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Background: 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. Objective: We characterized the genomic landscape of primary resistance to osimertinib among Hispanic patients with EGFR-mutant NSCLC. Methods: 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. Results: 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% and 100% for cohorts A and B, respectively (P = 0.0001). PFS was significantly higher in cohort B (27.4 months vs. 3.1 months; P = 0.0001) and ex19del patients versus L858R (24.5 months, 95% confidence interval [CI] 18.2-NR), vs. 7.6 months, 95% CI 4.8-21.1; P = 0.001). OS was considerably lower for cohort A (20.1 months vs. 36.0 months; P = 0.0001) and was better for patients with ex19del, no brain metastasis, and low tumor mutation burden. At the time of progression, more mutations were found in cohort A, identifying off-target alterations more frequently, including TP53, RAS, and RB1. Conclusion: EGFR-independent alterations are common among patients with primary resistance to osimertinib and significantly impact PFS and OS. Our results suggest that among Hispanic patients, other variables associated with intrinsic resistance include the number of commutations, high levels AXL mRNA, and low levels of BIM mRNA, T790M de novo, EGFR p.L858R presence, and a high tumoral mutational burden.

Supplemental Material for Application of Comprehensive Genomic Profiling-Based Next-Generation Sequencing Assay to Improve Cancer Care in a Developing Country by Claudia Cifuentes, Milton Lombana, Henry Vargas, Paola Laguado, Alejandro Ruiz-Patiño, Leonardo Rojas, Uriel Navarro, Carlos Vargas, Luisa Ricaurte, Oscar Arrieta, Lucia Zatarain-Barron, Leandro Zapata, Guido González, Carlos Ortiz, Laura Bernal, Juan G. Restrepo, Lucia Viola, Fabio Grosso, Ricardo Zapata, William Mantilla, Hernán Carranza, Iván Bustillo, Néstor Llinas, Ricardo Duarte, July Rodríguez, Pilar Archila, Jenny Ávila, Maritza Bermúdez, Tatiana Gámez, Carolina Sotelo, Jorge Otero, Elkin Forero, Mauricio Lema, Catalina Limpias, Camila Ordóñez-Reyes, Sergio Mejía, Christian Rolfo, Rafael Rosell, Andrés F. Cardona; ONCOL Group and CLICaP in Cancer Control.

Background: Women living with HIV (WLHIV) are more prone to persistent infection with high-risk Human Papillomavirus (HR-HPV) and development of cervical pre-cancer and cancer. Health systems should integrate HPV and HIV services considering particularities of WLHIV when offering comprehensive cervical cancer services. Objectives: To synthesize existing knowledge on cervical cancer epidemiology, as well as access to screening and prevention among women living with HIV in the Americas Region. Methods: Five PICO questions will orient a systematic review of published literature in Medline and LILACS; supplemented with cross-referencing and search of grey literature in Trip and Google-Scholar. The protocol will follow PRISMA-P standards. Two reviewers will screen titles and abstracts independently; disagreements will be solved by consensus. Verification of eligibility based on full-text reading will be carried out. Studies finally included will be assessed for risk of bias based on standard tools by type of study. Data extraction tables will be built for every PICO question and reported in a structured format. A meta-analysis will be performed depending upon the results. Discussion: This systematic review anticipates finding valuable information for policy makers and public health actors as it aims to provide new data on a special population from the Americas region. Resumen Contexto: Las mujeres que viven con VIH (WLHIV) tienen mayor riesgo de infección persistente por virus del papiloma humano (VPH) y de desarrollar lesiones precancerosas y cáncer cervicouterino. Los sistemas de salud deben integrar servicios de VIH y VPH que contemplen las particularidades de las WLHIV. Objetivos: Sintetizar la evidencia disponible sobre epidemiología del cáncer cervicouterino y el acceso a servicios de prevención y detección temprana en WLHIV en las Américas. Métodos: Cinco preguntas PICO orientaron una revisión sistemática de literatura publicada en Medline y LILACS, complementada con referencias cruzadas y literatura gris en Trip y Google-Scholar. El protocolo seguirá los estándares de PRISMA-P. Dos investigadores revisarán títulos y resúmenes de manera independiente; los desacuerdos se resolverán por consenso. La elegibilidad se determinará mediante una revisión de texto completo. El riesgo de sesgo se evaluará con instrumentos validados. Se elaborarán tablas de extracción de datos para cada pregunta PICO y se reportarán en formato estructurado. Dependiendo de los resultados, se hará un metanálisis. Discusión: Esta revisión anticipa encontrar información valiosa para decisores y actores de salud pública, ya que proveerá información nueva sobre esta población especial en las Américas.

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.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.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 burden5 mut/Mb.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.

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.