TEST:

FoundationOne® Heme CDx

Current best practices for the diagnosis, classification, prognostication, and treatment of AML call for the assessment of the presence and absence of numerous genomic alterations. Therefore, in contrast to single-gene or small-panel molecular testing, the F1H platform can simplify such assessment via a CGP approach.

Base substitution or indel variants were detected in TP53 (28% of cases), KMT2D (25%), CREBBP (14%), EZH2 (8%), MYD88 (8%), TNFRSF14 (8%), ATM (8%), NOTCH1 (7%), ARID1A (6%), B2M (6%), TNFAIP3 (6%), PIM1 (4%), CD79B (3%), BTK (2%, 97% of which were C481X ibrutinib resistance mutations in cases of CLL), MEF2B (2%), BCL2 (1%), and PLCG2 (1%)...Overall, 75% of FLs harbored a canonical IGH : : BCL2 rearrangement and 86% of MCLs harbored a canonical IGH : : CCND1 rearrangement.Conclusions : This analysis of 3,692 samples demonstrated that the F1H assay platform reliably detects a broad landscape of genomic alterations across a range of mature B-cell lymphoma/leukemia subtypes. By detecting all classes of genomic alterations in a single sequencing reaction, F1H provides an important advantage over single-gene and small-panel molecular tests in an era when the diagnosis, prognosis, and treatment of hematological malignancies increasingly rely on assessing the presence, as well as the absence, of numerous genomic alterations.

Among the LIT treated patients, 96 patients received treatment with an IDH inhibitor, and 237 patients received a hypomethylating agent (HMA) plus venetoclax...IDH2MUT was associated with a lower HR of death among patients treated with LIT, which was not seen in patients receiving IC. The high prevalence of IDH mutations suggests that IDH inhibitors used as single agents or in combination with lower-intensity therapies are an important class of drugs for this older patient population as they are generally well tolerated, that need further investigation.

Conclusions : This analysis of 2,637 samples comprising a variety of molecular subtypes of ALL demonstrated that the F1H assay detects pathogenic genomic alterations with diagnostic, prognostic, and therapeutic significance. As both the treatment landscape and disease classification system in ALL have continued to evolve over time, CGP assays such as F1H can play a critical role in clinical decision making by simultaneously assessing the presence and absence of numerous actionable genomic alterations and biomarkers with a single assay.

Conclusions : Rearrangements in the KMT2A gene in AML are common and may emerge as a new target of therapy for AML patients. This genomic landscape study reveals significant differences in import GA associated with AML in KMT2Ara and KMT2Anra cases.

"Foundation Medicine, Inc...announced it was awarded its second consecutive, five-year contract by the U.S. Department of Veterans Affairs (VA) to provide tumor molecular profiling tests and services to eligible Veterans living with cancer as part of the VA’s National Precision Oncology Program. The national contract covers Foundation Medicine’s tissue-based test FoundationOne®CDx, liquid-based test FoundationOne®Liquid CDx, tissue-based RNA sequencing test FoundationOne®RNA and FoundationOne®Heme for hematologic malignancies."

"Foundation Medicine, Inc. today announced a collaboration with Syndax Pharmaceuticals...to develop a companion diagnostic for the identification of acute myeloid leukemia (AML) patients harboring an NPM1 mutation. As part of the collaboration, Syndax will also support Foundation Medicine’s efforts to pursue regulatory approval of an assay based on the FoundationOne Heme platform....If approved, the assay could be the first next-generation sequencing companion diagnostic to detect genomic alterations in hematologic neoplasms, including enhancing the identification of patients with NPM1 mutations who may be eligible for revumenib."

CGP of non-myeloid hematologic malignancies identified variants of clinical significance in 72% of patients and led to changes in practice in 22% of patients. CGP was often sent late in the clinical course.

Rearrangements in rare cancers have at least, a similar rate as in common cancers and can be targeted. However, despite identification of the alterations, treatment access remains limited.

P1/2 | N=320 | Active, not recruiting | Sponsor: Centre Leon Berard | Recruiting ➔ Active, not recruiting

With a PPGV prevalence of 11% in this study, it is important to recognize PPGVs as it can prompt genetic counseling and confirmatory germline testing.

Our data demonstrate that CGP is a promising tool for detecting EBV together with genomic alterations in tumor specimens. Our approach could help reduce the complexity of biomarker testing, providing comprehensive results as part of a single sequencing reaction.

Among patients ≥60 yrs with ND AML given LIT, the current 2022 ELN risk system classifies most (79%)patients as adverse risk and does not reliably distinguish favorable from intermediate-risk, highlighting thelimitations of the model in this patient population. We propose a refined LLS classification using a "mutationscore" incorporating IDH2, MLL2, KRAS and TP53 mutations for those previously assigned ELN 2022 adverserisk, as well as redefining the definition of LLS-favorable risk.

Our results have shown that almost 50% of tested patients could have potential treatment benefit based on the detection of clinically relevant genomic alteration. Unfortunately, taking into consideration country level insurance eligibility criteria for CGP testing and number of potentially eligible cancer patients, we could say that only less than 5% of patients with metastatic disease were tested within first two years and that penetration of CGP is rather low, resulting with a significant number of patients underserved.

In conclusion, the AM classifier dichotomises VUS to either benign or pathogenic, but this is not based on either structural or functional predictions directly. We conclude that it should not be currently used in the analysis of clinical samples seeking actionable variants but could instead stratify potential pathogenic variants for functional investigation.

P=N/A; Trial completion date: Dec 2024 --> Mar 2026 | Trial primary completion date: Dec 2024 --> Mar 2026

The presence of PPGVs warrants formal genetic counselling and germline testing. Given the similar prevalence of PPGVs in this study compared with data from other countries, and the diagnostic and therapeutic implications of detecting incidental PPGVs, we underscore the need for cancer genetics to be incorporated into standard oncologic care in the Philippines.

Overall, in our uLMS analysis, CDK4 and/or MDM2 amplification was identified in a small subset (2%) of uLMS, the majority of which are TP53/RB1-wildtype. This may suggest that CDK4/MDM2 amplification can be an alternative tumorigenic mechanism in this distinct class of uLMS, which may have therapeutic clinical implications, including possible use of specific cyclin-dependent kinase inhibitors.

While exceedingly rarely, FH mutations may be found in uLMS. Confirmation of FH deficiency should not preclude the diagnosis of sarcoma in smooth muscle neoplasms that meet histologic criteria for malignancy.

Overall, in our uLMS analysis, CDK4 and/or MDM2 amplification was identified in a small subset (2%) of uLMS, the majority of which are TP53/RB1-wildtype. This may suggest that CDK4/MDM2 amplification can be an alternative tumorigenic mechanism in this distinct class of uLMS, which may have therapeutic clinical implications, including possible use of specific cyclin-dependent kinase inhibitors.

The proposed multimethodology provided IPO Lisboa decision makers with comprehensive and insightful information regarding each strategy's value-for-money, enabling an informed discussion on whether to move from the current Strategy S1 to other competing strategies.

Our study identified biologic differences between Hispanic and non-Hispanic AML patients with heterogeneity in genetic mutations. While Hispanic patients had lower income, they were younger at diagnosis and more likely to have favorable risk AML. Hispanic patients had better PFS and a trend towards improvement in OS.

Our data offer a cellular and molecular insight into a case of clinical pseudoprogression observed during tolinapant treatment. Understanding pseudoprogression is important for clinical investigators and patients to ensure treatment with tolinapant, or other IAP antagonists, are not discontinued prematurely.

Blue indicates positive correlation, red indicated negative correlation. Only significant correlations (p<0.01) are shown.

Our report represents one of the most extensive and detailed studies regarding the landscape of BCL11B point and indel mutations in human cancer. BCL11B alterations occur widely in mature, immature, B-cell, Tcell, and sarcomatous malignancies. TP53, PIM1, and SOCS1 are the most commonly co-mutated genes.

CD36 mutations were frequent in AML and MDS in our series, which might have implications in pathogenesis of myeloid neoplasm. Certain mutations (e.g., splice site) might have association with lymphoid malignancies.

We further observed that sarcomas with alterations in RAD51B or GID4 were enriched in samples with high telomeric content, specifically within uterus leiomyosarcoma for RAD51B and soft tissue sarcoma (not otherwise specified, nos) for GID4, Furthermore, RAD51B and POT1 alterations were mutually exclusive with ATRX and DAXX alterations, suggestive of functional redundancy. Our results propose a role played by RAD51B and GID4 in telomere elongation in sarcomas and open research opportunities for agents aimed at targeting this critical pathway in tumorigenesis.

KMT2C A2254T has only been reported in astrocytoma. To our knowledge, this is the first case report of FBXW7 and KMT2C mutations in FDCS, which may indicate biologic and therapeutic relevance (Figure 1.82, A–D).

Conclusions Tumor-agnostic CGP provides more treatment options to patients with advanced solid tumors when compared to organ-directed NGS panel testing. The national MTB provides recommendations within a clinically relevant timeframe and enhances the uptake of MGTs.

This study demonstrates performance characteristics that suggest Duoseq would perform well as a clinical-grade assay. Local laboratory factors that include staffing, case volumes, and reimbursement affect adoption and turnaround times in the individual clinical laboratory. However, we anticipate that Duoseq implementation will accelerate the diagnosis of hematologic malignancies and facilitate rapid, more cost-effective care to improve patient outcomes.

Premalignant mutations (e.g., ASXL1, TET2) predominated in our patients and tended to co-occur, increasing the overall mutational burden. Non-White patients were more likely to have IDH2 mutations. Adverse markers were common among AML & MDS patients, likely contributing to their dismal survival.

P1/2 | N=320 | Recruiting | Sponsor: Centre Leon Berard | N=120 ➔ 320

RWD based clinical genomic profiling confirms that the vast majority of RAS-alterations in CRC are SVs in exons 2, 3 and 4. Both TMB-high and MSI-high samples are significantly more abundant in the RAS/BRAF-altered cohort. RWD confirms that PI3K-, ERBB- and FGFR-signaling pathways are frequently altered in CRC.

She completed radiotherapy with concurrent and adjuvant temozolomide (TMZ) per Stupp protocol...She failed bevacizumab (bev) alone or in combination with TMZ. Therefore, BEEP (Bev 15mg/kg D0, etoposide 70/m2 D1-D3, cisplatin 70/m2 D1, Q21D) was given for salvage...Nested RT-PCR or NGS are better options. Legal entity responsible for the study The authors.

uLMS with heterologous differentiation shows genomic overlap with conventional uLMS with similar driver alterations. Comprehensive genomic profiling of uLMS with aberrant differentiation can help diagnose and improve tumor classification.

Recognizing and referring patients with possible germline mutations for appropriate genetic evaluation and testing provides insight into best patient care strategies along with education and testing opportunities for family members. Leukemia based NGS panels may aid as screening tools for detecting potential pathogenic germline variants.

We are reporting a positive correlation between MYD88 allelic burden and Clonal B-cell fraction in LPL. Quantitative molecular assay for MYD88 might be useful for evaluation of residual disease in LPL.

Cohesin mutations were frequent in AML-MRC in our series. Additional studies are needed for delineating any prognostic differences between the types of Cohesin mutations and for exploring the possibility of novel therapeutic targets.

CGP of PCLs reveals biomarkers, genomic alterations, and molecular classifications predictive of BTKi efficacy and potential ICPI efficacy. Given the limitations of standard of care for PCL, CGP is critical to identify potential therapeutic approaches for patients in this rare form of lymphoma.

"LB detected relevant genomic alterations in the majority of patients with a variety of HNs. Given its analytical sensitivity, LB may also detect low-level residual or emerging therapy-resistant clones unable to be detected in a single tissue specimen and may play a role in the evaluation of the patient's disease course and in associated treatment decisions. This pilot study suggests the potential value of LB in the clinical management of patients; however, further prospective evidence would be required to quantify the utility of LB for patients with HNs."

Our results may suggest that when healthcare access is not a barrier to treatment, Hispanic patients with AML can have similar, if not improved, outcomes to other populations. However, access to transplant remains a major barrier that needs to be further addressed to improve outcomes for this patient population.

P2 | "Notably, a complete SMARCB1/INI1 deletion (targetable by tazemetostat) was identified... NGS in conjunction with OGM demonstrated improved detection of clinically actionable alterations for this patient. Thus, both tests should be routinely considered as a part of the diagnostic regimen to better characterize key mutations in rare tumors and uncover actionable targets for treatment. Combining multiple types of molecular analyses uncovered that this patient was eligible for a novel clinical trial."