CCDC6-RET fusion

Although RET-positive tumors have been treated with multikinase inhibitors such as vandetanib or RET-selective inhibitors, ultimately resistance to them develops...Increased mitochondria were also observed in post-TKI biopsy specimens in 13/20 cases of NSCLC, suggesting a potential strategy targeting mitochondria to treat resistant tumors. Our data propose new promising therapeutic options to combat resistance to RET inhibitors in NSCLC.

The patient was initiated on selpercatinib, which was held after 3 weeks due to thrombocytopenia and hypertension. Pralsetinib was held during adjuvant chemoradiation for the GBM, and again for 4 weeks due to pneumonitis that resolved with steroids, and pralsetinib was restarted at a reduced dose. The patient has since demonstrated a stable reduction of the mediastinal mass for >15 months with RET inhibition therapy, despite several treatment interruptions.

We previously showed that the multi-kinase inhibitors vandetanib and cabozantinib increase the mitochondrial membrane potential (Δψm) in RET-mutated thyroid tumor cells and that this effect can be exploited to increase mitochondrial enrichment of Δψm-sensitive agents in the tumor cells...The quality of life of one patient significantly improved over a year until the tumor relapsed. This combination of selpercatinib with MitoQ may have therapeutic potential for patients with RET-mutated tumors and intolerant to regular selpercatinib doses.

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.

NGS after EGFR-TKI resistance may detect targetable drivers besides T790M. To do either liquid or tissue NGS only could miss patients with T790M. To do tissue and liquid NGS in parallel after EGFR-TKI resistance may find more patients with targetable cancers.

We provide further evidence for using molecular risk stratification as a promising predictor of disease outcomes. The results of this study may be limited by the extremely high prevalence of cancer in the cohort for clinical reference.

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.

This is the first case in the literature of metastatic TNBC with CCDC6-RET fusion treated with pralsetinib, an RET-specific antagonist. This case demonstrates the potential efficacy of pralsetinib in cases of TNBC with RET fusion mutations and suggests that NGS may reveal new opportunities and bring new therapeutic interventions to patients with refractory TNBC.

The cobas EGFR Mutation Test, ddPCR, and NGS appear to be feasible methods for analyzing CSF ctDNA in patients with NSCLC and LM. In addition, NGS may provide comprehensive information regarding the mechanisms underlying osimertinib resistance.

We found that CASTL1 expression is elevated in tumors with CCDC6-RET fusion which is the most frequent rearrangement in papillary thyroid carcinoma. Our results open a new venue for the studies of early oncogenesis in various tumor types, especially those associated with physical or chemical DNA damage.

Reduced FDG avidity of those lesions and decreased serum antithyroglobulin antibody titer were also noticed. This case illustrated successfully reinduced 131I avidity in papillary thyroid cancer through redifferentiation with target therapy to suppress tumor RET overexpression.

Moreover, we found that most LUAD cell lines and tissues expressed high levels of BCL2L1 and MCL1 mRNA but extremely low levels of BCL2. Together, these findings suggest that inhibiting BCL2L1 plus MCL1 may represent a new approach to treating LUAD cells irrespective of their driver mutations.

We confirmed the efficacy of osimertinib in patients with advanced EGFR mutation-positive NSCLC. At progression, the most frequent histomolecular alterations were MET amplification and EGFR C797S mutation.

Two FDA-approved RET inhibitors-pralsetinib and selpercatinib have been implied for the treatment of patients with RET S891L mutant UCEC and the treatment of patients with metastatic RET-fusion positive THCA and non-small cell lung cancer (NSCLC) at therapeutic level 1. At last, patients with higher expression and sequence variant frequency have a worse prognosis, such as sarcoma patients. This work provided a profound and comprehensive analysis of RET and co-occurred alterations, RET mRNA expression and the clinical significance in pan cancer, offering new insights into targeted therapy for patients with RET anomalies.

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 grade greater than or equal to 4 adverse events were observed. Lorlatinib induced durable intracranial responses in patients with ROS1-rearranged NSCLC and prior isolated CNS progression on crizotinib.

One patient had acquired EGFR T790M, STRN-ALK fusion, and EGFR amplification after gefitinib progression and was shortly resistant to osimertinib with MET amplification. The other patient developed to acquired EGFR T790M and MET amplification post-dacomitinib and acquired CCDC6-RET fusion after 4-month osimertinib treatment...The T790M accompanying diver gene resistance will be a new subtype after EGFR-TKIs progression and needs effective treatment options. Legal entity responsible for the study The authors.

15 received gefitinib, 27 received erlotinib, 16 received afatinib and 2 received osimertinib as the first-line therapy...One patient with MET CNG kept erlotinib and added-on capmatinib...Non-detectable variant in cfDNA NGS might predict better outcome in T790M-positive patients. Legal entity responsible for the study The authors.

No grade 5 adverse events were observed. The study was terminated early after enrollment of 16 of 22 planned patients due to the commercial availability of off-label lorlatinib.Conclusion s : The CNS-penetrant next-generation ROS1 inhibitor lorlatinib is an effective salvage therapy for patients experiencing isolated CNS progression on crizotinib.

In pediatric fusion-oncogene PTC cases with 131I-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric PTC patients.

Further studies are warranted to establish the role of co-occurring NF1/TP53 mutations as a positive predictive biomarker for pembrolizumab in NSCLC harboring RET fusion genes.

A 37-year-old woman with stage IVB adenocarcinoma of lung with osseous, hepatic and brain metastases initially received one cycle of carboplatin, pemetrexed and pembrolizumab...The treatment regimen was switched to atezolizumab, bevacizumab, paclitaxel and carboplatin combination therapy... It has been reported that co-occurring RET fusions in NSCLC patients with EGFR mutations may contribute to acquired resistance to EGFR inhibitors . Several successful cases of cabozantinib, a non-selective RET inhibitor, or pralsetinib, a selective RET inhibitor combined with EGFR inhibitor, have been reported to aid in overcoming the acquired resistance to EGFR inhibitors . To date, there has been no report of clinical benefit in adding a RET inhibitor based on ctDNA detection of RET fusion with minute variant allele frequency .

Funding: Foundation Medicine Background: The emergence of osimertinib (osi) as standard of care therapy for EGFR-mutant NSCLC has led to investigations into understanding and overcoming drug resistance... Osi resistance in EGFR-mutant NSCLC is a poor prognosis condition . EGFR C797S is a recurring resistance mut which, in a minority of cases, can co-occur with alternate on and off target resistance muts detected with tissue and liquid biopsy.

Uncommon ALK/ROS1/RET genomic breakpoint is an unreliable predictor of matched targeted therapy efficacy. Functional validation by RNA or protein assay may add value for accurate detection and interpretation of rare fusions.

RET mutations at the solvent front and the hinge are resistant to both drugs. Selpercatinib and pralsetinib use an unconventional mode to bind RET that avoids the interference from gatekeeper mutations but is vulnerable to non-gatekeeper mutations.

Additionally, we described two novel cases of CCDC6-RET fusion in glioma. Collectively, our findings indicate that targetable gene fusions are associated with aggressive biological behavior and can aid the clinical treatment strategy for glioma patients.

In RET rearranged NSCLC, selective RET TKI therapy is associated with improved survival outcomes, especially in CCDC6-RET positive patients. Immunotherapy has poor efficacy. NGS and FISH testing methods may also result in significant discordance.

Consistent with local standard of care, she received treatment with tamoxifen plus goserelin from March through June 2019, but these were discontinued for progression in the right breast and new lesions in the left lower lung... Selpercatinib demonstrated anti-tumor activity in a patient with RET fusion-positive breast cancer. To our knowledge, this is the first report of a breast cancer patient with a sustained response to selective, RET-targeted therapy and adds to the diversity of RET fusion-positive tumor types that may benefit from selective RET inhibition.