NCOA4-RET fusion

These tumors demonstrate the potential for aggressive local growth and regional metastasis. We propose a unifying diagnostic term for these lesions to reflect their common morphologic and molecular features and, most importantly, low malignant potential.

Neoadjuvant use of tyrosine kinase inhibitors seems extremely effective in downstaging surgically unresectable differentiated thyroid cancers to achieve R0 resection while avoiding unnecessary surgical morbidities. A multidisciplinary approach with early genomic profiling to guide personalized neoadjuvant use of tyrosine kinase inhibitors is essential. Prospective studies are urgently needed to define the potential role of neoadjuvant tyrosine kinase inhibitors in advanced thyroid cancer management.

SAMS is on a morphologic and molecular genetic spectrum with EFH, with a similar body site distribution, frequent clinical presentation as an exophytic skin tumor, and invariably benign outcomes; we conclude that SAMS should be considered a histologic variant of EFH. Some morphologically typical examples harbor alternate RET and NTRK3 fusions, such that SAMS is not an appropriate designation for this morphologic class; instead, to highlight the clinicopathologic similarities to EFH, we propose the diagnostic term "myxoid spindle cell variant of epithelioid fibrous histiocytoma."

Of four patients with PD-L1 overexpression (>50%) one received pembrolizumab and the other three patients received pemetrexed, carboplatin, and pembrolizumab or camrelizumab. Fifteen patients received selective RET inhibitors (pralsetinib and selpercatinib), resulting in an ORR of 53.3% (8/15) and median PFS of 10.0 months (95% CI 5.2-14.9). ICIs for PD-L overexpression and treatment naive patients offer comparable benefits for RET fusion-positive NSCLC, warranting further investigation.

She responded to selpercatinib treatment with the elimination of supplemental oxygen need, marked reduction in pulmonary nodules and mediastinal lymphadenopathy, and biomarker decline. The response was maintained despite 2 dose reductions for possibly related weight gain.

Selpercatinib increases RAI avidity in adolescents with metastatic RET fusion‐positive PTC. Further investigations into the use of targeted therapies prior to RAI therapy or to resensitize patients to RAI therapy in patients with metastatic fusion positive PTC are warranted.

The patients examined in our study could serve as a model representative of a significant proportion of the U. S. military. Tumors from individuals with history of exposure to radiation in adulthood have pronounced invasive features. A significant proportion of these tumors harbor gene fusions suggesting a possible association between irradiation in adulthood and development of radiation‐inducible PTCs.

RET fusions were identified in multiple tumor types. With a higher median TMB and commonly MSI-H, RET fusion positive CRC may be a unique molecular subset of CRC.

Conclusions Molecular screening in non-BRAF PTC patients is useful to identify patients harboring RET fusions who may benefit from targeted therapies. As other potentially actionable gene fusions are also found in these patients, routine implementation of NGS analysis warrants a comprehensive biomarker study.

We treated both mouse models with multikinase inhibitors (MKI) (cabozantinib, lenvatinib and axitinib) or with a selective RET inhibitor (BLU667)...Such immune reaction affected the gene expression of both cancer (human) and stroma (mouse) cells. Conclusions These results pave the way for a rational combination of RET inhibitors and immunotherapy in the two scenarios, as primary therapy to reduce the minimal residual disease and at time of resistance to selective RET inhibition.

Although selective tyrosine kinase inhibitors (TKI) (selpercatinib and pralsetinib) are available in several countries, there are no real-world data on the characteristics and outcomes of Hispanic patients with RET fusions treated with various regimens. This retrospective study included patients with advanced-stage RET-positive NSCLC from five Latin American countries. Hispanic patients with RET-fusion NSCLC exhibited homogeneous biological behavior. The results of the first-line treatment were in agreement with the literature. However, the number of patients treated with RETsi in the first- and second-line treatment was small, although it showed benefits in OS and PFS for the 2nd line.

Selpercatinib demonstrated clinically meaningful and durable intracranial activity in Chinese patients with brain metastases from RET-altered NSCLC, consistent with the global LIBRETTO-001 trial.

For patients with EGFR-mutant NSCLC with an acquired RET fusion as a mechanism of EGFR inhibitor resistance, the addition of selpercatinib to osimertinib was feasible, safe, and offered clinical benefit, supporting the prospective evaluation of this combination.

"This study revealed the comprehensive mutational landscape of advanced NSCLC through liquid biopsy, providing novel biomarkers for clinical diagnosis and targeted therapy mechanism studies."

Purpose: RET fusions drive oncogenesis in 1-2% of non-small cell lung cancer (NSCLC) and are sensitive to the selective RET inhibitors selpercatinib and pralsetinib. In the largest RET fusion-positive NSCLC cohort to date, RET fusions frequently co-occurred with other genomic alterations, most commonly in TP53. TP53 alterations are associated with a significant reduction in overall survival in patients treated with the selective RET inhibitors. Additional analysis is underway.

Based on CUP tumor profiling by this platform, positive treatment response has been observed in 3 out of 4 CUP patients thus far, e.g., one patient with metastatic disease that showed high TMB and immune infiltrated microenvironment treated with Ipilimumab and Nivolumab had a sustained response. Therapy in oncology is often determined by the tissue origin, making CUP a therapeutic challenge. In this study, we demonstrate the application of an integrative WES and RNAseq platform to not only predict the site of origin, but also to identify relevant biomarkers and therapeutic targets in CUP.

BRAF, RET and NTRK alterations are prevalent across multiple tumors. Although rare, together they are found in around 3.4% of all human cancers. Further analysis of co-occurring TP53, TERT and SETD2 alterations and their impact on response to targeted therapies is warranted, in order to tailor personalized treatments for patients harboring these alterations.Table 1: Tissue spectrum of activity for anticancer drugs with tissue-agnostic approvalsApproved AlterationMost Common DiagnosesPrevalence in LiteraturePrevalence in Disease Specific AnalysisApproved Drug(s)Tissue Agnostic FDA Approval YearTissue Agnostic ORR from Clinical TrialsNTRK FusionsBreast Cancer0.08-0.13%0.3%Larotrectinib; Entrectinib2018 (Larotrectinib); 2019 (Entrectinib)ORR: 75% and DOR: NR (Larotrectinib); ORR: 57% and 12mDOR: 45% (Entrectinib)Glioma0.55%0.4%Thyroid Cancer2.22-2.28%1.7%Soft Tissue Sarcoma0.68-1.17%0.8%NSCLC0.16-0.23%0.1%Salivary Gland Cancer79.6-84.9%3%CRC0.26-0.35%0.2%Gastroesophageal CancerN/A0.4%Pancreatic Cancer0.30-0.34%0.3%Melanoma0.36-0.540.2%RET FusionsNSCLC2%0.9%Selpercatinib2022ORR: 44% and DOR: 24.5mThyroid Cancer5-10%4.1%CRC<1%0.1%Breast Cancer0%0.1%Gastroesophageal Cancer0%0.2%Carcinoma of Unknown primary2%0.1%Glioman/a0.04%Prostate Cancer0%0.1%Soft Tissue Sarcoma0%0.1%Bladder Cancer0%0.1%BRAF V600E MutationsMelanoma26.1%20.2%Dabrafenib + Trametinib2022ORR: 41% and 24mDOR: 44%CRC10%7.8%Thyroid Cancer41%39.7%Glioma7%3.9%NSCLC1-2%1.4%Mature B-Cell Neoplasms1-100%1.8%Histiocytosis25.7%18%Carcinoma of Unknown primary3%1.7%Ovarian Cancer2%0.9%Non-melanoma Skin Cancer1%3.4%NR=not reached; m=month; DOR: Duration of Response; ORR: Objective Response Rate

Pralsetinib and EGFR-TKI combination therapy was generally well tolerated, with AEs consistent with known profile of the two drugs. Conclusions Pralsetinib-based therapy may be a potential strategy to overcome the acquired RET-fusion after resistance of EGFR/ALK-TKIs.

p16 and human papillomavirus (HPV) studies differentiate HPV-related squamous cell carcinoma from non-HPV-related neoplasms with overlapping features. NCOA4:RET fusion protein is the main fusion in intraductal carcinoma.

The most common grade ≥3 treatment-related adverse events were neutropenia (31%) and anemia (14%). These data validate RET as a tissue-agnostic target with sensitivity to RET inhibition, indicating pralsetinib's potential as a well-tolerated treatment option with rapid, robust and durable anti-tumor activity in patients with diverse RET fusion-positive solid tumors.

There was no correlation between RET fusion partners and MSI status. Table: 72P Conclusions Outside of approved indications of NSCLC and thyroid cancers, RET fusions were identified in multiple tumor types such as colorectal, breast, cancer of unknown primary and pancreatic cancer.

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.

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.

Both IHC and FISH demonstrated lower sensitivity for NCOA4-/others-RET fusions. Clinical benefit with chemotherapy is different between CCDC6-RET and KIF5B-RET fusion patients, optimal treatment should be considered when selecting therapies for patients with RET-rearranged lung cancers.

We recommend targeted NGS for the diagnoses and targeted therapy of cancer patients.

We identified a high association with immune-escape signaling in the immune-hot group with aggressive clinical factors of Korean thyroid cancer patients. Moreover, RET fusion differentially regulated PI3K and MAPK signaling depending on the partner gene of RET, and HOXD9 was found to be a recurrence marker for advanced PTC patients.

One patient with PD-L1 tumor proportion score 90% responded to first-line pembrolizumab with progression-free survival (PFS) of 5.5 months...15 patients received selective RET inhibitors (pralsetinib, selpercatinib)... Selective RET inhibitors showed durable efficacy compared with cabozantinib for RET fusion NSCLC. ICIs especially for PD-L high and combined strategies may offer comparable benefit for RET fusion NSCLC, warranting further investigation. Legal entity responsible for the study: Jie Wang.

Approval of selpercatinib for treatment of lung and thyroid cancer with RET gene mutations or fusions calls for studies to explore RET fusion partners and their eligibility for RET-based targeted therapy...Co-occurrence of EGFR mutations and RET fusions with rare partner genes (rather than KIF5B) in LC patients was correlated with EGFR-TKI resistance and may predict response to targeted therapies. Findings from this study provide a guide to clinicians in determining tumors with specific fusion patterns as candidates for RET targeted therapies.

The GENEFUSION assay is an accurate method for rapid fusion detection in ALK, ROS1, RET, and MET exon 14 splice variants. Due to the limited number of NTRK fusion positive cases analyzed, the performance of this gene is unclear. Further evaluation of non-targeted fusions is necessary to evaluate the performance of expression imbalance.

Recently, 2 highly selective RET tyrosine kinase inhibitors (TKIs), selpercatinib and pralsetinib, received FDA approval for RET-altered solid tumors. Given the acceptable performance, low cost, and shorter TAT, a sequential approach starting with Oncomine assay appears reasonable in solid tumors. Yet subsequent reflexing of all negative cases to anchored multiplex PCR (AMP) panel is necessary to detect novel RET fusions that are not covered by Oncomine.

The cytomorphology of IDC overlaps with other benign and malignant salivary gland neoplasms. Immunohistochemistry limits the differential diagnosis, but definitive classification requires molecular analysis. A diagnosis of IDC has potential implications for patient management.

The novel potential targets for HT precision oncology are also clustered based on the anatomic origin. This study shed light into the biology of these rare cancers, and may have important consequences for treatment decision and clinical trial selection for HT patients.

Notably, patients with stage IV ADC who had novel RORB-ALK or AFF2-RET fusions, but no other known oncogenic driver mutations, demonstrated favorable clinical outcomes on tyrosine kinase inhibitors. Our data provide a comprehensive overview of the landscape of oncogenic kinase fusions in lung cancer, which assist in recognizing potentially druggable fusions that can be translated into therapeutic applications.

The most frequent partner in this retrospective series of consecutive PTCs was CCDC6. Accordingly, the concordance between FISH and RNA-based NGS was perfect, with a 0% failure rate. The interpretation of RET FISH was straightforward in all cases due to the absence of subtle split signals or complex patterns.

This finding of a redifferentiation effect with selpercatinib targeting a RET fusion gene, reinforces the proof of concept of this new therapeutic opportunity. Therefore, future clinical trials and treatment strategies must not forget to evaluate the redifferentiating effect of drugs targeting gene rearrangements. Furthermore, the combined approach with a targeted therapy and radioactive iodine may increase anti-tumor efficacy and minimize acquired resistance to RET inhibitors.

Funding This study was mainly funded by Lilly. We also thank Instituto de Salud Carlos III (ISCIII) (Fondos FEDER and Plan Estatal I+D+I 2008–2011 &lsqb;PI11/02866] and 2013–2016 &lsqb;PI14-01176 y PI17-01001]) and the iLUNG Program (B2017/BMD-3884) from the Comunidad de Madrid.

IDC of the minor salivary glands is exceedingly rare. We discuss diagnostic problems associated with minor salivary gland lesions, and the "basal-like" phenotype of this case.

Typically regarded to have ETV6-NTRK3 fusions, secretory carcinomas may alternatively arise with RET fusions as well. Adding our cohort of 6 NCOA4-RET fusion-positive IC compared with 4 cases of secretory carcinoma with ETV6-RET fusions and a single case of fusion-negative IC with salivary duct carcinoma-like genetics, we propose a diagnostic algorithm that integrates histological elements, including atypia and invasiveness, and the likelihood of specific molecular alterations to increase diagnostic accuracy in what can be a very subtle diagnosis with important clinical implications.

We found one classic EGFR activing mutation (L747_A750delinsP) and one MAP2K1 activating mutation (F53_Q58delinsL), which can be targeted by EGFR-TKIs and MEK inhibitor trametinib, respectively...We also found STK11/TSC2 inactivating mutations and a dominant-negative mutation of PTEN (R130Q) which could be targeted by mTOR inhibitor everolimus and AKT inhibitor capivasertib, respectively... The mutational landscape of our PDAC cohort provided compelling evidence that targetable driver mutations accounted for a significant portion of KRAS wide-type tumors . Our findings demonstrated that genomic profiling of PDAC patients can enable physicians to optimize their clinical management and enroll them into genomically matched clinical trials.

Pralsetinib showed robust, durable antitumor activity in patients with multiple RET fusion‒positive, heavily pre-treated, advanced solid tumors, and was well tolerated . These data highlight the need for broad RET testing to identify candidates who could benefit from treatment with pralsetinib . Enrollment of patients with other RET fusion–positive solid tumors in ARROW is ongoing.

FDA has approved Retevmo (Selpercatinib) for lung and thyroid cancers with RET gene mutations or fusions... This study revealed the molecular features of RET rearrangement in Chinese cancer pts, which might result in more effective personalized diagnoses and therapies.