TP53 mutation is a potential marker for worse prognosis in surgically resected LADC; immunohistochemistry for p53 could be a surrogate method to identify patients with LADC with a worse prognosis.

ctDNA detection was associated with shortened overall survival following CSF collection. Next-generation sequencing of CSF, collected through a minimally invasive lumbar puncture in a routine hospital setting, provides clinically actionable cancer genotype information in a large fraction of patients with CNS tumors.

In this Japanese cohort, 42.2% of high-grade OSs had potentially actionable alterations per CKDB. Concurrent gene amplifications of KIT , KDR , and PDGFRA at 4q12, and VEGFA and CCND3 at 6p12-21, might offer promising therapeutic options for patients with recurrent/metastatic OS resistant to conventional chemotherapy.

This study reveals how age-associated somatic mutations in the microenvironment may be driving DCC reactivation and relapse. These findings may provide a new genetic biomarker of relapse and inform CH-targeted trials to improve breast cancer patient outcomes.

In this workshop we review the development, validation and clinical implementation of Pillar Biosciences' rapid 21-gene solid tumor & heme panel oncoReveal Nexus by Memorial Sloan Kettering Cancer Center (MSKCC). We will review this assay's concordance with the MSKCC's MSK-IMPACT® panels and discuss how this type of rapid testing can be leveraged by other clinical laboratories as tool to help sub-select and inform which patients should have CGP testing performed.

Join us and experts from MSK to: • Discover the clinical utility of MSK-IMPACT® at MSK. • Explore the decentralized workflow, robust technology, and analytical performance of MSK-IMPACT® powered with SOPHiA DDM™.