BRAF V600E Mutation Research Articles

Journey through tumorverse: Creating models to decode PXA mysteries

Pleomorphic xanthoastrocytoma (PXA) is a rare pediatric low-grade glioma (pLGG), of which 60%-80% exhibit the BRAF V600E mutation, that enhances the aggressiveness and progression to an eventual pediatric high-grade glioma (pHGG). Despite the aggressiveness of this mutational status, the mechanisms underlying the progression of BRAF V600E tumors remain poorly understood, primarily due to limited insights into their invivo growth dynamics. In this issue,Rajappa and colleagues leverage a novel immunocompetent RCAS-BRAF V600E murine glioma model to profile the immunological dynamics taking place in BRAF V600E pLGG.

Melanoma Brain Metastases Patient-Derived Organoids: An In Vitro Platform for Drug Screening.

Brain metastases are prevalent in the late stages of malignant melanoma. Multimodal therapy remains challenging. Patient-derived organoids (PDOs) represent a valuable pre-clinical model, faithfully recapitulating key aspects of the original tumor, including the heterogeneity and the mutational status. This study aimed to establish PDOs from melanoma brain metastases (MBM-PDOs) and to test the feasibility of using them as a model for in vitro targeted-therapy drug testing. Surgical resection samples from eight patients with melanoma brain metastases were used to establish MBM-PDOs. The samples were enzymatically dissociated followed by seeding into low-attachment plates to generate floating organoids. The MBM-PDOs were characterized genetically, histologically, and immunohistologically and compared with the parental tissue. The MBM-PDO cultures were exposed to dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) followed by a cell viability assessment. Seven out of eight cases were successfully cultivated, maintaining the histological, immunohistological phenotype, and the mutational status of the parental tumors. Five out of seven cases harbored BRAF V600E mutations and were responsive to BRAF and MEK inhibitors in vitro. Two out of seven cases were BRAF wild type: one case harboring an NRAS mutation and the other harboring a KIT mutation, and both were resistant to BRAF and MEK inhibitor therapy. We successfully established PDOs from melanoma brain metastases surgical specimens, which exhibited a consistent histological and mutational profile with the parental tissue. Using FDA-approved BRAF and MEK inhibitors, our data demonstrate the feasibility of employing MBM-PDOs for targeted-therapy in vitro testing.

Adherence to national Lynch syndrome testing guidelines for colorectal cancer in an Aotearoa New Zealand hospital-based population.

Lynch syndrome (LS) is estimated to affect 1-3.9% of patients with colorectal cancer (CRC). Testing for LS is important in determining management and establishing surveillance for "Lynch families". Previous studies have identified poor rates of testing for LS in CRC patients. This study aimed to describe adherence to guidelines for testing of newly diagnosed CRC for LS. A single institution cohort study of patients over 18 years with colorectal adenocarcinoma from 2018-2022 in Te Tai Tokerau, Aotearoa New Zealand was conducted. Rates of baseline immunohistochemistry (IHC) testing for mismatch repair (MMR) deficiency, further testing for MLH1-deficient cases and rates of germline mutational analysis were audited to determine adherence to national guidelines. The rate of LS in newly diagnosed CRC was estimated. Six hundred and sixty patients were eligible for universal testing for LS, of which 84% (n=553) completed initial IHC testing. MMR deficiency was reported in 20% (n=114) cases. Eighty-nine percent (n=101) was attributable to MLH1 deficiency, of which 99% (n=100) were appropriately tested for BRAF-V600E mutation. Sixty-four percent (4/11) patients indicated for hypermethylation testing were appropriately tested. Seventeen patients had an indication for germline mutational analysis, of which only 29% (n=5) were tested. The estimated incidence of LS in newly diagnosed CRC was 0.7-3.8%. Compliance with initial IHC testing was good. However, there is a need to improve rates of confirmation genetic testing. The incidence of confirmed LS in this study is 0.7%, however this may be as high as 3.9%.

Differences in BRAF V600E mutation between the epithelium and mesenchyme in classic ameloblastoma

PurposeLaser capture microdissection (LCM) was used to pinpoint the mutated tissue in ameloblastoma and investigate whether B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutation is the main pathogenic gene in classic ameloblastoma. Study DesignA total of 24 patients with ameloblastoma scheduled to undergo surgery between 2000 and 2024 were included in the study. LCM was used to isolate tumor cells. Oxford nanopore technology (ONT) was used to analyze the collected cells. GO and KEGG enrichment analyses were then performed on the 300 most highly expressed genes in the epithelial tissue and mesenchyme. ResultsMandibular follicular ameloblastoma showed BRAF V600E mutations in all epithelial cells but not in the mesenchyme. The mutation rate was significantly higher in mandibular ameloblastomas compared to the maxilla (p<0.05). RNA-seq showed that traditional follicular ameloblastoma epithelium was enriched in "growth factor receptor binding" and "angiogenesis regulation", while the mesenchyme was enriched in "ECM receptor interaction". KEGG enrichment analysis showed differential gene expression, mainly in MAPK and PI3K-AKT pathways. ConclusionClassical follicular ameloblastoma shows the presence of BRAF V600E mutation in epithelial tissue, with a higher mutation rate in the mandible than in the maxilla. The signaling pathways of MAPK and PI3K may be significantly involved in epithelial signal transduction.

Gene Expression Profiles of AHNAK2, DCSTAMP, FN1, and TERT Correlate With Mutational Status and Recurrence in Papillary Thyroid Carcinoma.

Papillary thyroid carcinoma (PTC), the most common malignancy of follicular cell derivation, is generally associated with good prognosis. Nevertheless, it is important to identify patients with aggressive PTCs and unfavorable outcome. Molecular markers such as BRAFV600E mutation and TERT promoter mutations have been proposed for risk stratification. While TERT promoter mutations have been frequently associated with aggressive PTCs, the association of BRAFV600E mutation with increased recurrence and mortality is less clear and has been controversially discussed. The aim of the present study was to analyze whether differentially expressed genes can predict BRAFV600E mutations as well as TERT promoter mutations in PTCs. RNA sequencing identified a large number of differentially expressed genes between BRAFV600E and BRAFwildtype PTCs. Of those, AHNAK2, DCSTAMP, and FN1 could be confirmed in a larger cohort (n = 91) to be significantly upregulated in BRAFV600E mutant PTCs using quantitative RT-PCR. Moreover, individual PTC expression values of DCSTAMP and FN1 were able to predict the BRAFV600E mutation status with high sensitivity and specificity. The expression of TERT was detected in all PTCs harboring TERT promoter mutations and in 19% of PTCs without TERT promoter mutations. Tumors with both TERT expression and TERT promoter mutations were particularly associated with aggressive clinicopathological features and a shorter recurrence-free survival. Altogether, it will be interesting to explore the biological function of AHNAK2, DCSTAMP, and FN1 in PTC in more detail. The analysis of their expression patterns could allow the characterization of PTC subtypes and thus enabling a more individualized surgical and medical treatment.

Tovorafenib: First Approval.

Tovorafenib (OJEMDA™) is a once-weekly oral, selective, brain-penetrant, type II RAF kinase inhibitor being developed by Day One Biopharmaceuticals, Inc., under a license from Takeda Oncology, for the treatment of paediatric low-grade glioma (pLGG) and solid tumours. Most pLGGs harbour alterations in the MAPK pathway, such as a BRAF mutation or BRAF fusion, which result in aberrant intracellular signalling. Tovorafenib is an inhibitor of mutant BRAF V600E, wild-type BRAF and wild-type CRAF kinases and BRAF fusions. In April 2024, tovorafenib received its first approval in the USA for the treatment of patients aged ≥ 6 months with relapsed or refractory pLGGs harbouring a BRAF fusion or rearrangement, or BRAF V600 mutation. It received accelerated approval for this indication based on the response rate and duration of response achieved in this population in the ongoing, pivotal, phase 2 FIREFLY-1 study. Clinical development of tovorafenib is underway in numerous countries worldwide. This article summarizes the milestones in the development of tovorafenib leading to this first approval for relapsed or refractory pLGG with an activating BRAF alteration.

Molecular aspects of BRAF and HER2 in prognosis of periampullary carcinoma

BackgroundBiological behaviour of Periampullary cancers (PACS) differs from pancreatic head cancer, and analysis of molecular alteration is needed. BRAF and HER2 are keys members of the RAS/RAF and EGFR pathway, playing roles in prognostic markers and therapeutic targets. MethodsA study on 89 PACS patients, undergoing Whipple Pancreaticoduodenectomy, PCR-RFLP, and qPCR methods used for SNP and mRNA expression studies. Clinicopathological and survival data collected. Molecular changes were correlated with Clinicopathological parameters. Survival outcomes were assessed by Kaplan Meir Log rank test. ResultsThe study revealed that homozygous mutant BRAF V600E was significantly higher in PAC compared to a healthy control (p = 0.0012). Whereas the genotype frequency of HER2 I1655V was similar among PAC and healthy control. The A > G change in HER2 was associated with tumor arising from duodenum (p = 0.004) and showed poor survival outcome (p = 0.001). Upregulation of BRAF and HER2 was found in 43 % of patients with synergistic effect, the median overall survival (OS) being 50.5 ± 13 months. The increased expression of HER2 was higher in early stage (p = 0.04) PAC. The gene expression did not impact the OS, whereas female gender, G3 tumors, T3-T4 depth of tumour, advanced stage, LN metastasis, LVI and PNI were poor predictors of OS. ConclusionsBRAF V600E SNP was associated with disease susceptibility, and had increased mRNA expression while HER2 I1655V SNP was associated with poor survival outcome in PAC. The increased expression of BRAF and HER2 in early tumors and their co-expression in PAC exhibit cross talk between RAS/RAF and EGFR pathway in PAC.

Future perspective of targeted treatments in pediatric low-grade glioma (pLGG): the evolution of standard-of-care and challenges of a new era.

While surgery, when possible, remains the mainstay of pediatric low-grade glioma (pLGG) management, adjuvant therapy has significantly evolved over time. Radiation therapy was commonly used in the late 1990s for tumors that could not be resected or recurred. This resulted in significant late morbidity in this population and mortality related to secondary malignancies and chronic health conditions. Chemotherapy became the mainstay of adjuvant therapy but children still experienced late morbidity secondary to exposure to multiple lines of treatment over time. Targeted therapies emerged after the identification of frequent genetic alterations in the mitogen activated protein kinase (MAPK) pathway including KIAA1549-BRAF fusions and BRAF-V600 mutations and the near universal upregulation of the MAPK pathway in these tumors. Both BRAF and MEK inhibitors have shown efficacy in the treatment of pLGG and have led to prolonged stability in some cases. Multiple phase III clinical trials are now comparing targeted therapy to standard-of-care chemotherapy regimens setting the stage for targeted therapy to replace chemotherapy as the first-line treatment in some cases. Targeted therapy, however, is not without its challenges. There are clear examples of resistance and mechanisms of resistance have not been fully elucidated. There is also no clear duration for these therapies and rebound growth is a well-known phenomenon especially in BRAF-V600 mutant tumors. Targeted therapies are also fairly recent developments and long-term toxicities and functional outcomes are still being monitored. Very young and adolescent/young adult LGGs also carry molecular features that may not be addressed by inhibition of the MAPK pathway. Adjuvant therapy for pLGG has evolved from radiation for all unresectable or residual tumors to molecularly driven targeted therapies with improved quality of life, late effects, and less off-target toxicities. While there is still much to learn in regard to newer targeted therapies for pLGG, the era of targeted therapies for pediatric LGG is upon us.

An Automated Real-Time PCR Assay versus Next-Generation Sequencing in the Detection of BRAF V600 Mutations in Melanoma Tissue Samples.

Next-generation sequencing (NGS) is the most commonly used method for determining BRAF mutational status in patients with advanced melanoma. Automated PCR-based methods, such as the IdyllaTM system, are increasingly used for mutation diagnostics, but it is unclear what impact the choice of diagnostic method has on the management of melanoma. To compare the concordance rate of BRAF V600 mutational analysis using IdyllaTM and NGS and to analyze the technical and clinical turnaround time. The clinical relevance is compared by analyzing the impact on the treatment decision. In this monocentric prospective cohort study, the BRAF mutation status of 51 patients was determined using both methods in parallel. BRAF V600 mutation was detected in 23/51 cases (45%). IdyllaTM showed a 100% concordant result with a faster turnaround time (0.2 days) compared to NGS (12.2 days). In general, less tumor material was required for IdyllaTM than for NGS. Most patients received immunotherapy as a first-line therapy regardless of the BRAF V600 status. IdyllaTM testing proved to be a reliable and rapid alternative to NGS in the determination of BRAF V600 mutation. Although BRAF. status was available earlier, this had no influence on the treatment decision in most cases.

The elusive BAP1 mutation in pediatric melanocytic tumors.

Cutaneous BAP1-inactivated melanocytomas (BIM) are melanocytic proliferations defined histopathologically by an epithelioid, predominantly dermal melanocytic proliferation with loss of BAP1, and have been largely characterized in adult patients but less well-described in pediatric cohorts. BIM share overlapping histological features with those seen in Spitz nevi; however, unlike Spitz nevi, the majority of BIM carry both BAP1 and BRAFV600E mutations. This study investigated the potential overlap of BIMs with pediatric Spitz nevi by performing immunohistochemical staining of BAP1 and BRAFV600E on pediatric melanocytic tumors with banal Spitz and dermal features. None of the stained tumors in our study exhibited the concurrent BAP1 loss and BRAFV600E positivity that are characteristic of adult BIM, suggesting that this is a low-frequency mutation among banal tumors in the pediatric population.

Identification of the Clinical Candidate PF-07284890 (ARRY-461), a Highly Potent and Brain Penetrant BRAF Inhibitor for the Treatment of Cancer.

Mutant BRAFV600E is one of the most common oncogenic drivers in metastatic melanoma. While first generation BRAFV600E inhibitors are capable of controlling tumors systemically, they are unable to adequately treat tumors that have metastasized to the brain due to insufficient penetration across the blood-brain barrier (BBB). Through a combination of structure-based drug design (SBDD) and the optimization of physiochemical properties to enhance BBB penetration, we herein report the discovery of the brain-penetrant BRAFV600E inhibitor PF-07284890 (ARRY-461). In mice studies, ARRY-461 proved to be highly brain-penetrant and was able to drive regressions of A375 BRAFV600E tumors implanted both subcutaneously and intracranially. Based on compelling preclinical safety and efficacy studies, ARRY-461 was progressed into a Phase 1 A/B clinical trial (NCT04543188).

Ultrasound features as predictive markers of BRAFV600E mutation in thyroid cancer: a systematic review and meta-analysis.

Conflicting evidence exists on the predictive value of ultrasound characteristics for BRAFV600E gene expression in thyroid cancer. This study aimed to determine the predictive value of ultrasound features for BRAFV600E gene expression status in thyroid cancer. A systematic review of studies published before December 31, 2023, was conducted in the PubMed, Web of Science, and Cochrane Library databases. Studies evaluating the ultrasonographic features for predicting BRAFV600E gene mutations in thyroid cancer were included. The relevant data were extracted, and the quality of eligible studies was independently assessed by two reviewers. Statistical analysis was performed using RevMan 5.4 and Stata 12.0 software. The meta-analysis included 13 studies involving a total of 2,250 thyroid cancer patients. Ultrasound features significantly associated with BRAFV600E gene expression status in thyroid cancer (P<0.05) comprised hypoechogenicity, absence of halo, irregular borders, and vertical orientation. Contrastingly, no significant differences were observed in solid composition, irregular shape, and microcalcifications (P>0.05). Among the seven ultrasound features, the ones with superior combined sensitivity for nodules were hypoechogenicity, solid composition, absence of halo, and irregular borders, with sensitivities of 0.93 [95% confidence interval (CI): 0.87-0.96], 0.93 (95% CI: 0.86-0.97), 0.83 (95% CI: 0.72-0.91), and 0.74 (95% CI: 0.64-0.83), respectively. Finally, the areas under the summary receiver operating characteristic (SROC) curve with the highest diagnostic performance were the absence of halo and hypoechogenicity, with area under the curve (AUC) of 0.84 (95% CI: 0.80-0.87) and 0.81 (95% CI: 0.77-0.84), respectively. The expression status of the BRAFV600E gene in thyroid cancer correlates with nodules exhibiting hypoechogenicity, absence of halo, irregular borders, and taller-than-wide shape. Notably, the absence of a halo and hypoechogenicity were identified as the most predictive ultrasonic features. However, due to the limited sample size, there may be bias in the meta-analysis results, and more extensive research is necessary.

Pyrimidine-Dependent UV-Mediated Cross-Linking Magnifies Minor Genetic or Epigenetic Changes in Clinical Samples.

Detection of minor DNA allele alterations is becoming increasingly important for early detection and monitoring of cancer. We describe a new method that uses ultraviolet light to eliminate wild-type DNA alleles and enables improved detection of minor genetic or epigenetic changes. Pyrimidine-dependent UV-based minor-allele enrichment (PD-UVME) employed oligonucleotide probes that incorporated a UVA-sensitive 3-cyanovinylcarbazole (CNVK), placed directly opposite interrogated pyrimidines, such as thymine (T) or cytosine (C) in wild-type (WT) DNA. Upon UVA-illumination, CNVK cross-linked with T/C, preventing subsequent amplification. Mutations that removed the T/C escaped cross-linking and were amplified and detected. Similarly, CNVK discriminated between methylated and unmethylated cytosine in CpG dinucleotides, enabling direct enrichment of unmethylated DNA targets. PD-UVME was combined with digital droplet PCR (ddPCR) to detect serine/threonine-protein kinase B-Raf (BRAF) V600E mutations in model systems, thyroid patient cancer tissue samples, and circulating DNA of tumor origin (ctDNA) from melanoma patients. One thyroid cancer sample out of 9, and 6 circulating-DNA samples out of 7 were found to be BRAF V600E-positive via PD-UVME while classified as negative by conventional ddPCR. Positive samples via conventional ddPCR were also found positive via PD-UVME. All 10 circulating cell-free DNA (cfDNA) samples obtained from normal volunteers were negative via both approaches. Furthermore, preferential enrichment of unmethylated alleles in MAGEA1 promoters using PD-UVME was demonstrated. PD-UVME mutation/methylation enrichment performed prior to ddPCR magnifies low-level mutations or epigenetic changes and increases sensitivity and confidence in the results. It can assist with clinical decisions that hinge on the presence of trace alterations like BRAF V600E.

Approach to the Patient: New Era Emerges for Craniopharyngioma Management.

Papillary craniopharyngioma (PCP) and adamantinomatous craniopharyngioma (ACP) are distinct, slow-growing tumors of the suprasellar region. Their location, composition, and biology have historically evaded successful surgical radiation and medical therapy. Meanwhile compromise of critical structures either by tumor or treatments increase morbidity, impacting patient and carer quality of life. There has been a paradigm shift in the management of PCP, stemming from the discovery of BRAFV600E mutation in its tumorigenesis. Such a treatment breakthrough may soon be the case for ACP, changing the landscape of craniopharyngioma management. We use a case of ACP partially responding to ERK inhibitor therapy to demonstrate chronicity of disease progression and discuss modern management strategies highlighting the importance of access to tumor agnostic clinical trials, and future directions.

Cyclic tachyplesin I kills proliferative, non-proliferative and drug-resistant melanoma cells without inducing resistance

Acquired drug resistance is the major cause for disease recurrence in cancer patients, and this is particularly true for patients with metastatic melanoma that carry a BRAF V600E mutation. To address this problem, we investigated cyclic membrane-active peptides as an alternative therapeutic modality to kill drug-tolerant and resistant melanoma cells to avoid acquired drug resistance. We selected two stable cyclic peptides (cTI and cGm), previously shown to have anti-melanoma properties, and compared them with dabrafenib, a drug used to treat cancer patients with the BRAF V600E mutation. The peptides act via a fast membrane-permeabilizing mechanism and kill metastatic melanoma cells that are sensitive, tolerant, or resistant to dabrafenib. Melanoma cells do not become resistant to long-term treatment with cTI, nor do they evolve their lipid membrane composition, as measured by lipidomic and proteomic studies. In vivo studies in mice demonstrated that the combination treatment of cTI and dabrafenib resulted in fewer metastases and improved overall survival. Such cyclic membrane-active peptides are thus well suited as templates to design new anticancer therapeutic strategies.

Impact of Genomic Mutation on Melanoma Immune Microenvironment and IFN-1 Pathway-Driven Therapeutic Responses.

The BRAFV600E mutation, found in approximately 50% of melanoma cases, plays a crucial role in the activation of the MAPK/ERK signaling pathway, which promotes tumor cell proliferation. This study aimed to evaluate its impact on the melanoma immune microenvironment and therapeutic responses, particularly focusing on immunogenic cell death (ICD), a pivotal cytotoxic process triggering anti-tumor immune responses. Through comprehensive in silico analysis of the Cancer Genome Atlas data, we explored the association between the BRAFV600E mutation, immune subtype dynamics, and tumor mutation burden (TMB). Our findings revealed that the mutation correlated with a lower TMB, indicating a reduced generation of immunogenic neoantigens. Investigation into immune subtypes reveals an exacerbation of immunosuppression mechanisms in BRAFV600E-mutated tumors. To assess the response to ICD inducers, including doxorubicin and Me-ALA-based photodynamic therapy (PDT), compared to the non-ICD inducer cisplatin, we used distinct melanoma cell lines with wild-type BRAF (SK-MEL-2) and BRAFV600E mutation (SK-MEL-28, A375). We demonstrated a differential response to PDT between the WT and BRAFV600E cell lines. Further transcriptomic analysis revealed upregulation of IFNAR1, IFNAR2, and CXCL10 genes associated with the BRAFV600E mutation, suggesting their involvement in ICD. Using a gene reporter assay, we showed that PDT robustly activated the IFN-1 pathway through cGAS-STING signaling. Collectively, our results underscore the complex interplay between the BRAFV600E mutation and immune responses, suggesting a putative correlation between tumors carrying the mutation and their responsiveness to therapies inducing the IFN-1 pathway, such as the ICD inducer PDT, possibly mediated by the elevated expression of IFNAR1/2 receptors.

Hotspot Exon 15 Mutations in BRAF Are Uncommon in Feline Tumours.

BRAF is one of multiple RAF proteins responsible for the activation of the MAPK cell signalling cascade involved in cell growth, differentiation, and survival. A hotspot BRAFV600E mutation, in exon 15, was determined to be a driver in 100% hairy cell leukaemias, 50%-60% of human melanomas, 30%-50% of human thyroid carcinomas and 10%-20% of human colorectal carcinomas. The orthologous BRAFV595E mutation was seen in 67% and 80% of canine bladder transitional cell carcinomas and prostatic adenocarcinomas, respectively. Since veterinary and human cancers exploit similar pathways and BRAF is highly conserved across species, BRAF can be expected to be a driver in a feline cancer. Primers were developed to amplify exon 15 of feline BRAF. One hundred ninety-six feline tumours were analysed. Sanger sequencing of the 211 bp PCR amplicon was done. A BRAF mutation was found in one tumour, a cutaneous melanoma. The mutation was a BRAFV597E mutation, orthologous to the canine and human hotspot mutations. A common synonymous variant, BRAFT586T, was seen in 23% (47/196) of tumours. This variant was suspected to be a single nucleotide polymorphism. BRAF was not frequently mutated in common feline tumours or in tumour types that frequently harbour BRAF mutations in human and canine cancers. As is seen in canine cancer genomics, the mutational profile in feline tumours may not parallel the histologic equivalent in human oncology.

Genotype-relevant neuroimaging features in low-grade epilepsy-associated tumors.

Low-grade epilepsy-associated tumors are the second most common histopathological diagnoses in cases of drug-resistant focal epilepsy. However, the connection between neuroimaging features and genetic alterations in these tumors is unclear, prompting an investigation into genotype-relevant neuroimaging characteristics. This study retrospectively analyzed neuroimaging and surgical specimens from 46 epilepsy patients with low-grade epilepsy-associated neuroepithelial tumors that had genetic mutations identified through panel sequencing to investigate their relationship to genotypes. Three distinct neuroimaging groups were established: Group 1 had indistinct borders and iso T1-weighted and slightly high or high T2-weighted signal intensities without a diffuse mass effect, associated with 93.8% sensitivity and 100% specificity to BRAF V600E mutations; Group 2 exhibited sharp borders and very or slightly low T1-weighted and very high T2-weighted signal intensities with a diffuse mass effect and 100% sensitivity and specificity for FGFR1 mutations; and Group 3 displayed various characteristics. Histopathological diagnoses including diffuse low-grade glioma and ganglioglioma showed no clear association with genotypes. Notably, postoperative seizure-free rates were higher in Group 1 tumors (BRAF V600E) than in Group 2 tumors (FGFR1). These findings suggest that tumor genotype may be predicted by neuroimaging before surgery, providing insights for personalized treatment approaches.

Efficacy of chemotherapy plus immune checkpoint inhibitors in patients with non-small cell lung cancer who have rare oncogenic driver mutations: a retrospective analysis

BackgroundTargeted therapy is now the standard of care in driver–oncogene-positive non-small cell lung cancer (NSCLC). Its initial clinical effects are remarkable. However, almost all patients experience treatment resistance to targeted therapy. Hence, chemotherapy is considered a subsequent treatment option. In patients with driver–oncogene-negative NSCLC, combined immune checkpoint inhibitors (ICIs) and chemotherapy as the first-line therapy has been found to be beneficial. However, the efficacy of ICI plus chemotherapy against driver–oncogene-positive NSCLC other than epidermal growth factor receptor mutation and anaplastic lymphoma kinase fusion is unclear.MethodsUsing the hospital medical records, we retrospectively reviewed advanced or recurrent NSCLC patients who were treated with chemotherapy with or without ICIs at Aichi Cancer Center Hospital between January 2014 and January 2023. Patients with druggable rare mutations such as KRAS-G12C, MET exon 14 skipping, HER2 20 insertion, BRAF-V600E mutations, and ROS1 and RET rearrangements were analyzed.ResultsIn total, 61 patients were included in this analysis. ICI plus chemotherapy was administered in 36 patients (the ICI-chemo group) and chemotherapy in 25 patients (the chemo group). The median progression-free survival (PFS) rates were 14.0 months in the ICI-chemo group and 4.8 months in the chemo group (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.28–1.01). The median overall survival rates were 31.3 and 21.7 months in the ICI-chemo and chemo groups, respectively (HR = 0.70, 95% CI = 0.33–1.50). Multivariate Cox regression analysis of PFS revealed that HER2 exon 20 insertion mutation was significantly associated with a poorer PFS (HR: 2.39, 95% CI: 1.19–4.77, P = 0.014). Further, ICI-chemo treatment was significantly associated with a better PFS (HR: 0.48, 95% CI: 0.25–0.91, P = 0.025).ConclusionICI plus chemotherapy improves treatment efficacy in rare driver–oncogene-positive NSCLC.

PD-L1 Expression and Its Modulating Factors in Anaplastic Thyroid Carcinoma: A Multi-institutional Study.

Anti-PD immunotherapy is currently under investigation in anaplastic thyroid carcinoma (ATC). Tumor cell surface PD-L1 expression is considered predictive of therapeutic response. Although papillary thyroid carcinoma has been widely studied for PD-L1 expression, there are limited data on ATC. In this retrospective multi-institutional study involving 9 centers across Asia, 179 ATCs were assessed for PD-L1 expression using the SP263 (Ventana) clone. A tumor proportion score (TPS) ≥1% was required to consider a case PD-L1-positive. PD-L1 expression was compared with the histological patterns, the type of specimen (small or large), tumor molecular profile ( BRAF V600E and TERT promoter mutation status), and patient outcome. PD-L1 expression in any co-existent differentiated thyroid carcinoma (DTC) was evaluated separately and compared with ATC. Most ATCs (73.2%) were PD-L1-positive. The median TPS among positive cases was 36% (IQR 11% to 75%; range 1% to 99%). A high expression (TPS ≥ 50%) was noted in 30.7%. PD-L1-negative cases were more likely to be small specimens ( P =0.01). A negative result on small samples, hence, may not preclude expression elsewhere. ATCs having epithelioid and pleomorphic histological patterns were more likely to be PD-L1-positive with higher TPS than sarcomatoid ( P <0.01). DTCs were more frequently negative and had lower TPS than ATC ( P <0.01). Such PD-L1 conversion from DTC-negative to ATC-positive was documented in 71% of cases with co-existent DTC. BRAF V600E, but not TERT promoter mutations, correlated significantly with PD-L1-positivity rate ( P =0.039), reinforcing the potential of combining anti-PD and anti-BRAF V600E drugs. PD-L1 expression, however, did not impact the patient outcome.