e20761 Background: The prognostic role of serial circulating tumor DNA (ctDNA) dynamics during osimertinib treatment has been described mainly in Asian and European populations; however, it remains poorly defined in Hispanic patients with advanced EGFR-mutant non–small cell lung cancer (NSCLC). Our aim was to determine whether serial plasma EGFR testing identifies patients at high risk of early mortality. Methods: This multicenter, retrospective study included 64 Hispanic patients with stage IIIB–IV EGFR-mutant NSCLC treated with first-line osimertinib between 2018 and 2023. Tumor tissue genotyping was performed using hybrid-capture next-generation sequencing. Plasma EGFR mutations were assessed at baseline, week 8, and week 24. Overall survival (OS) and progression-free survival (PFS) were analyzed using Cox models adjusted for p53 status, RAF-pathway alterations, and metastatic burden. Results: The cohort had a median age of 61 years, with 65.6% of patients being female and 56.2% being never-smokers. Sensitizing EGFR mutations consisted mainly of exon 19 deletion (59.4%) and L858R (39.1%). Relevant co-mutations were identified in TP53 (29.7%) and RAF-pathway genes (6.2%). Plasma ctDNA remained positive in 42.2% of patients at week 8 and 22.0% at week 24. Week-8 ctDNA persistence was strongly associated with an inferior OS (HR 9.36, 95% CI 3.80–23.03, p < 0.001) after multivariable adjustment. Week-24 positivity also predicted worse OS (HR 3.34, 95% CI 1.13–9.89, p = 0.02). ctDNA status at week 8 or 24 was not significantly associated with PFS. Patients with TP53 or RAF pathway mutations demonstrated higher rates of molecular persistence. Conclusions: In Hispanic patients receiving Osimertinib, ctDNA positivity at 8-24 weeks is able to identify patients with poor survival outcomes. ctDNA monitoring may provide an early, non-invasive biomarker to guide treatment intensification and trial enrollment in EGFR-mutant NSCLC.

Background: Genetic insights from diverse populations are key to advancing cancer detection, treatment, and prevention. Unlike other Latin American countries, Colombia lacks a centralized registry for germline and somatic mutations in breast and ovarian cancer. This study describes the country’s first national variant registry, and the occurrence of recurrent mutations and potential founder effects in Colombia. Methods: To address this gap, we implemented the first capturing protocol using the REDCap system. In a group of 213 breast and/or ovarian cancer patients harboring genetic mutations, we collected genetic, clinical, and demographic data from 13 regional centers across Colombia. Statistical analyses assessed variant distribution and patient demographics. Results: Among 229 identified variants (105 germline, 124 somatic), most were classified as pathogenic or likely pathogenic (72.4% germline, 87% somatic). BRCA1 and BRCA2 accounted for the majority of recurrent mutations. Germline recurrent variants (seen >3 times) were recorded for BRCA1 (77.7%; 21/27) and BRCA2 (22.3%; 6/27). Similarly, recurrent somatic variants were identified for BRCA1 (82.6%; 38/46) and BRCA2 (17.4%; 8/46). Notably, four recurrent variants were previously reported as founder mutations: BRCA1 c.1674del (14.3% germline and 23.7% somatic), BRCA1 c.3331_3334del (33.3% germline and 52.6% somatic), BRCA1 c.5123C>A (52.4% germline and 23.7% somatic), and BRCA2 c.2808_2811del (50% germline and 50% somatic). Most cases originated from the Andean region, highlighting regional disparities. Conclusions: This registry offers the first overview of genetic variants in Colombian breast and ovarian cancer patients. Recurrent and region-specific mutations highlight the need for population-focused data to guide targeted screening and personalized care strategies.

Background:Clonality is an intrinsic phenomenon of disease evolution, with specific clones conferring increased aggressiveness. We aimed to evaluated the different divergent and unique mutational patterns in brain metastases (BM). Methods:This retrospective cohort study included patients with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma and BM. All the patients underwent three next-generation sequencing (NGS)-based genomic profiling assessments. Two analyses involved tissue samples from the lung and brain lesions, whereas the third utilized either liquid or tissue biopsy. Treatment consisted of Osimertinib and Stereotactic radiosurgery. Results:Thirty patients were included (73% female). Central nervous system (CNS) involvement was noted in 90% of the patients at diagnosis, with a median of two BM. 46% exhibited Ex19del, while the remainder had an L858R mutation. The most frequently co-mutated gene in primary lesions was TP53 (50%), followed by RBM10. All patients showed an increase in tumor mutational burden (TMB) from the primary lung lesions to the CNS metastases, rising from a median of 3.2 to 8.5 mut/Mb. Additionally, 30% of the EGFR mutations were lost. Regarding co-mutations in BM, alterations in PIK3CA/PTEN/AKT at 36%, BRAF (11%), and RB1 (13%) were presented. MET amplification was detected in 15% of cases upon systemic disease progression, while small cell transformation occurred in 7%. PIK3CA and BRAF mutations, initially found solely in BM, re-emerged in systemic disease in 16% of the cases. Conclusions:The molecular features of BM differ from those of the primary tumor. These results indicate that specific brain metastatic clones can also result in systemic progression.

PURPOSEMultidisciplinary molecular tumor boards (MTBs) decode complex genomic data into clinical recommendations. Although MTBs are well-established in the oncology practice in developed countries, this strategy needs to be better explored in developing countries. Herein, we describe the possible benefits and limitations of the first MTB established in Colombia.METHODSDemographic, clinical, and genomic information was collected between August 2020 and November 2021. By mid-2020, an MTB strategy was created to discuss clinical cases with one or more genomic alterations identified by next-generation sequencing using an open-access virtual platform. We characterized the patient population as benefiting from the recommended treatment option. We assessed the benefits and access to available targeted therapies that have the potential to change clinical management by making recommendations to treating oncologists on the basis of genomic profiling. However, we did not assess the treatment oncologists' compliance with MTB recommendations because they were not intended to replace clinical judgment/standard of care.RESULTSA total of 146 patients were included in the discussions of the MTB. The median age was 59 years, and 59.6% were women. Genomic results prompting a change in therapeutic decisions were obtained in 53.1% of patients (95% CI, 44.9 to 61.3). The most prevalent malignancy was non–small-cell lung cancer (51%). Other malignancies represented 60%, 50%, and 30% of patients with soft-tissue sarcomas, brain tumors, and breast cancer, respectively.CONCLUSIONUsing an open-access virtual platform, MTBs were feasible in low- and middle-income countries on the basis of the capability to provide the benefits and access to available targeted therapies that are not standard of care. Furthermore, MTB recommendations were made available to the treating oncologist in different locations across Colombia, providing the option to modify clinical management in most of these patients.

Epidermal growth factor receptor (EGFR) mutations (EGFRm) represent one of the most common genomic alterations identified among patients with non-small cell lung cancer (NSCLC). Several targeted agents for patients with EGFRm have been proven safe and effective, including the third-generation tyrosine kinase inhibitor (TKI) osimertinib. Nonetheless, some patients will present with or develop EGFR-TKI resistance mechanisms. We characterized the genomic landscape of primary resistance to osimertinib among Hispanic patients with EGFR-mutant NSCLC. An observational longitudinal cohort study was conducted with two groups of patients, those with intrinsic resistance (cohort A) and those with long-term survival (cohort B). All patients were treated and followed between January 2018 and May 2022. All patients were assessed for Programmed Cell Death Ligand 1 (PD-L1) expression and Bcl-2-like protein 11 (BIM)/AXL mRNA expression before starting TKI. After 8 weeks of treatment, a liquid biopsy was performed to determine the presence of circulating free DNA (cfDNA), and next-generation sequencing (NGS) was used to identify mutations at the time of progression. In both cohorts, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. We found a homogeneous distribution of EGFR-sensitizing mutations in both cohorts. For cohort A, exon 21 mutations were more common than exon 19 deletions (ex19dels) for cohort B (P = 0.0001). The reported ORR for osimertinib was 6.3

Background:DICER1 alterations are associated with intracranial tumors in the pediatric population, including pineoblastoma, pituitary blastoma, and the recently described "primary DICER1-associated CNS sarcoma" (DCS). DCS is an extremely aggressive tumor with a distinct methylation signature and a high frequency of co-occurring mutations. However, little is known about its treatment approach and the genomic changes occurring after exposure to chemoradiotherapy.Methods:We collected clinical, histological, and molecular data from eight young adults with DCS. Genomic analysis was performed by Next-generation Sequencing (NGS). Subsequently, an additional germline variants analysis was completed. In addition, an NGS analysis on post-progression tumor tissue or liquid biopsy was performed when available. Multiple clinicopathological characteristics, treatment variables, and survival outcomes were assessed.Results:Median age was 20 years. Most lesions were supratentorial. Histology was classified as fusiform cell sarcomas (50%), undifferentiated (unclassified) sarcoma (37.5%), and chondrosarcoma (12.5%). Germline pathogenic DICER1 variants were present in two patients, 75% of cases had more than one somatic alteration in DICER1, and the most frequent commutation was TP53. Seven patients were treated with surgery, Ifosfamide, Cisplatin, and Etoposide (ICE) chemotherapy and radiotherapy. The objective response was 75%, and the median time to progression (TTP) was 14.5 months. At progression, the most common mutations were in KRAS and NF1. Overall survival was 30.8 months.Conclusions:DCS is an aggressive tumor with limited therapeutic options that requires a comprehensive diagnostic approach, including molecular characterization. Most cases had mutations in TP53, NF1, and PTEN, and most alterations at progression were related to MAPK, RAS and PI3K signaling pathways.

Purpose Identifying actionable oncogenic mutations have changed the therapeutic landscape in different types of tumors. This study investigated the utility of comprehensive genomic profiling (CGP), a hybrid capture-based next-generation sequencing (NGS) assay, in clinical practice in a developing country. Methods In this retrospective cohort study, CGP was performed on clinical samples from patients with different solid tumors recruited between December 2016 and November 2020, using hybrid capture-based genomic profiling, at the individual treating physicians’ request in the clinical care for therapy decisions. Kaplan–Meier survival curves were estimated to characterize the time-to-event variables. Results Patients median age was 61 years (range: 14–87 years), and 64.7% were female. The most common histological diagnosis was lung primary tumors, with 90 patients corresponding to 52.9% of the samples (95% CI 45.4-60.4%). Actionable mutations with FDA-approved medications for specific alterations correspondent to tumoral histology were identified in 58 cases (46.4%), whereas other alterations were detected in 47 different samples (37.6%). The median overall survival was 15.5 months (95% CI 11.7 months-NR). Patients who were subjected to genomic evaluation at diagnosis reached a median overall survival of 18.3 months (95% CI 14.9 months-NR) compared to 14.1 months (95% CI 11.1 months-NR) in patients who obtained genomic evaluation after tumor progression and during standard treatment ( P = .7). Conclusion CGP of different types of tumors identifies clinically relevant genomic alterations that have benefited from targeted therapy and improve cancer care in a developing country to guide personalized treatment to beneficial outcomes of cancer patients.

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 dosrecurrencias (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.

El presente manuscrito revisa las aplicaciones actuales de la inteligencia artificial (IA) en genómica funcional. La reciente explosión de la IA sigue a los notables logros que ha hecho posible el “aprendizaje profundo”, junto con una explosión de “grandes conjuntos de datos” que pueden satisfacer su necesidad. Esto ha sido posible gracias a los enormes avances en el campo de las tecnologías de alto rendimiento, aplicadas para determinar cómo los componentes individuales de un sistema biológico trabajan juntos para lograr diferentes procesos. Las disciplinas que contribuyen a este volumen de datos se conocen colectivamente como genómica funcional. Consisten en estudios de: i) la información contenida en el ADN (genómica); ii) las modificaciones que el ADN puede sufrir de forma reversible (epigenómica); iii) las transcripciones de ARN originadas por un genoma (transcriptómica); iv) el conjunto de modificaciones químicas que decoran diferentes tipos de transcripciones del ARN (epitranscriptómica); v) los productos de las transcripciones que codifican proteínas (proteómica); y vi) las pequeñas moléculas producidas a partir del metabolismo celular (metabolómica) presentes en un organismo o sistema en un momento dado, en condiciones fisiológicas o patológicas.

Colombia is a country on the northwest of South America, and it is divided into 32 departments, a capital district, 1121 municipalities, and indigenous territories. Population growth in the period 1990 to 2016 was 42.0%, during which time population structure became regressive and older, with most living in urban areas (82%) (Fig. 1A–C). The Colombian health system is made up of a social security sector and a private sector. The system's backbone is the General Social Security Health System, with a coverage near to 100%.1Martinez-Piedra R. Quintanilla G.F. González M.A. et al.Health in the Americas. Pan Americam Health Organization.https://www.paho.org/salud-en-las-americas-2017/Date accessed: February 18, 2022Google Scholar According to data from GLOBOCAN, 6876 incident cases of lung cancer (LC) occur every year in Colombia. LC represents the sixth place among the malignant neoplasms documented annually in the country, with an estimated age-standardized incidence rate of 10.5 per 100,000 inhabitants.2World Health OrganizationCancer today. global cancer observatory.https://gco.iarc.fr/Date accessed: February 15, 2021Google Scholar LC ranked second in overall cancer mortality in both sexes, accounting for 11.8% of deaths. It was the third cause of death in men (7.1% of the total) and the fourth in women (4.7%). The country's age-adjusted rate for mortality from this cancer was 11.5 per 100,000 in men and 6.4 per 100,000 in women, with a gradual decrease in the last two decades (Fig. 2A and B).3Pardo C. De Vries E. Buitrago L. Atlas of cancer mortality in Colombia. Fourth Ed.https://www.cancer.gov.co/ATLAS_de_Mortalidad_por_cancer_en_Colombia.pdfDate: 2017Date accessed: February 14, 2022Google Scholar The highest rates were observed in men in all departments. The regions with a higher concentration of risk for LC, by standardized mortality ratio, were Antioquia and departments of the Coffee Region (Risaralda, Quindío, and Caldas). On the contrary, the areas with the lowest risk for both sexes were found in the southern departments of Nariño and Cauca. From 1994 to 2013, the mortality trend for LC in men slightly decreased in the average annual percentage change (−0.02%), but in women, it increased (0.5%).3Pardo C. De Vries E. Buitrago L. Atlas of cancer mortality in Colombia. Fourth Ed.https://www.cancer.gov.co/ATLAS_de_Mortalidad_por_cancer_en_Colombia.pdfDate: 2017Date accessed: February 14, 2022Google Scholar,4Piñeros M. Sierra M.S. Forman D. Descriptive epidemiology of lung cancer and current status of tobacco control measures in Central and South America.Cancer Epidemiol. 2016; 44: S90-S99Crossref PubMed Scopus (19) Google Scholar Exposure to occupational carcinogens and specific circumstances are factors associated with LC. Nowadays, 28 substances, work situations, and associated occupations (group I—International Agency for Research on Cancer) have been described as risk factors for LC. Furthermore, air pollution, socioeconomic status, and diet could be additional risk factors for LC.5Sierra M.S. Soerjomataram I. Forman D. Etiology of lung cancer (C33–34) in Central and South America. International Agency for Research on Cancer.https://gco.iarc.fr/includes/CSA_Chp_4-6_Lung.pdfDate accessed: February 15, 2022Google Scholar Cancer is a high-cost disease, and considering the need for real-world information with a national scope, the National Cancer Information System, managed by the High-Cost Diseases Fund (CAC), was created to improve the decision-making process through the evaluation of access to cancer diagnosis and follow-up into the National Health System (NHS).6Hernández Vargas J.A. Ramírez Barbosa P.X. Valbuena-Garcia A.M. Acuña-Merchán L.A. González-Diaz J.A. Lopes G. National cancer information system within the framework of health insurance in Colombia: a real-world data approach to evaluate access to cancer care.JCO Glob Oncol. 2021; 7: 1329-1340Crossref PubMed Scopus (2) Google Scholar According to the CAC, for 2020, LC was the seventh cause of cancer-related deaths, and it had an adjusted incidence and mortality rate of 2.89 and 3.00 per 100,000 inhabitants, respectively (Fig. 3A and B).7High cost accountColombian Fund for High-Cost Diseases. Situation of cancer in a population treated in the General System of Social Security in Health of Colombia.https://cuentadealtocosto.org/site/publicaciones/situacion-del-cancer-en-la-poblacion-adulta-atendida-en-el-sgsss-de-colombia-2020/Date accessed: February 15, 2021Google Scholar According to the National Study of Consumption of Psychoactive Substances in Colombia, carried out in 2019,8Ministerio de justicia y del derecho – observatorio de drogas de ColombiaEstudio Nacional de Consumo de Sustancias Psicoactivas Colombia 2019.https://www.unodc.org/documents/colombia/2013/septiembre/Estudio_Nacional_Consumo_1996.pdfDate accessed: February 14, 2022Google Scholar 12.1% of people surveyed declared having smoked tobacco in the last year (16.9% men and 7.6% women) (Fig. 2C) and approximately 10% reported having smoked in the previous month (13.8% men and 6% women). In addition, 5.7% of the population declared smoking daily, mainly men (8.1%), between 45 and 64 years (7.3%), and among those with less socioeconomic development (6.4%). The most frequent age of onset of tobacco use was 18 years, and 25% of people who have smoked did so for the first time at age less than 15 years. A significant percentage of the people (85%) consider smoking cigarettes as a health risk; however, teenagers see it as a minor problem. Law 1335 of 2009 sought to guarantee compliance with environments 100% free of tobacco smoke in the nation. In addition to that, it increased 100% in taxes indexed to the Consumer Price Index and the Gross Domestic Product for tobacco products and its derivatives before 2021. Besides that, the sizes of health warnings in tobacco packing have been increased.9Rivera E. Niño A. ABC of the Anti-Tobacco Law (Law 1335 of 2009).Ministry Health Soc Protect. 2009; 2: 1-8Google Scholar Some clinical trials revealed the importance of early detection of LC with low-dose radiation chest tomography (LDCT) and reduction in specific mortality from LC, resulting in the mandatory use of LDCT in high-risk populations in many countries.10de Koning H.J. van der Aalst C.M. de Jong P.A. et al.Reduced lung-cancer mortality with volume CT screening in a randomized trial.N Engl J Med. 2020; 382: 503-513Crossref PubMed Scopus (1030) Google Scholar Since 2012, the Colombian Ministry of Health has established priorities for the care of the most common cancers, LC included. In 2014, the first National Guideline for the Management of LC was published. The Guideline defined the recommendations for early detection in high-risk populations (aged 50–74 y, cigarette consumption with a pack-year index > 30, and cessation in the past 15 y).11Ministry of Health and Social Protection, Colciencias, Institute of Technological Assessment in HealthClinical practice guideline for the early detection, diagnosis, staging, and treatment of lung cancer. Guide for patients and caregivers. Guide number 36. 2014.https://www.minsalud.gov.co/sites/rid/Lists/BibliotecaDigital/RIDE/DE/CA/gpc-cancer-pulmon-padres.pdfDate accessed: February 18, 2022Google Scholar Besides the existence of standardized guidelines for screening and detecting LC in Colombia, its implementation is challenging. The main difficulties for this have been realted to a fragmented NHS, access to established programs, LDCT or specialists with knowledge of early detection, few institutions with the necessary infrastructure, and care focused on other types of cancer. Four years ago, a structured program for the early detection of LC was established in a respiratory care-focused institution at Bogotá. This is a hybrid, private program where the patient finances the costs of tests and clinical follow-up (near 300 U.S. per y). The program was implemented considering the recommendations of the American Thoracic Society and the U.S. Preventive Task Force.12Moyer V; U.S. Preventive Services Task ForceScreening for lung cancer: U.S. Preventive Services Task Force recommendation statement.Ann Intern Med. 2014; 160: 330-338PubMed Google Scholar,13American Thoracic Society, American Lung AssociationLung cancer screening, Implementation Guide.https://www.lungcancerscreeningguide.org/Date accessed: February 18, 2022Google Scholar In addition to LDCT, pulmonary function tests and advice for tobacco cessation are applied. Structured reporting of LDCT is performed using the Lung-RADS,14McKee B.J. Regis S.M. McKee A.B. Flacke S. Wald C. Performance of ACR lung-RADS in a clinical CT lung screening program.J Am Coll Radiol. 2015; 12: 273-276Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar and abnormal test results suggestive of LC are discussed in a multidisciplinary tumor board. Nowadays, the center has reached a high adherence to the program, with the main difficulties being the referral and follow-up of candidates and lung-RADS-based reading. Disease phenotypes are diverse among different latitudes. Variation in EGFR-sensitizing mutation frequencies has been widely described especially when comparing Asian with Western cohorts. In the case of Colombia, it is a nation with ancestral contributions from southeast Asia, native America, western Europe, Mediterranean, and Africa.15Chacón-Duque J.C. Adhikari K. Fuentes-Guajardo M. et al.Latin Americans show wide-spread Converso ancestry and imprint of local Native ancestry on physical appearance.Nat Commun. 2018; 9: 5388Crossref PubMed Scopus (70) Google Scholar A recent study analyzed samples from Latin American patients, including 552 nonsmoker Colombian patients. It revealed that with increased representation of native American haplotypes (southeast Asian), EGFR mutation frequency increases proportionately. Furthermore, KRAS mutation frequency was inversely associated with native American marker allelic frequency.16Carrot-Zhang J. Soca-Chafre G. Patterson N. et al.Genetic ancestry contributes to somatic mutations in lung cancers from admixed Latin American populations.Cancer Discov. 2021; 11: 591-598Crossref PubMed Scopus (27) Google Scholar Interestingly, ancestral distribution is heterogeneous across Colombia, with some regions enriching one or more of the populations mentioned previously.15Chacón-Duque J.C. Adhikari K. Fuentes-Guajardo M. et al.Latin Americans show wide-spread Converso ancestry and imprint of local Native ancestry on physical appearance.Nat Commun. 2018; 9: 5388Crossref PubMed Scopus (70) Google Scholar By evaluating the prevalence of the KRAS-G12C mutation across the LC samples, we were able to identify regional differences in terms of local prevalence. We constructed a model based on genomic identification markers using short tandem repeats to reveal that the population composition played a role in determining these variations. The model considered the different allelic frequencies of each marker across sampled regions and the corresponding local KRAS-G12C frequency. With an adjusted R2 of 0.946, the model revealed that differences in ancestral composition are highly associated with this type of mutation.17Ruiz-Patiño A. Rodríguez J. Cardona A.F. et al.p.G12C KRAS mutation prevalence in non-small cell lung cancer: contribution from interregional variability and population substructures among Hispanics.Transl Oncol. 2022; 15: 101276Crossref PubMed Scopus (1) Google Scholar We also conducted a similar study using the same short tandem repeat methodology evaluating population composition and its impact on EGFR mutations, programmed death-ligand 1 (PD-L1) expression, and ALK translocations. By analyzing more LC markers and grouping administrative regions in clusters, we also determined that the geographic distribution of tumor markers is highly associated with population composition (data in print). Another contribution of germline composition found in patients in Colombia related to the BIM gene. This polymorphism leads to anti–EGFR tyrosine kinase inhibitor (TKI) resistance. With an estimated 15.7% prevalence among EGFR-positive sample patients, it becomes relevant when considering approximately 26% of EGFR positivity in Colombia.18Cardona A.F. Rojas L. Wills B. et al.BIM deletion polymorphisms in Hispanic patients with non-small cell lung cancer carriers of EGFR mutations.Oncotarget. 2016; 7: 68933-68942Crossref PubMed Scopus (0) Google Scholar These examples of germline contributions to LC phenotypes strengthen the hypothesis of disease modulation by individual genomic composition, especially in our country. In Colombia, few institutions can implement interventional pulmonology. The main indications for bronchoscopy are the suspicion of LC, mediastinal staging, and infections (tuberculosis). Seven centers have an endobronchial ultrasound for invasive diagnosis and staging. The main difficulties are the disposition of these centers in main cities and that the personnel trained for their realization and the support personnel (pathologists and cytotechnologists) are scarce. In institutions where minimally invasive endoscopic and surgical diagnostic techniques are available (conventional bronchoscopy, endobronchial ultrasound, mediastinoscopy), these would be preferred over traditional approaches.19Murillo R. González A. Galvis J.C. et al.Radiation oncology workforce in Colombia.JCO Glob Oncol. 2020; 6: 190-194Crossref PubMed Scopus (4) Google Scholar Thoracic surgery has been a differentiated surgery specialty in Colombia since the 1950s when some thoracic surgeons trained in the United States returned to the country. In 1990, the first and only training program in General Thoracic Surgery opened. It is a 2-year program for general surgeons, and since 2009 it has had a clear emphasis on oncologic thoracic surgery. There are 86 certified thoracic surgeons across the country. The relationship with the population is one thoracic surgeon per 586,000 inhabitants, distributed in 18 department capitals. Of the 33 regions in Colombia, 15 do not have thoracic surgeons in their hospitals. In addition, 12 (14%) general thoracic surgeons are not trained in advanced minimally invasive thoracic surgery. Still, approximately 74% of the thoracic surgeons have enough learning curve in video-assisted thoracic surgery (VATS) to offer a high-quality lobectomy with a systematic or lobe-specific lymphadenectomy. Recent efforts to implement LC screening strengthen the need to advance in the performance of anatomical segmentectomies in tumors diagnosed earlier, but it is still a developing practice (Table 1).2World Health OrganizationCancer today. global cancer observatory.https://gco.iarc.fr/Date accessed: February 15, 2021Google Scholar,20Vinck E.E. General thoracic surgery as a subspecialty in Colombia.J Thorac Cardiovasc Surg. 2019; 157: 2542-2546Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 21National Cancer InstituteOncological Services in Colombia.http://www.cancer.gov.co/files/libros/archivos/Servicios Oncologicos Boletín.pdfDate accessed: February 18, 2022Google Scholar, 22Ochoa Zuluaga L.F. Informe de PASANTIA Y trabajo de grado de la maestria. En: salud pública: análisis sobre la cantidad de especialistas en el sistema de salud colombiano y la incidencia de los cupos de residencia medica sobre estos.https://repository.urosario.edu.co/bitstream/handle/10336/18305/OchoaZuluaga-Luis Fernando-2018 .pdf;jsessionid=6F2A2956172949C5F6ED917FACF3E2B0?sequence=1Date accessed: February 18, 2022Google ScholarTable 1Total Number of Specialists Related With Diagnosis or Treatment of LC in Colombia According to the National StatisticsMedical SpecialtyNumber of SpecialistsRelation With Population (Specialist/Number of Habitants)Number of Specialists Over Incident LC Cases (Specialist/New LC Cases Over Year)Pulmonologists3001/153,8001/22Interventional pulmonologists211/2.197,0001/325Medical oncologists and hemato-oncologists2181/211,6001/560Radiation oncologists1011/473,6701/68Thoracic surgeons861/586,0001/84Radiologists12801/37,3501/6Data obtained from national organizations record and Ministry of Health projections about the number of registered specialists in the country. The relation of specialist over population was obtained with the number of medical specialists over 100,000 habitants over 18 years of age and the number of specialist over incident cases was obtained with the relation of medical specialist over new LC cases in Colombia according to GLOBOCAN data.2World Health OrganizationCancer today. global cancer observatory.https://gco.iarc.fr/Date accessed: February 15, 2021Google Scholar Some of the date can underestimate the actual numbers because affiliation to associations such as the Colombian Society of Pulmonology and Thoracic Surgery, Colombian Association of Hematology and Oncology, and Colombian Association of Radiologists is not mandatory for clinical practice in the country.20Vinck E.E. General thoracic surgery as a subspecialty in Colombia.J Thorac Cardiovasc Surg. 2019; 157: 2542-2546Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar,21National Cancer InstituteOncological Services in Colombia.http://www.cancer.gov.co/files/libros/archivos/Servicios Oncologicos Boletín.pdfDate accessed: February 18, 2022Google Scholar,22Ochoa Zuluaga L.F. Informe de PASANTIA Y trabajo de grado de la maestria. En: salud pública: análisis sobre la cantidad de especialistas en el sistema de salud colombiano y la incidencia de los cupos de residencia medica sobre estos.https://repository.urosario.edu.co/bitstream/handle/10336/18305/OchoaZuluaga-Luis Fernando-2018 .pdf;jsessionid=6F2A2956172949C5F6ED917FACF3E2B0?sequence=1Date accessed: February 18, 2022Google ScholarLC, lung cancer. Open table in a new tab Data obtained from national organizations record and Ministry of Health projections about the number of registered specialists in the country. The relation of specialist over population was obtained with the number of medical specialists over 100,000 habitants over 18 years of age and the number of specialist over incident cases was obtained with the relation of medical specialist over new LC cases in Colombia according to GLOBOCAN data.2World Health OrganizationCancer today. global cancer observatory.https://gco.iarc.fr/Date accessed: February 15, 2021Google Scholar Some of the date can underestimate the actual numbers because affiliation to associations such as the Colombian Society of Pulmonology and Thoracic Surgery, Colombian Association of Hematology and Oncology, and Colombian Association of Radiologists is not mandatory for clinical practice in the country.20Vinck E.E. General thoracic surgery as a subspecialty in Colombia.J Thorac Cardiovasc Surg. 2019; 157: 2542-2546Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar,21National Cancer InstituteOncological Services in Colombia.http://www.cancer.gov.co/files/libros/archivos/Servicios Oncologicos Boletín.pdfDate accessed: February 18, 2022Google Scholar,22Ochoa Zuluaga L.F. Informe de PASANTIA Y trabajo de grado de la maestria. En: salud pública: análisis sobre la cantidad de especialistas en el sistema de salud colombiano y la incidencia de los cupos de residencia medica sobre estos.https://repository.urosario.edu.co/bitstream/handle/10336/18305/OchoaZuluaga-Luis Fernando-2018 .pdf;jsessionid=6F2A2956172949C5F6ED917FACF3E2B0?sequence=1Date accessed: February 18, 2022Google Scholar LC, lung cancer. VATS technology is available nationwide, but robotic-assisted thoracic surgery (RATS) is performed only in Bogotá. Colombia pioneered RATS in Latin America in 2012, when a trained surgeon performed the first lobectomies several years in other neighboring nations. Nevertheless, RATS lobectomy is an expensive procedure, and it is available only in three hospitals in Bogotá. The National Guidelines for LC recommend lobectomy for early stage NSCLC and induction therapy in locally advanced disease.11Ministry of Health and Social Protection, Colciencias, Institute of Technological Assessment in HealthClinical practice guideline for the early detection, diagnosis, staging, and treatment of lung cancer. Guide for patients and caregivers. Guide number 36. 2014.https://www.minsalud.gov.co/sites/rid/Lists/BibliotecaDigital/RIDE/DE/CA/gpc-cancer-pulmon-padres.pdfDate accessed: February 18, 2022Google Scholar Nevertheless, the number of surgeries with curative intent is low. Still, following these procedures, the rate of minimally invasive thoracic surgery lobectomies in Colombia is approximately 75%, most of them performed by VATS. Nowadays, more thoracic surgeons evaluate patients for possible resection of residual disease after treatment of initially unresectable disease. The general landscape of Radiation Oncology in Colombia has been changing rapidly in the last decades. In 2005, a study by the Colombian National Cancer Institute reported the availability of 14 megavoltages, 26 cobalt, and 25 brachytherapy machines to deliver radiotherapy in Colombia.21National Cancer InstituteOncological Services in Colombia.http://www.cancer.gov.co/files/libros/archivos/Servicios Oncologicos Boletín.pdfDate accessed: February 18, 2022Google Scholar In 2018, these numbers doubled and the cobalt machines were replaced with new estimates of 67 megavoltage machines and 28 brachytherapies authorized. Despite the many significant advances, there are several challenges to providing radiotherapy care for patients with LC in Colombia. For once, the amount of treatment units is insufficient to meet the country's demands, with an estimated deficit of approximately 47 megavoltage machines.21National Cancer InstituteOncological Services in Colombia.http://www.cancer.gov.co/files/libros/archivos/Servicios Oncologicos Boletín.pdfDate accessed: February 18, 2022Google Scholar Moreover, there is a high concentration of radiotherapy units in capital cities, while 11 of the 33 districts in the country do not have radiotherapy services.23Gartrelle K.J. Schaff E.M. Kirsch C. et al.Implementing surface guided stereotactic radiotherapy (SG-SRT) at One Institution in Colombia: experience of the first year of a new paradigm of radiotherapy in a developing country.Int J Radiat Oncol Biol Phys. 2020; 108: e431-e432Abstract Full Text Full Text PDF Google Scholar Furthermore, the number of radiation oncologists is significantly below the local requirements. Finally, and importantly for the treatment of LC requiring stereotactic body radiation therapy (SBRT), few of the available treatment units are dedicated radiosurgery and stereotactic machines; hence, many patients end up receiving inferior quality treatments. Nevertheless, there are plenty of reasons to believe that radiation oncology in Colombia will continue improving. First, the availability of megavoltage machines is expected to increase, some of them with the creation of a new major national cancer center. Second, thanks to the use of technologies such as surface-guided radiotherapy, it is now possible to provide LINAC-based SBRT, and it has been successfully done for the treatment of early stage LC or oligometastatic disease.23Gartrelle K.J. Schaff E.M. Kirsch C. et al.Implementing surface guided stereotactic radiotherapy (SG-SRT) at One Institution in Colombia: experience of the first year of a new paradigm of radiotherapy in a developing country.Int J Radiat Oncol Biol Phys. 2020; 108: e431-e432Abstract Full Text Full Text PDF Google Scholar Remarkably, this strategy has been increasingly adopted to upgrade the installed capacity to provide SBRT. According to the Colombian cancer situation report in 2020, most new LC cases were in advanced stages; 67.7% of LC cases were in stage IV and 15.6% in stage III.4Piñeros M. Sierra M.S. Forman D. Descriptive epidemiology of lung cancer and current status of tobacco control measures in Central and South America.Cancer Epidemiol. 2016; 44: S90-S99Crossref PubMed Scopus (19) Google Scholar Systemic therapy was administrated in 42.2% of the population, and almost 40% did not receive any active treatment (radiation, surgery, chemotherapy [CT]). The mean time between diagnosis and first treatment was 49 days, and it was longer in poor or rural populations. The distribution by histopathology subtypes was led by adenocarcinoma (80% of patients).24Alarcón M. Bruges R. Carvajal C. Vallejo C. Beltrán R. Características de los pacientes con cáncer de pulmón de célula no pequeña en el Instituto Nacional de Cancerología de Colombia.Rev Colomb Cancerol. 2011; 17: 642-647Google Scholar The selection of systemic therapy depends on the molecular characteristics of the tumor (Fig. 4). In this regard, approximately 50% to 60% of Colombian patients with LC have access to molecular profiling, usually patients who received treatment in institutions located in main Colombian cities. The molecular characterization in Colombia is focused on EGFR, ALK, and PD-L1. In the last year, reactive oxygen species (ROS) evaluation was added considering the recent local approval of Crizotinib. Data in the local cohort revealed that patients with ALK rearrangement, EGFR mutation, or PD-L1 expression greater than or equal to 50% have better overall survival than patients without these features.24Alarcón M. Bruges R. Carvajal C. Vallejo C. Beltrán R. Características de los pacientes con cáncer de pulmón de célula no pequeña en el Instituto Nacional de Cancerología de Colombia.Rev Colomb Cancerol. 2011; 17: 642-647Google Scholar In the nonmutant driver population (EGFR wild type, ALK, ROS1 negative), CT combined with immunotherapy (IO) was the most frequent systemic therapy administered.4Piñeros M. Sierra M.S. Forman D. Descriptive epidemiology of lung cancer and current status of tobacco control measures in Central and South America.Cancer Epidemiol. 2016; 44: S90-S99Crossref PubMed Scopus (19) Google Scholar The most common cytotoxic agents used were carboplatin, pemetrexed, paclitaxel, and cisplatin. Pembrolizumab was the most frequent IO used, alone or combined with CT. IO was introduced in Colombia in 2016 as second-line therapy. Furthermore, in 2017, it was approved for patients with PD-L1 greater than or equal to 50%; in 2018, in combination with CT for nonsquamous NSCLC regardless of PD-L1; and in 2019 for squamous NSCLC. The local regulatory agency (Instituto Nacional de Vigilancia de Medicamentos y Alimentos) approved other combinations of IO-CT (atezolizumab-bevacizumab-CT) in 2020 and IO-IO-CT (Checkmate 9LA regimen) more recently. For patients with EGFR mutations (nearly 22% of the population), osimertinib (most frequently used), erlotinib, gefitinib, and afatinib are approved.7High cost accountColombian Fund for High-Cost Diseases. Situation of cancer in a population treated in the General System of Social Security in Health of Colombia.https://cuentadealtocosto.org/site/publicaciones/situacion-del-cancer-en-la-poblacion-adulta-atendida-en-el-sgsss-de-colombia-2020/Date accessed: February 15, 2021Google Scholar,24Alarcón M. Bruges R. Carvajal C. Vallejo C. Beltrán R. Características de los pacientes con cáncer de pulmón de célula no pequeña en el Instituto Nacional de Cancerología de Colombia.Rev Colomb Cancerol. 2011; 17: 642-647Google Scholar Some combinations such as erlotinib plus bevacizumab, erlotinib, or gefitinib plus CT are also approved but less frequently used. It caused a concern about budget impact in NHS, considering significant differences in prices between third- and first- or second-generation agents, which could reduce their access. For patients with ALK rearrangement (10% of the population),25Arrieta O. Cardona A.F. Bramuglia G. et al.Molecular epidemiology of ALK rearrangements in advanced lung adenocarcinoma in Latin America.Oncology. 2019; 96: 207-216Crossref PubMed Scopus (17) Google Scholar crizotinib and alectinib are approved. Third-generation agents are not available, and in case of failure to crizotinib or alectinib, CT is still an option. Less frequent molecular alterations such as BRAF mutations or RET rearrangements do not have approved treatments in Colombia. There is a law figure to access medicines not available in the country, called not available-vital medicine, which consists in individual importation; however, its success is rare. The limitation to access to targeted therapies besides EGFR or ALK causes a low interest between oncologists to perform comprehensive molecular profiling in LC. In contrast, access to these therapies is unequally distributed, and it depends on the health insurance administrator company who can persuade or even deny access to treatment. At the beginning of this year, the Colombian Ministry of Health included 11 pharmacologic therapies for treatment of NSCLC in the national health plan, previously approved by the Instituto Nacional de Vigilancia de Medicamentos y Alimentos. Nevertheless, these drugs have a different financial coverage mechanism from the national health plan, limiting their real access. Among the new inclusions are five TKIs, one antiangiogenic drug (bevacizumab), five immune checkpoint inhibitors, and one CT agent for SCLC (etoposide). A significant number of these new drugs correspond to checkpoint inhibitors (anti–programmed cell death protein-1 and anti–PD-L1), facilitating access to the group of patients with NSCLC without driver mutations. For patients with driver mutations in EGFR, ALK, and ROS1, Colombia has included the TKI treatment; however, other therapies for mutations in BRAF, NTRK, or HER2 are still pending for approval. Even in clinical scenarios of NSCLC with rearrangement in ALK, only crizotinib and alectinib are available, limiting the treatment for second- or third-line therapies. So, clinicians are forced to use CT and IO as the second line with higher clinical and financial toxicity odds. In addition, in patients with NSCLC and EGFR mutation, there are no available drugs for exon-20 insertions or combinations with antiangiogenics (ramucirumab) as first line. As can be deduced, we have a heterogeneous situation in Colombia, with wide availability of options for the first line of NSCLC without oncogenic addiction, but with essential limitations for almost 40% of patients who have driver mutations, not only in terms of their treatment but also in the possibility of molecular profiling at the beginning of the therapeutic process. Andrés F. Cardona: Conceptualization, Methodology, Validation, Formal analysis, Data curation, Writing—original draft, Supervision. Sergio A. Mejía, Lucia Viola, Leonardo Rojas Alejandro Ruíz-Patiño: Conceptualization, Writing—original draft. Diego F. Chamorro: Data curation, Resources, Writing—original draft, Writing—review and editing. Adriana Serna, Stella Martínez: Formal analysis, Writing—original draft. Álvaro Muñoz, July Rodríguez, Juan E. García-Robledo, Luis Eduardo Pino, Zyanya Lucia Zatarain-Barrón: Formal analysis, Data curation. Oscar Arrieta: Conceptualization, Methodology, Writing—review and editing.

Background: Mutations in STK11 (STK11(Mut)) and, frequently co-occurring, KEAP1 mutations (KEAP1(Mut)) 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 STK11(Wt)/KEAP1(Wt) 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 KRAS(Mut) + STK11(Mut), KRAS(Mut) + STK11(Mut) + KEAP1(Mut), STK11(Mut) + KEAP1(Mut), and KRAS(Mut) + KEAP1(Mut), respectively. Based on KRAS status, STK11 alterations were associated with significantly lower PD-L1 expression among those with KRAS(Wt) (p = 0.023), whereas KEAP1 mutations were predominantly associated with lower PD-L1 expression among KRAS(Mut) cases (p = 0.047). Tumors with KRAS(Mut) + KEAP1(Mut) 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 KEAP1(mut) 6.1 months versus STK11(Mut) 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 [STK11(Mut) 14.2 months versus STK11(Wt) 27.0 months (p = 0.0001)] or KEAP1 [KEAP1(Mut) 12.0 months versus KEAP1(Wt) 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.

Introduction: Mutations in the promoter region of telomerase reverse transcriptase occur frequently in meningiomas. Objective: To estimate the prognostic value of telomerase reverse transcriptase mutations in Colombian patients with grade II and III meningioma. Materials and methods: Multicenter retrospective cohort study of patients diagnosed with refractory or recurrent WHO grade II and III meningioma, recruited between 2011 and 2018, managed with systemic therapy (sunitinib, everolimus +/-octreotide and bevacizumab). Mutation status of the telomerase reverse transcriptase promoter was performed by PCR. Results: 40 patients were included, of which telomerase reverse transcriptase mutations were found in 21 (52.5%), the most frequent variants being C228T and C250T, 87.5% and 14.3%, respectively. These were more frequent among patients with anaplastic meningiomas (p = 0.18), with >2 recurrences (p = 0.04), and in lesions of the parasagittal region and anterior fossa (p = 0.05). Subjects characterized as having punctual alterations were more frequently exposed to the sequence E -Su -Bev (p = 0.06). OS after initiation of medical treatment was 23.7 months (95% CI 13.1-34.2) and 43.4 months (95% CI 37.5-49.3; p = 0.0001) between subjects with and without mutations, respectively. In multivariate analysis, it was shown that only the number of recurrences and the presence of telomerase reverse transcriptase mutations negatively affected OS. Conclusions: Telomerase reverse transcriptase allows identifying high-risk patients and could be useful to select the best sequence of medical treatment.

Abstract Inherited lung cancer risk, particularly in nonsmokers, is poorly understood. In particular, the frequency of somatic EGFR and KRAS mutations in lung cancer varies by ethnicity. Somatic EGFR mutation rates are higher in lung cancers from patients with East Asian ancestry and lower in patients with European or African ancestry. Somatic KRAS mutation rates show the opposite pattern. In patients from Latin America, somatic lung cancer EGFR mutation rates vary by country, highest in countries with more Native American ancestry. To ask whether the somatic genome in lung cancer is affected by ethnicity related germline risk, we studied genomes from 1,153 lung cancers from Mexico and Colombia. This study revealed striking associations between ancestry and somatic lung cancer alterations, including tumor mutational burden, and specific driver mutations in EGFR, KRAS, and STK11. A local ancestry score was more strongly correlated with EGFR mutation frequency compared with global ancestry correlation, suggesting that germline genetics (rather than environmental exposure) underlie these disparities. Our study suggests that the variation in EGFR and KRAS mutation frequency in lung cancer is associated with genetic ancestry in patients from Latin America, and suggests further studies to identify germline alleles that underpin this association. If we find a germline locus, this might help in improving lung cancer prevention and screening for populations of Latin American origin and others. Furthermore, multiple studies now highlight the special importance of EGFR mutation screening and EGFR-directed targeted therapy for lung cancer patients in Latin America and with origins in Latin America. Citation Format: Jian Carrot-Zhang, Giovanny Soca-Chafre, Nick Patterson, Aaron Thorner, Anwesha Nag, Jacqueline Watson, Giulio Genovese, July Rodriguez, Maya Gelbard, Luis Corrales-Rodriguez, Yoichiro Mitsuishi, Gavin Ha, Joshua Campbell, Geoffrey Oxnard, Oscar Arrieta, Andres Cardona, Alexander Gusev, Matthew Meyerson. Genetic ancestry and lung cancer somatic mutations in patients of Latin American descent: Etiology and treatment implications [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr IA-07.

La oncología de precisión, definida como la perfilación molecular de los tumores para identificar alteraciones modulables, se ha desarrollado rápidamente para integrarse en la práctica clínica. Las pruebas genómicas involucran diversas partes interesadas que trabajan coordinada y articuladamente para controlar la logística de las muestras de tejido tumoral y desarrollar las pruebas en laboratorios con altos parámetros de calidad, donde el análisis apropiado conduce a resultados reproducibles. Los médicos deben estar familiarizados con las variantes genómicas informadas y con la tecnología utilizada para determinarlas, incluidas las limitaciones de los informes y las metodologías actuales. La interpretación de los hallazgos genómicos se realiza de manera óptima gracias al aporte multidisciplinario, necesario para reducir la incertidumbre de las recomendaciones relacionadas con las variantes documentadas. Los genes 1/2/3 del receptor neurotrópico de la quinasa para la tropomiosina (NTRK) codifican las quinasas del receptor de tropomiosina (TRK) A/B/C, respectivamente. Los reordenamientos cromosómicos que causan fusiones del gen NTRK pueden dar como resultado la activación constitutiva de las proteínas TRK, que actúan como impulsores oncogénicos a través de la activación de diversas vías de crecimiento celular. Las fusiones del gen NTRK ocurren en ~0,3 % de los tumores sólidos, aunque su incidencia varía según el tipo de cáncer. Su prevalencia es >90 % en algunas neoplasias raras como el carcinoma secretor de mama y el carcinoma secretor análogo de la glándula salivar (MASC). Los inhibidores de TRK (larotrectinib, entrectinib y repotrectinib) son activos en los tumores positivos para la fusión de NTRK, y han permitido cambiar el curso natural de múltiples enfermedades. El artítuculo desarrolla una revisión integral sobre la perspectiva de la medicina de precisión y su implementación en pacientes pediátricos y adultos con genes de fusión NTRK en Colombia.

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.

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.

PURPOSE BIM activation is essential for epidermal growth factor receptor ( EGFR)-tyrosine kinase inhibitor (TKI)–triggered apoptosis in EGFR-mutant non–small-cell lung cancer (NSCLC). A deletion in the intron two of the BIM gene results in generation of alternatively spliced isoforms that impairs their apoptotic response to TKIs, conferring the NSCLC cells intrinsic resistance to these medications. Patients with both alterations have poor clinical evolution. The current study aimed to investigate the clinical efficacy and tolerability of EGFR-TKIs plus bevacizumab (Bev) versus EGFR-TKIs alone as first-line treatment in advanced NSCLC patients with EGFR mutations and BIM deletions ( BIMdel). MATERIALS AND METHODS A retrospective analysis was conducted. BIMdel was detected using polymerase chain reaction analysis and direct sequencing of DNA. BIM protein expression was investigated by immunohistochemistry, and BIM mRNA levels by reverse transcriptase-polymerase chain reaction. Clinical characteristics, overall survival, progression-free survival (PFS), overall response rate (ORR), and treatment-related adverse events were compared between both groups. RESULTS Thirty-three patients were included; 15 received EGFR-TKIs, and 18 received EGFR-TKIs plus Bev. The median age was 63 years, with a majority of recruited female patients. All included individuals had an Eastern Cooperative Oncology Group performance score of 2 or less. The addition of Bev resulted in a significantly higher ORR (94.4% v 40%, P > .001). Median PFS was longer with the use of the combination therapy (11.12 v 7.87 months; P = .001). Median overall survival tended to be longer in the EGFR-TKIs plus Bev (30.9 v 25.4 months; P = .06) but failed to reach statistical significance. Response in terms of both partial and complete as well as overall favorably affected PFS. CONCLUSION EGFR-TKIs plus Bev conferred a significantly higher ORR and PFS in advanced NSCLC patients with EGFR mutation and BIMdel. Further prospective studies are needed to validate these findings.