Prognostic significance of telomerase reverse transcriptase promoter gen mutations in high grade meningiomas / Importancia pronóstica de las mutaciones del gen promotor de la transcriptasa inversa de la telomerasa en los meningiomas de alto grado

Introduction: Mutations in the promoter region of telomerase reverse transcriptase occur frequently in meningiomas. Objective: To estimate the prognostic importance of telomerase reverse transcriptase mutations in Colombian patients with grades II and III meningioma. Materials and methods: This was a multicenter retrospective cohort study of patients diagnosed with refractory or recurrent WHO grades II and III meningiomas, recruited between 2011 and 2018, and treated with systemic therapy (sunitinib, everolimus ± octreotide, and bevacizumab). Mutation status of the telomerase reverse transcriptase promoter was established by PCR. Results: Forty patients were included, of which telomerase reverse transcriptase mutations were found in 21 (52.5%), being C228T and C250T the most frequent variants with 87.5 % and 14.3 %, respectively. These were more frequent among patients with anaplastic meningiomas (p=0.18), with more than 2 recurrences (p=0.04); and in patients with parasagittal region and anterior fossa lesions (p=0.05). Subjects characterized as having punctual mutations were more frequently administered with everolimus, sunitinib and bevacizumab drug series (p=0.06). Overall survival was 23.7 months (CI95% 13.1-34.2) and 43.4 months (CI95% 37.5-49.3; p=0.0001) between subjects with and without mutations, respectively. Multivariate analysis showed that the number of recurrences and the presence of telomerase reverse transcriptase mutations were tthe only variables that negatively affected overall survival. Conclusions: Mutations in telomerase reverse transcriptase allows the identification of high-risk patients and could be useful in the selection of the best medical treatment.

Introducción. En los meningiomas, ocurren con frecuencia mutaciones en la región promotora de la transcriptasa inversa de la telomerasa. Objetivo. Estimar la importancia pronóstica de las mutaciones de la transcriptasa inversa de la telomerasa en pacientes colombianos con meningiomas de grados II y III. Materiales y métodos. Es un estudio de cohorte, retrospectivo y multicéntrico, que incluyó pacientes con diagnóstico de meningioma persistente o recidivante, de grados II y III, según la clasificación de la OMS, reclutados entre el 2011 y el 2018, con tratamiento sistémico (sunitinib, everolimus con octreótido o sin él, y bevacizumab). El estado de la mutación del promotor de la transcriptasa inversa de la telomerasa se determinó por medio de la PCR. Resultados. Se incluyeron 40 pacientes, en 21 (52,5 %) de los cuales se encontraron mutaciones en la transcriptasa inversa de la telomerasa, siendo las variantes más frecuentes la C228T (87,5 %) y la C250T (14,3 %). Estas fueron más frecuentes entre los pacientes con meningiomas anaplásicos (p=0,18), en aquellos con más de dos recurrencias (p=0,04), y en los que presentaron lesiones en la región parasagital y la fosa anterior (p=0,05). Los sujetos caracterizados por tener alteraciones puntuales fueron tratados con mayor frecuencia con la serie de medicamentos everolimus, sunitinib y bevacizumab (p=0,06). Tras el inicio del tratamiento médico, la supervivencia global fue de 23,7 meses (IC95% 13,1-34,2) en los pacientes con mutaciones y, de 43,4 meses (IC95% 37,5-49,3), entre aquellos sin mutaciones (p=0,0001). Los resultados del análisis multivariado demostraron que, únicamente, el número de recurrencias y la presencia de mutaciones en el gen de la transcriptasa inversa de la telomerasa, fueron factores que afectaron negativamente la supervivencia global. Conclusiones. Las mutaciones en el gen promotor de la transcriptasa inversa de la telomerasa permiten identificar los pacientes con alto riesgo, cuya detección podría ser de utilidad para seleccionar el mejor esquema terapéutico.

Importancia pronóstica de las mutaciones del gen promotor de la transcriptasa inversa de la telomerasa en los meningiomas de alto grado / Prognostic significance of telomerase reverse transcriptase promoter gen mutations in high grade meningiomas

Introducción. En los meningiomas, ocurren con frecuencia mutaciones en la región promotora de la transcriptasa inversa de la telomerasa. Objetivo. Estimar la importancia pronóstica de las mutaciones de la transcriptasa inversa de la telomerasa en pacientes colombianos con meningiomas de grados II y III. Materiales y métodos. Es un estudio de cohorte, retrospectivo y multicéntrico, que incluyó pacientes con diagnóstico de meningioma persistente o recidivante, de grados II y III, según la clasificación de la OMS, reclutados entre el 2011 y el 2018, con tratamiento sistémico (sunitinib, everolimus con octreótido o sin él, y bevacizumab). El estado de la mutación del promotor de la transcriptasa inversa de la telomerasa se determinó por medio de la PCR. Resultados. Se incluyeron 40 pacientes, en 21 (52,5 %) de los cuales se encontraron mutaciones en la transcriptasa inversa de la telomerasa, siendo las variantes más frecuentes la C228T (87,5 %) y la C250T (14,3 %). Estas fueron más frecuentes entre los pacientes con meningiomas anaplásicos (p=0,18), en aquellos con más de dos recurrencias (p=0,04), y en los que presentaron lesiones en la región parasagital y la fosa anterior (p=0,05). Los sujetos caracterizados por tener alteraciones puntuales fueron tratados con mayor frecuencia con la serie de medicamentos everolimus, sunitinib y bevacizumab (p=0,06). Tras el inicio del tratamiento médico, la supervivencia global fue de 23,7 meses (IC95% 13,1-34,2) en los pacientes con mutaciones y, de 43,4 meses (IC95% 37,5-49,3), entre aquellos sin mutaciones (p=0,0001). Los resultados del análisis multivariado demostraron que, únicamente, el número de recurrencias y la presencia de mutaciones en el gen de la transcriptasa inversa de la telomerasa, fueron factores que afectaron negativamente la supervivencia global. Conclusiones. Las mutaciones en el gen promotor de la transcriptasa inversa de la telomerasa permiten identificar los pacientes con alto riesgo, cuya detección podría ser de utilidad para seleccionar el mejor esquema terapéutico.

Introduction: Mutations in the promoter region of telomerase reverse transcriptase occur frequently in meningiomas. Objective: To estimate the prognostic importance of telomerase reverse transcriptase mutations in Colombian patients with grades II and III meningioma. Materials and methods: This was a multicenter retrospective cohort study of patients diagnosed with refractory or recurrent WHO grades II and III meningiomas, recruited between 2011 and 2018, and treated with systemic therapy (sunitinib, everolimus ± octreotide, and bevacizumab). Mutation status of the telomerase reverse transcriptase promoter was established by PCR. Results: Forty patients were included, of which telomerase reverse transcriptase mutations were found in 21 (52.5%), being C228T and C250T the most frequent variants with 87.5 % and 14.3 %, respectively. These were more frequent among patients with anaplastic meningiomas (p=0.18), with more than 2 recurrences (p=0.04); and in patients with parasagittal region and anterior fossa lesions (p=0.05). Subjects characterized as having punctual mutations were more frequently administered with everolimus, sunitinib and bevacizumab drug series (p=0.06). Overall survival was 23.7 months (CI95% 13.1-34.2) and 43.4 months (CI95% 37.5-49.3; p=0.0001) between subjects with and without mutations, respectively. Multivariate analysis showed that the number of recurrences and the presence of telomerase reverse transcriptase mutations were the only variables that negatively affected overall survival. Conclusions: Mutations in telomerase reverse transcriptase allows the identification of high-risk patients and could be useful in the selection of the best medical treatment.

Mechanisms of Resistance to First-Line Osimertinib in Hispanic Patients With EGFR Mutant Non-Small Cell Lung Cancer (FRESTON-CLICaP).

INTRODUCTION: Osimertinib is a third generation EGFR-TKI inhibitor approved in the first-line setting for patients with advanced non-small cell lung cancer (NSCLC). Additionally, it represents the treatment of choice in patients who present with T790M mutations and evidence of relapse of the disease. Effectiveness and safety of this drug have been studied in multiple clinical trials and observational studies, however, information regarding outcomes among Hispanic patients treated with Osimertinib is scarce. The objective of this study was to examine real-world effectiveness and safety of first-line Osimertinib in a cohort of Hispanic patients with NSCLC, emphasizing post-progression outcomes. METHODS: This is a multicenter, multinational, retrospective cohort study of Hispanic patients treated with Osimertinib as first-line for EGFR-mutated NSCLC. Patients with a confirmed diagnosis of metastatic EGFR-mutated NSCLC who received Osimertinib (80mg/day until evidence of disease progression or presence of intolerable adverse effects) were identified and included. NGS was performed in tumor samples or liquid biopsies among patients who had disease progression. The primary outcome was progression-free survival, and the secondary outcome was post-progression survival. RESULTS: A total of 94 patients from Mexico, Argentina, Costa Rica, Colombia, Panama, Chile and the USA were included, with a median age of 59 years. Identified mutations included EGFR Exon 19 deletions and EGFR pL858R point mutations. Median progression-free survival (PFS) was 14.4 months (95%CI 12.4-18.2 months). Lung/pleura and lymph nodes were the most common sites of progression. Median post-progression survival was 7.73 months (95%CI 4.07 months-Not reached). Factors which negatively affected PFS included presence of liver metastases at diagnosis and a tumor mutational burden > 5 mut/Mb. CONCLUSION: Treatment with first line osimertinib represents an effective and safe option for Hispanic patients with metastatic NSCLC. Liver metastases and a higher tumor mutation burden were associated with a lower PFS. Despite effectiveness, different mechanisms of resistance were identified among the patients in this cohort, including mutations which can be targeted by other therapeutic options.

STK11 and KEAP1 mutations in non-small cell lung cancer patients: Descriptive analysis and prognostic value among Hispanics (STRIKE registry-CLICaP).

BACKGROUND: Mutations in STK11 (STK11Mut) and, frequently co-occurring, KEAP1 mutations (KEAP1Mut) are associated with poor survival in metastatic Non-small Cell Lung Cancer (mNSCLC) patients treated with immunotherapy. However, there are limited data regarding the prognostic or predictive significance of these genomic alterations among Hispanics. METHODS: This retrospective study analyzed a cohort of Hispanic patients (N = 103) diagnosed with mNSCLC from the US and seven Latin American countries (LATAM) treated with immune checkpoint inhibitors (ICI) alone or in combination as first-line (Cohort A). All cases were treated in routine care between January 2016 and December 2021. The main objectives were to determine the association of mutations in STK11 or KEAP1 in these patients' tumors with overall (OS) and progression-free survival (PFS), presence of KRAS mutations, tumor mutational burden (TMB), and other relevant clinical variables. To compare outcomes with a STK11Wt/KEAP1Wt population, historical data from a cohort of Hispanic patients (N = 101) treated with first-line ICI was used, matching both groups by country of origin, gender, and Programed Death-ligand 1 (PD-L1) expression level (Cohort B). RESULTS: Most tumors had mutations only in STK11 or KEAP1 (45.6%) without KRAS co-mutation or any other genomic alteration. Besides, 35%, 8.7%, 6.8%, and 3.9% were KRASMut + STK11Mut, KRASMut + STK11Mut + KEAP1Mut, STK11Mut + KEAP1Mut, and KRASMut + KEAP1Mut, respectively. Based on KRAS status, STK11 alterations were associated with significantly lower PD-L1 expression among those with KRASWt (p = 0.023), whereas KEAP1 mutations were predominantly associated with lower PD-L1 expression among KRASMut cases (p = 0.047). Tumors with KRASMut + KEAP1Mut had significantly higher median TMB when compared to other tumors (p = 0.040). For Cohort A, median PFS was 4.9 months (95%CI 4.3-5.4), slightly longer in those with KEAP1mut 6.1 months versus STK11Mut 4.7 months (p = 0.38). In the same cohort, PD-L1 expression and TMB did not influence PFS. OS was significantly longer among patients with tumors with PD-L1 ≥ 50% (30.9 months), and different from those with PD-L1 1-49% (22.0 months), and PD-L1 < 1% (12.0 months) (p = 0.0001). When we compared the cohorts A and B, OS was significantly shorter for patients carrying STK1 [STK11Mut 14.2 months versus STK11Wt 27.0 months (p = 0.0001)] or KEAP1 [KEAP1Mut 12.0 months versus KEAP1Wt 24.4 months (p = 0.005)] mutations. PD-L1 expression significantly affected OS independently of the presence of mutations in STK11, KEAP1, or KRAS. TMB-H favored better OS. CONCLUSIONS: This is the first large Hispanic cohort to study the impact of STK11 and KEAP1 mutations in NSCLC patient treated with ICI. Our data suggest that mutations in the above-mentioned genes are associated with PD-L1 expression levels and poor OS.

p.G12C KRAS mutation prevalence in non-small cell lung cancer: Contribution from interregional variability and population substructures among Hispanics.

BACKGROUND: The KRAS exon 2 p. G12C mutation in patients with lung adenocarcinoma has been increasing in relevance due to the development and effectiveness of new treatment medications. Studies around different populations indicate that regional variability between ethnic groups and ancestries could play an essential role in developing this molecular alteration within lung cancer. METHODS: In a prospective and retrospective cohort study on samples from lung adenocarcinoma from 1000 patients from different administrative regions in Colombia were tested for the KRAS p.G12C mutation. An analysis of STR populations markers was conducted to identify substructure contributions to mutation prevalence. RESULTS: Included were 979 patients with a national mean frequency for the KRAS exon 2 p.G12C mutation of 7.97% (95%CI 6.27-9.66%). Variation between regions was also identified with Antioquia reaching a positivity value of 12.7% (95%CI 9.1-16.3%) in contrast to other regions such as Bogota DC (Capital region) with 5.4% (2.7-8.2%) and Bolivar with 2.4% (95%CI 0-7.2%) (p-value = 0.00262). Furthermore, Short tandem repeat population substructures were found for eight markers that strongly yielded association with KRAS exon 2 p.G12C frequency reaching an adjusted R2 of 0.945 and a p-value of < 0.0001. CONCLUSIONS: Widespread identification of KRAS exon 2 p.G12C mutations, especially in cases where NGS is not easily achieved is feasible at a population based level that can characterize regional and national patterns of mutation status. Furthermore, this type of mutation prevalence follows a population substructure pattern that can be easily determined by population and ancestral markers such as STR.

Efficacy of osimertinib plus bevacizumab in glioblastoma patients with simultaneous EGFR amplification and EGFRvIII mutation.

BACKGROUND: Amplification of EGFR and its active mutant EGFRvIII are common in glioblastoma (GB). While EGFR and EGFRvIII play critical roles in pathogenesis, targeted therapy with EGFR-tyrosine kinase inhibitors or antibodies has shown limited efficacy. To improve the likelihood of effectiveness, we targeted adult patients with recurrent GB enriched for simultaneous EGFR amplification and EGFRvIII mutation, with osimertinib/bevacizumab at doses described for non-small cell lung cancer. METHODS: We retrospectively explored whether previously described EGFRvIII mutation in association with EGFR gene amplification could predict response to osimertinib/bevacizumab combination in a subset of 15 patients treated at recurrence. The resistance pattern in a subgroup of subjects is described using a commercial next-generation sequencing panel in liquid biopsy. RESULTS: There were ten males (66.7%), and the median patient's age was 56 years (range 38-70 years). After their initial diagnosis, 12 patients underwent partial (26.7%) or total resection (53.3%). Subsequently, all cases received IMRT and concurrent and adjuvant temozolomide (TMZ; the median number of cycles 9, range 6-12). The median follow-up after recurrence was 17.1 months (95% CI 12.3-22.6). All patients received osimertinib/bevacizumab as a second-line intervention with a median progression-free survival (PFS) of 5.1 months (95% CI 2.8-7.3) and overall survival of 9.0 months (95% CI 3.9-14.0). The PFS6 was 46.7%, and the overall response rate was 13.3%. After exposure to the osimertinib/bevacizumab combination, the main secondary alterations were MET amplification, STAT3, IGF1R, PTEN, and PDGFR. CONCLUSIONS: While the osimertinib/bevacizumab combination was marginally effective in most GB patients with simultaneous EGFR amplification plus EGFRvIII mutation, a subgroup experienced a long-lasting meaningful benefit. The findings of this brief cohort justify the continuation of the research in a clinical trial. The pattern of resistance after exposure to osimertinib/bevacizumab includes known mechanisms in the regulation of EGFR, findings that contribute to the understanding and targeting in a stepwise rational this pathway.

Case Report: Differential Genomics and Evolution of a Meningeal Melanoma Treated With Ipilimumab and Nivolumab.

Primary melanocytic tumors of the CNS are extremely rare conditions, encompassing different disease processes including meningeal melanoma and meningeal melanocytosis. Its incidence range between 3-5%, with approximately 0.005 cases per 100,000 people. Tumor biological behavior is commonly aggressive, with poor prognosis and very low survivability, and a high recurrence rate, even after disease remission with multimodal treatments. Specific genetic alterations involving gene transcription, alternative splicing, RNA translation, and cell proliferation are usually seen, affecting genes like BRAF, TERT, GNAQ, SF3B1, and EIF1AX. Here we present an interesting case of a 59-year-old male presenting with neurologic symptoms and a further confirmed diagnosis of primary meningeal melanoma. Multiple therapy lines were used, including radiosurgery, immunotherapy, and chemotherapy. The patient developed two relapses and an evolving genetic makeup that confirmed the disease's clonal origin. We also provide a review of the literature on the genetic basis of primary melanocytic tumors of the CNS.