EGFR fusion

We identify a previously unappreciated cDC mechanism mediating Treg tumor infiltration after RT. Our findings suggest blocking the cDC1-CCL22-Treg axis augments RT efficacy. αEGFR-IFNα added to RT provided robust antitumor responses better than systemic free interferon administration, and may overcome clinical limitations to interferon therapy. Our findings highlight the complex behavior of cDC after RT and provide novel therapeutic strategies for overcoming RT-driven immunosuppression to improve RT efficacy.

All patients harboring a targetable alteration were >50 years of age and most of them had >15 pack-years, questioning restrictive molecular testing strategies. Based on our real-world data, we propose a reflex testing workflow using DNA- and RNA-based NGS that includes all newly diagnosed NSCLC cases, irrespective of histology, but also irrespective of age or smoking status.

Conclusions NGS-ctDNA provided clinically informative results for 26% of pts with advanced lung SCC, including 6% for whom targeted therapies are available in routine practice or clinical trials (4% ESMO ESCAT tier I and 2% ESMO ESCAT tier IIB). These results suggest that molecular profiling, including plasma NGS testing, should be considered in this population.

In summary, EGFRvIII is rare, occurring primarily in glioblastoma and rarely in breast sarcomatoid neoplasm, with no instances identified in other tumor types in our series. This select group of patients may benefit from chemotherapy and/or targeted anti-EGFR therapy.

On June 20, 2020, the patient's treatment regimen was as following: (1)Anti-tumor: aumolertinib 110mg qd; (2)Intracranial pressure reduction: mannitol 250mg q12h, glycerin fructose 125ml q12h; (3)Improve cardiac function: furosemide 20mg qd, spironolactone 20mg bid; (4)Epilepsy control: Levetiracetam + phenobarbital sodium, intermittent administration of midazolam; (5)Nutritional support therapy: Rego 1000ml tube feeding qd (1500Kcal); (6) Puncture and drainage of pleural effusion, oxygen therapy, airway management.Three days later, the patient regained consciousness, no seizures occurred again. In this case, we reported a right lung adenocarcinoma cT3N3M1 patient with brain metastasis, malignant pleural effusion, and a positive EGFR 19del mutation who obtained a remarkable curative effect and good tolerance,after treatment with aumolertinib. This was the first report successfully applied aumolertinib to an EGFR sensitive lung patient with brain metastases with epilepsy as the initial symptom and in poor physical condition, and suggested the fast and good therapeutic potential of aumolertinib in this population.

The only notable adverse event was grade 3 elevated transaminase, that was effectively managed by dose reduction. These data may support the use of selpercatinib in patients with RET/EGFR co-mutated NSCLC.

EGFR-TKI treatment is effective for MPE of EGFR-mutant LUAD patients, especially for those harboring exon 19 deletion.

The results supported the lack of a general association with high PD-L1 and high TMB calls for biomarker informed treatment options for nsqNSCLC patients. We reported a subpopulation of nsqNSCLC patients that can be described by certain genetic alteration, of which some were associated with ICI-related biomarkers for which patients might benefit from a future precision oncology approach utilizing combined targeted and ICI treatment.

Osimertinib-resistant YU-1097 harboring EGFR resistance mutation (E19del/T790M/C797S) revealed sensitivity to BLU-945 (IC50, 108nM), a novel fourth-generation EGFR-TKI. A similar inhibition of cell viability was observed with repotrectinib (IC50, 21nM), a next-generation ROS1-TKI and lorlatinib (IC50, 9nM) in YU-1078 harboring CD74-ROS1, whereas more robust tumor regression was seen with repotrectinib in YU1078-derived xenograft model. Amivantamab, a EGFR-MET bispecific antibody, showed a robust activity in YU-1163 and YUO-036 in vitro and in vivo. PDC/PDO models can be utilized for evaluating activity of novel agents and will accelerate novel drug development in NSCLC.

Although the mammalian target of rapamycin (mTOR) inhibitor rapamycin and AMP-activated protein kinase (AMPK) activator metformin are ineffective when treated as single drugs, a combination of these drugs (met+rap) prolonged the anti-glioma effect of CAR-T cells under hypoxic conditions...Interestingly, the glioma tissues infiltrated by met+rap pre-treated CAR-T cells were infiltrated by significantly fewer Ly6c+ CD11b+ monocytic myeloid-derived suppressor cells. As a major translational significance, because the CAR-T cells were pre-treated with the drugs during the in vitro expansion with no need for in vivo drug administrations, our strategy would circumvent any toxicity associated with in vivo treatments with the same medications.These data warrant a translational and clinical evaluation of met+rap pre-treated CAR-T cells in human settings and the development of a CAR-T cell trial using this approach.

At microscopic examination, it was a CD34 and S100-positive soft tissue tumour showing a multilobulated growth pattern composed of cells with pale cytoplasm and abundant normal smooth muscle stroma. The genetic profile showed alterations affecting EGFR gene represented by a novel MYH9::EGFR fusion transcript and the p.K714N mutation.

This validation study supports the feasibility of applying NGS testing to leftover fixed urine cytology specimens. In addition, the potential utility of urine NGS testing as an adjunct to urine cytology in the early detection of HGUC for cases in which cytology is negative and/or atypical/suspicious should be investigated further.

Grade 3-4 adverse events (IS) had occurred in 69.1 % of the PPAB cohort pts and 51.4 % of the PPA cohort; IS of 3-4 grade linked to the Atzolizumab occurred in 27.9 % and 15.3 %, respectively. Conclusion The combined approach of the Platine-Pemeterxed association with the Aszolizumab with or without Bevacizumab showed a promising activity in this PTS subgroup after TKI failure, with an acceptable security profile.

We included 200 LBCL patients with a median age of 66 (IQR 20-86) that were treated with CD19 CAR T cells (50% axicabtagene ciloleucel, 32% tisagenlecleucel, 18% lisocabtagene maraleucel) between 2016 and 2022. In this largest study to date on renal injury in CAR T patients, we find acute kidney injury as a common complication of CAR-T cell therapy, exceeding 10%. The association between renal injury and subsequent mortality suggests that AKI is a clinically and prognostically significant complication. The discovery that readily available biomarkers reflecting physiological reserve, disease burden, and systemic inflammation inform on renal injury risk may support personalized stratification for risk mitigation.

Our study revealed that complementary information regarding the EGFR status and response to EGFR-TKI can be provided by subregional radiomics. The proposed radiomics models may be new markers to guide treatment plans for NSCLC patients with BM.

Our study is the first to report comprehensive genomic features and mutational signatures in Chinese ASC patients. Results obtained from our study will help the scientific community better understand signature-related mutational processes in ASC.

NF1 mutation was associated with higher TMB and higher PD-L1 tumor cell expression. Immune Checkpoint Inhibitors may be considered as an option for patients with NSCLC harboring NF1 mutations.

Our study systematically evaluated the genetic landscape underlying RET fusions as a rare driver gene and provide important insights into secondary resistance to EGFR TKIs in Chinese NSCLCs, which will be important considerations in improving the efficacy and clinical outcome of existing RET inhibitors and facilitating the development of new therapeutics.

No abstract available

Finally, paired biopsies at presentation were available from 3 patients showing MET amplification at progression to osimertinib (n=2) and lorlatinib (n=1). A significant number of NSCLC patients with targetable alterations present with MET amplification or very high expression. Clinical trials should determine if first line combination treatment could be beneficial in this setting

EGFR amplification was the most common mutation type. There were 122 SNV and Indel subtypes altogether and occurred throughout almost the entire exon region, in which exon7 contained maximum 21 different subtypes and the p.A289V was the main type. The distribution of subtypes in ECD were much more than in ICD.

In the era of comprehensive genomic profiling, several resistance alterations with extremely low prevalence may be detected, especially in CRCs that do not bear other genomic drivers. Negative ultra-selection may represent a relevant step forward in precision medicine in patients with RAS/BRAF wt MSS mCRC potentially eligible for EGFR blockade.

EGFR mutations were more likely to occur in non-smoking, stage III-IV, and female patients with lung adenocarcinoma, whereas ALK&ROS1 gene fusions were more likely to occur in young patients with lung adenocarcinoma. Emphysema was less common in patients with EGFR mutations.

Our new syngeneic CAR Tg mouse model can serve as a useful tool to address clinically relevant questions and develop future immunotherapeutic strategies.

The EGFR-IGR fusion mutation is unreported, and thus, there are no studies targeting this fusion together with EGFR amplification in lung adenocarcinoma. Our brief study provides clinical evidence that combined targeted therapy with gefitinib and cetuximab could result in a significant antitumor response in patients with the EGFR-IGR fusion and EGFR amplification.

EGFR fusions were detected in 0.32% (29/9097) of our Chinese patients. EGFR-TKIs may be effective therapeutic options in tumors harboring EGFR fusions. Combined with the diverse distribution of EGFR fusion breakpoints and the high frequency of gene-intergenic/intergenic-gene fusion, a comprehensive analysis of EGFR fusions may require the support of multiple platforms.

T cells transduced with a synNotch-CAR circuit primed by the CNS-specific antigen MOG also exhibited precise and potent control of intracerebral PDX without evidence of priming outside of the brain. In summary, by using circuits that integrate recognition of multiple imperfect but complementary antigens, we improve the specificity, completeness, and persistence of T cells directed against glioblastoma, providing a general recognition strategy applicable to other solid tumors.

ERBB gene fusions are detectable at low frequency in various tumor types and may represent a unique genomic subset of cancer . Identification of novel ERBB gene fusions warrants further investigation to determine the potential pathogenicity and actionability of these fusions.

Targeted RNA-seq can effectively identify genomic rearrangements that are undetectable by DNA-seq and provide lung adenocarcinoma patients with more opportunities for targeted therapy . Therefore, it should be recommended for all patients, in whom DNA-seq fails to detect driver alteration.

Mucinous adenocarcinoma had a low frequency of targetable genetic variants and PD-L1 immunoreactivity; however, KRAS mutations were frequent. Pneumonic appearance on CT imaging and KRAS mutations were clinicopathological features associated with a worse prognosis.

Compared with EGFR or ALK mono-mutation, abundance of dominant clone comprising either mutated EGFR or ALK-fusion in co-mutation samples is lower, which was proved by the reported poor TKI efficacy in co-mutated patients. CTS can evaluate dominant clone for NSCLC with co-mutated driver genes. Indicated by CTS, tumor with EGFR/ALK co-mutation tends to form a single dominant clone.

Background: NTRK rearrangements, though rare in common cancers, are clinically actionable targets with two FDA-approved drugs for pan-cancer indications, larotrectinib and entrectinib. NTRK1 fusions were detected in cfDNA at a similar prevalence to tissue NGS, demonstrating high sensitivity of plasma-based assays to detect these fusions. NTRK1 fusion partners were diverse, with the majority of partner genes observed only once across the cohort. Both clonal and subclonal NTRK1 rearrangements were detected, affirming that this biomarker can emerge as an oncogenic driver or as a mechanism of resistance.

"In this particular case, we show that ARID1A gene mutations with sporadic MSI due to somatic MLH1 gene promoter methylation and MLH1 gene mutation could change the prognosis and define the response to immunotherapy in a patient with lung adenocarcinoma. Comprehensive solid and liquid biopsy tests are useful to find out resistance mechanisms to immune checkpoint inhibitors. Our data encourages the development of new therapies against ARID1A mutations and epigenomic methylation when involved in MSI neoplasms."