TEST:

Oncomine™ Comprehensive Assay v3M

LB NGS resulted in a higher detection rate for BRCA1/2 alterations in comparison to conventional TT NGS (20% vs 9%). Ideally, BRCA1/2 testing should be based on both approaches to identify all patients with mPC eligible for PARP inhibitor therapy.

This was an ad hoc analysis of a KSCC1301 randomized phase II trial in which patients with untreated resectable LARC were randomly assigned to receive S-1 and oxaliplatin or folinic acid, 5-fluorouracil, and oxaliplatin as NAC...NAC was associated with increased expression of ICMs and TILs. Rectal cancer could be susceptible to combined immunotherapy with chemotherapy.

In summary, PTEN IHC expression was retained in the majority of PTEN- and POLE-mutated ECs with frequent missense mutations in codon 130. Some codon 130 mutations (e.g., R130Q) are known to be associated with protein stability. Nearly half of PTEN-mutated MMR-d ECs were associated with PTEN expression (retained, reduced or subclonal loss).

In summary, our results indicate that PTEN IHC staining is present in majority of ECs with four common dominant-negative PTEN mutations (retained or less commonly reduced). While recent literature suggests complementary use of PTEN IHC and sequencing to assess PTEN status in EC, these results further highlight that IHC may not be helpful in assessment of PTEN abnormality in cases with dominant-negative PTEN mutations.

The frequency of Tier 1/2 HRD in metastatic PC is twice that of primary PC (p=0.001). No association was identified between CC/IDC morphology and HRD in primary cases, or between HRD and site of metastases. Additional work exploring less frequent HR genes in primary and metastatic PC is ongoing.

"Five genes showed a different mutational status across samples and/or panels: 4 discordant results involved NBF samples. In conclusion, acid-deprived fixatives (GAF and ADF) guarantee the highest DNA preservation/sequencing performance, thus allowing more complex molecular profiling of tissue samples."

Conclusion Tumor-based NGS frequently provides clinically significant information. It holds the potential to reveal specific therapeutic targets and contribute to clinical decision-making

Our study depicted the mutational patterns of BRCA1, BRCA2, and PALB2 in Taiwanese breast cancer patients through tumor-only sequencing. This highlights the growing importance of BRCA1/2 and PALB2 alterations in breast cancer susceptibility risk and the treatment of index patients. We also emphasized the need to meticulously annotate variants in cancer-driver genes as well as actionable mutations across multiple databases.

Key eligibility criteria include allowing hydroxyurea cytoreduction to a WBC <10,000/mm3 for proliferative disease and excluding pts with need for emergent disease-directed therapy as well as prior therapy for myeloid malignancy other than hydroxyurea or thrombopoietic/erythropoietin stimulating agents. Planned exploratory studies include the use of: 1) RNA-seq to evaluate if differences in baseline transcriptional programs appear to be predictive of response to ASTX727 and ASTX727+venetoclax, 2) next generation (Oncomine Comprehensive Assay (OCAv3)/whole exome sequencing to uncover biomarkers predictive of response/outcome, validate risk modeling to stratify these pts and detect/monitor measurable residual disease (MRD) on serial marrow samples that can predict depth of response with translation in improvement in event-based endpoints, and 3) circulating tumor DNA as a non-invasive means (i.e., without need for a marrow evaluation) of prospective MRD detection for prognostic use. This ongoing, randomized study may inform frontline therapeutic options, provide prospective data for venetoclax combination after HMA failure, and generate striking correlative science for pts with "high risk" MDS/MPN.

Fusions are overall uncommon events in endometrial carcinoma. We present a rare case of an FGFR3::TACC3 fusion in a case of endometrial carcinoma. In our institutional cohort, we demonstrated that FGFR3::TACC3 fusions are most frequently identified in high-grade gliomas, but can be seen in other tumor types as well.

HER2 status was determined by IHC/FISH and NGS in 45 cases: 19 serous, 18 high-grade (unspecified histologic type, HGU), 5 endometrioid 1 carcinosarcoma, 1 undifferentiated and 1 gastric- type. IHC-FISH HER2 was positive in 11/45 (24.4%) of cases, all serous or HGU. NGS identified 3 cases as amplified (concordant) and 1 non-pathogenic SNV.

The most prevalent mutant genes were TP53 (68.3%) and KRAS (53.5%), while the PIK3CA (39.4%), AKT1 (45.9%), and ERBB2 (17.1%) mutations constituted biomarkers for FDA-approved therapeutics. Our study showed that tumor tissue should be the source of actionable mutation detection for early breast cancers, considering that the concordance rate between tumor and liquid biopsy was only one-quarter.

Case 1: 73-year-old woman, January 2014 retroperitoneal leiomyosarcoma of the ureter - R0 en bloc resection with partial resection of the ureter and left hemicolectomy - Transcriptome-guided adjuvant treatment: Sorafenib and Riluzole due to GRM1 gene overexpression - Scapular recurrence with bone infiltration in Sept...Treatment with Tazemetostat in December 2022...- Neoadjuvant chemotherapy and radiotherapy treatment, R0 wide surgery with adequate preservation of functionality and IORT - Early chest wall dermal/subcutaneous recurrence (resected) after initiation of immunotherapy – Nivolumab – due to a favorable profile for immunotherapy in tumor transcriptome - Genome of recurrence: BRAF V600E mutation. Treatment with Dabrafenib + Trametinib... STS are tumors with complex surgical and oncological management and a poor response to conventional chemotherapy protocols. Given its heterogeneity, precision oncology through molecular profiling with next-generation massive sequencing (panels for tumor genome and transcriptome) allows the development of personalized therapeutic strategies in patients with STS, and opens up the possibilities for targeted treatments for molecular alterations, immunotherapy and the development of new agents.

Accordingly, the patient continued Osimertinib combined with Carboplatin/Pemetrexed and with additional palliative irradiation due to a new symptomatic spinal cord compression at L3. Acquired EML4-ALK fusion represents an extremely rare (1%) acquired mechanism of Osimertinib-resistance, which enables further effective and feasible therapy by combining EGFR- and ALK-TKI. Rebiopsies, when possible, are of noteworthy value even in heavily pretreated and fragile patients.

In our cohort, the most frequent KRAS mutation found was G12C and the most frequent co-mutation was TP53. We found a high response rate and a long PFS of KRAS mutant patients treated with chemoimmunotherapy or immunotherapy. Further prospective studies are needed to derive definitive conclusions.

The patient initially received 1st line Erlotinib with remission maintained more than 4 years, despite an early dose reduction due to skin toxicity. Despite loss of the original compound EGFR mutation, the rebiopsy revealed a new pathogenic and druggable driver (BRAF p.V600E), which gave the patient a new possibility of further treatment. Yet, replacing Osimertinib with a BRAF/MEK-Is combination resulted only in mixed response, suggesting that some lesions might have remained, at least in part, dependent on the original EGFR mutations. Indeed, re-challenge with Osimertinib in reduced dose together with continuation of Dabrafenib and Trametinib resulted in SD and reflected spatial and temporal heterogeneity of NSCLC.

In conclusion, we present a mutational landscape of actionable genes in CRC for the SA population in patients without a familial history of CRC. Additionally, we address the clinical relevance of low variant allele frequency variants. A comprehensive analysis of population-specific molecular markers for CRC can provide insights into the disease progression, with an aim of optimizing individualized therapeutic options and treatment regimens in the management of CRC in the SA population.

With this approach, the detection rate of NTRK fusions was 20 times higher (5.57%) by only screening 323 patients than the largest cohort in the literature (0.30%) comprising several hundred thousand patients. Based on our findings, we propose a multiparametric strategy (ie, "supervised tumor-agnostic approach") when pathologists start searching for NTRK fusions.

NERoNE evaluates data from NGS profiling of three OU mapping key actionable molecular alterations in a large population of aNSCLC also accounting for PDL1 status. This preliminary analysis will be the starting point for further evaluations in order to improve the personalized approach to aNSCLC. >*For 15 pts PDL1 expression was not known.

As more comprehensive biomarker testing became available, more AGAs are identified with an increase in TAT from biopsy to sign-out and treatment start. Despite our institutional policy of reflex testing, future endeavours will be focus on ways to reduce TAT. >

Palbociclib was used in 80%, ribociclib in 17% and abemaciclib in 3%, mostly as early lines (1L 65%, 2L 22%). Pathogenic gBRCA1/2-PALB2 and higher aneuploidy were associated with shorter survival. Profiling of aneuploidy, HRD, TMB and APOBEC in all pts is ongoing including 55 baseline ctDNA samples and 361 samples from the GENIE BPC cohort. Results will account for FDR, left truncation and optimal cutoffs.

Our results revealed the mutational frequencies of BRCA1, BRCA2, and PALB2 with a commercial targeted sequencing panel. The prevalence of BRCA1, BRCA2, and PALB2 genomic alterations were 3%, 5%, and 8%, respectively. Co-occurrence among these 3 genes was observed.

P=N/A; Trial completion date: Dec 2022 --> Dec 2024 | Trial primary completion date: Dec 2022 --> Dec 2024

Targeted sequencing with Oncomine Comprehensive Assay V3 did not reveal particular mutational patterns between the two Luminal A groups. Nevertheless, radiomic analysis of mammographic images of the cancer, as well as single cell phenotyping of the tumor microenvironment with protein multiplexing will be incorporated to further characterise elements that are phenotypically different, and potentially identify mechanistic drivers contributing to late recurrence in Luminal A cancers.

Overall, targetable gene fusions have a prevalence of 7%. Moreover, 38% of overall cases harbor mutations in genes coding for tyrosine kinases potentially targetable and/or have defects in the MMR that claim a potential role for immunotherapy.

Our study demonstrated that amplicon-based NGS assays can be routinely applied to clinical samples to detect amplification. However, they are not sufficiently sensitive in detecting amplification when tumor celluarity is less than 30%, which is a major limitation that should be clearly stated in NGS reporting.

OCS is a locally aggressive neoplasm. Outcome correlates are limited, but necrosis may suggest an aggressive course. Clear cell morphology is common.

"We described a patient with lung adenocarcinoma harboring METex14del as a potential acquired resistance to osimertinib, who responded to subsequent tepotinib therapy. Re-biopsy and re-analysis of genetic profiles should be considered in NSCLC patients who develop osimertinib resistance."

DSVPTC is an aggressive type of PTC affecting mostly young patients and is characterized by frequent lymph node and distant metastases. Fusion genes especially RET‐PTC1 are the most common genetic alterations. BRAF V600E and other usual somatic point mutations are rare to absent.

Thirty-three of 34 tumor samples with copy number gains called by NGS were confirmed by an orthogonal method. Investigation of the only false-positive calling by NGS showed that the sample exhibited a much higher MAPD score, approaching the manufacturer's established cut-off. Overall, the analytical specificity of OCAv3 and OFA in detecting copy number gain is greater than 95%.

The samples containing low IS all had strong positive IS fusion read counts, indicating that ≥110 NT fusions should have been detected. The native ELM4-ALK and MET-EX14 fusions had >70-fold higher abundance than the IS spike-in. SNAQ-SEQ IS ability to provide standardized abundance measurement could eliminate the less accurate read-based thresholds, and instead allow NGS platforms to use established reporting range analytic validation like other quantitative RNA technologies.

Introduction: Based on the SOLAR-1 study, the PI3Kα-specific inhibitor alpelisib has been approved in combination with fulvestrant for postmenopausal women, and men, with HR+/HER2-, PIK3CA-mutated, advanced or metastatic breast cancer (BC). In terms of PIK3CA molecular testing, NGS should be the preferred method in comparison with RT-PCR. Primary tumors represent a valid biospecimen to be used for this analysis in the absence of the metastatic sample.

From breast cancer actionability, PIK3CA (39.4%) mutation is a biomarker for the FDA-approved PI3Ka inhibitor such as alpelisib, AKT1 (45.9%) mutation for agents such as capivasertib (AZD5363) and ipatasertib, and ERBB2 mutation for tyrosine kinase inhibitor such as neratinib. Table 1. Distributions of variants from common targeted genes (n=6) from cfDNA and TMO comprehensive assay.

Testing with in vivo models of each drug combination has thus far confirmed that each is synergistic per CDI metrics. Those combinations are currently being tested for efficacy in the metastatic setting with a set of basal-like PDXs.

P=N/A, N=500, Recruiting, National Cancer Centre, Singapore | Trial completion date: Dec 2022 --> Dec 2025 | Trial primary completion date: Dec 2022 --> Dec 2024

Conclusion : In summary, our results indicate that ETS transcription factor inhibition by TK216 exerts antitumour activity in our TERT promoter mutant meningioma cell model. Additionally, the sensitivity against TK216 is superior to YK-4-279 and therefore TK216 may represent a promising new therapeutic option for patients with aggressive, TERT promoter mutated meningioma.

The TAT of larger comprehensive versus smaller NGS panels appears similar. The impact on patient treatment will be updated for ESMO 2022.

Five-year survival rate for patients with EGFR-mutant metastatic lung adenocarcinoma treated with Erlotinib or Gefitinib have been reported to be up to 15%, and ex19dels, non-smoking habit, and absence of extrathoracic or brain metastases have previously been associated with prolonged survival. The current case fits well into that in general. However, most such patients need several lines of medical antineoplastic therapy, radiotherapy or have had previous surgery, neither of which has been the case for our patient.

The patient was unfit for platin-based doublet chemotherapy but was offered Pemetrexed, continuing Osimertinib in standard doses...This variant is characteristic for neuroblastomas and known to be Crizotinib-resistant... Liquid biopsy-guided approach at progression in elderly patients with reduced PS may offer a feasible and effective therapy, as in this case by combining ALK- and EGFR-TKI. The treatment is ongoing and current progression-free survival is now 8 months, which is the longest under the whole treatment course. Effective combination of Osimertinib and Alectinib has been reported in single cases of disseminated EGFR-mutant NSCLC becoming resistant to Osimertinib through acquired ALK-fusions.

Nuclear plemorphism is an underrecognized histological feature of RET fusion-positive NSCLCs. If NGS is not perfomed, orthogonal testing should be considered after a negative RET single-test result. The likelihood of a false-negative outcome with a real-time PCR assay is influenced by the molecular epidemiology of RET fusions in a given population.

These preliminary results confirm the feasibility of the program in the real world practice scenario, supporting the implementation of NGS based molecular characterization of advanced NSCLC samples in highly specialized centers with the availability of MTB in order to reduce the unequal access to tests, drugs and clinical trials in Europe.

We found no association between FGFR1-3 aberrations and PT PD-L1 expression (p=0.379). Our data emphasize the need for further studies in predictive biomarkers.