Molecular Tumor Board Improves Outcomes for Hispanic Patients With Advanced Solid Tumors.

PURPOSE: Multidisciplinary 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. METHODS: Demographic, 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. RESULTS: A 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. CONCLUSION: Using 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.

DICER1-associated central nervous system sarcoma: A comprehensive clinical and genomic characterization of case series of young adult patients.

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.

Application of Comprehensive Genomic Profiling-Based Next-Generation Sequencing Assay to Improve Cancer Care in a Developing Country.

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.

Genomic Landscape of Primary Resistance to Osimertinib Among Hispanic Patients with EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC): Results of an Observational Longitudinal Cohort Study.

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.

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.

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.

Characteristics and outcomes of thymomas in Latin America: Results from over 10 years of experience (CLICaP-LATimus).

BACKGROUND: Thymomas are a group of rare neoplasms of the anterior mediastinum. The objective of this study was to describe the demographics, clinical characteristics and treatment approaches in Latin America. METHODS: This was a retrospective multicenter cohort study including patients with histologically proven thymomas diagnosed between 1997 and 2018. Demographics, clinicopathological characteristics and therapeutic outcomes were collected locally and analyzed in a centralized manner. RESULTS: A total of 135 patients were included. Median age at diagnosis was 53 years old (19-84), 53.3% (n = 72) of patients were female and 87.4% had an ECOG performance score ranging from 0-1. A total of 47 patients (34.8%) had metastatic disease at diagnosis. Concurrent myasthenia gravis occurred in 21.5% of patients. Surgery was performed in 74 patients (54.8%), comprising 27 (20%) tumorectomies and 47 (34.8%) thymectomies. According to the Masaoka-Koga system, overall survival (OS) at five-years was 73.4%, 63.8% and 51%, at stages I-II, III-IVA and IVB, respectively (p = 0.005). Furthermore, patients with low lactate dehydrogenase (LDH) (≤373 IU/L) at baseline and myasthenia gravis concurrence showed significantly better OS (p = 0.001 and p = 0.008, respectively). In multivariate analysis, high LDH levels (HR 2.8 [95% confidence interval [CI]: 1.1-7.8]; p = 0.036) at baseline and not performing a surgical resection (HR 4.1 [95% CI: 1.3-12.7]; p = 0.016) were significantly associated with increased risk of death. CONCLUSIONS: Our data provides the largest insight into the clinical characteristics and outcomes of patients with thymomas in Latin America. Survival in patients with thymomas continues to be very favorable, especially when subjected to adequate local control.

EGFR Inhibitors Plus Bevacizumab are Superior Than EGFR Inhibitors Alone as First-Line Setting in Advanced NSCLC With EGFR Mutations and BIM Deletion Polymorphisms (BIM-CLICaP).

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.

Antibiotics impair immune checkpoint inhibitor effectiveness in Hispanic patients with non-small cell lung cancer (AB-CLICaP).

BACKGROUND: The intestinal microbiota is an important factor in modulating immune-mediated tumor cell destruction. Alterations in the microbiome composition have been linked to reduced efficacy of immune checkpoint inhibitor (ICI) therapies. Therefore, antibiotic treatment (ATB), which modifies the diversity of the gut bacteria populations, could lead to a reduced efficacy of ICI treatments. METHODS: This was a retrospective cohort study. Patients with advanced non-small cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 (PD-L1) alone, or in combination in three different countries in Latin America were included. After identification, patients were placed into three groups: Non-ATB exposed (no-ATB), exposed within 30 days of the first dose of ICI (pre-ICI ATB) and patients receiving ATB concomitantly with ICI (ICI-ATB). Progression-free survival (PFS), overall survival (OS) and response rates to treatment with ICI were assessed. RESULTS: A total of 140 patients were included, of which 32 patients (23%) received ATB treatment. The most common ATB types were fluoroquinolones and B-lactams. No differences in survival according to antibiotic type were identified. Median OS in patients not exposed to ATB was 40.6 months (95% CI: 32-67.7), compared with 20.3 months (95% CI: 12.1-non-reached [NR]) for patients with pre-ICI ATB treatment and 24.7 months (95% CI: 13-NR) for patients treated with ATB concomitantly with ICI. There were no significant differences in terms of PFS, or response rates across all treatment groups. CONCLUSIONS: Antibiotic treatment was associated with reduced OS in Hispanic patients with NSCLC treated with ICIs.

Immunotherapy at any line of treatment improves survival in patients with advanced metastatic non-small cell lung cancer (NSCLC) compared with chemotherapy (Quijote-CLICaP).

BACKGROUND: To compare survival outcomes of patients with advanced or metastatic non-small cell lung cancer (NSCLC) who received immunotherapy as first-, second- or beyond line, versus matched patients receiving standard chemotherapy with special characterization of hyperprogressors. METHODS: A retrospective cohort study of 296 patients with unresectable/metastatic NSCLC treated with either, first-, second-, third- or fourth-line of immunotherapy was conducted. A matched comparison with a historical cohort of first-line chemotherapy and a random forest tree analysis to characterize hyperprogressors was conducted. RESULTS: Median age was 64 years (range 34-90), 40.2% of patients were female. A total of 91.2% of patients had an Eastern Cooperative Oncology Group (ECOG) performance score ≤ 1. Immunotherapy as first-line was given to 39 patients (13.7%), second-line to 140 (48.8%), and as third-line and beyond to 108 (37.6%). Median overall survival was 12.7 months (95% CI 9.67-14 months) and progression-free survival (PFS) of 4.27 months (95% CI 3.97-5.0). Factors associated with increased survival included treatment with immunotherapy as first-line (P < 0.001), type of response (P < 0.001) and PD-L1 status (P = 0.0039). Compared with the historical cohort, immunotherapy proved to be superior in terms of OS (P = 0.05) but not PFS (P = 0.2). A total of 44 hyperprogressors were documented (19.8%, [95% CI 14.5-25.1%]). Leukocyte count over 5.300 cells/dL was present in both hyperprogressors and long-term responders. CONCLUSIONS: Patients who receive immune-checkpoint inhibitors as part of their treatment for NSCLC have better overall survival (OS) compared with matched patients treated with standard chemotherapy, regardless of the line of treatment.

Genotyping Squamous Cell Lung Carcinoma in Colombia (Geno1.1-CLICaP).

BACKGROUND: Lung cancer is a public health problem, and squamous cell carcinoma (SCC) is the second most prevalent subtype of this neoplasm. Compared to other subtypes, including adenocarcinoma, SCC is less well understood in terms of molecular pathogenesis, limiting therapeutic options among targeted agents approved for other disease subgroups. In this study, we sought to characterize the SCC genomic profile using a validated Next Generation Sequencing (NGS) platform. METHODS: The comprehensive NGS assay (TruSight Tumor 170) was used in order to target the full coding regions of 170 cancer-related genes on SCC samples. PD-L1 expression in tumor cells (TCs) was assessed using clone 22C3 (Dako). Clinical outcomes were correlated with molecular profile, including progression free survival (PFS), overall response rate (ORR), and overall survival (OS). RESULTS: A total of 26 samples were included, median age was 67 years (r, 33-83) and 53.8% were men. Tobacco consumption was identified in all subjects (mean 34-year package). For first-line treatment 80.8% of patients received cisplatin or carboplatin plus gemcitabine. In terms of molecular profile, we identified a high prevalence of inactivating mutations in TP53 (61.5%), PIK3CA (34.6%), MLL2 (34.6%), KEAP1 (38.4%), and NOTCH1 (26.9%). PD-L1 expression ranged from negative, 1, 2-49, and ≥50% in 23.1, 38.5, 26.9, and 11.5%, respectively. Interestingly, the genetic alterations did not have an effect in PFS, OS or ORR in this study. However, PDL1 expression was higher among those who had mutations in TP53 (p = 0.037) and greater expression of PDL1 was related to PIK3CA alterations (p = 0.05). CONCLUSIONS: The genomic profile of SCC encompasses important genes including TP53, PIK3CA and KEAP1. TP53 mutations could be associated with PDL1 expression, generating hypothesis regarding specific treatment options.

Multigene Mutation Profiling and Clinical Characteristics of Small-Cell Lung Cancer in Never-Smokers vs. Heavy Smokers (Geno1.3-CLICaP).

Objectives: Lung cancer is a heterogeneous disease. Presentation and prognosis are known to vary according to several factors, such as genetic and demographic characteristics. Small-cell lung cancer incidence is increasing in never-smokers. However, the disease phenotype in this population is different compared with patients who have a smoking history. Material and Methods: To further investigate the clinical and genetic characteristics of this patient subgroup, a cohort of small cell lung cancer patients was divided into smokers (n = 10) and never/ever-smokers (n = 10). A somatic mutation profile was obtained using a comprehensive NGS assay. Clinical outcomes were compared using the Kaplan-Meier method and Cox proportional models. Results: Median age was 63 years (46-81), 40% were men, and 90% had extended disease. Smoker patients had significantly more cerebral metastases (p = 0.04) and were older (p = 0.03) compared to their non-smoker counterparts. For never/ever smokers, the main genetic mutations were TP53 (80%), RB1 (40%), CYLD (30%), and EGFR (30%). Smoker patients had more RB1 (80%, p = 0.04), CDKN2A (30%, p = 0.05), and CEBPA (30%, p = 0.05) mutations. Response rates to first-line therapy with etoposide plus cisplatin/carboplatin were 50% in smokers and 90% in never/ever smokers (p = 0.141). Median overall survival was significantly longer in never smokers compared with smokers (29.1 months [23.5-34.6] vs. 17.3 months [4.8-29.7]; p = 0.0054). Never/ever smoking history (HR 0.543, 95% CI 0.41-0.80), limited-stage disease (HR 0.56, 95% CI 0.40-0.91) and response to first-line platinum-based chemotherapy (HR 0.63, 95% CI 0.60-0.92) were independently associated with good prognosis. Conclusion: Our data supports that never/ever smoker patients with small-cell lung cancer have better prognosis compared to their smoker counterparts. Further, patients with never/ever smoking history who present with small-cell lung cancer have a different mutation profile compared with smokers, including a high frequency of EGFR, MET, and SMAD4 mutations. Further studies are required to assess whether the differential mutation profile is a consequence of a diverse pathological mechanism for disease onset.

Characteristics and long-term outcomes of advanced pleural mesothelioma in Latin America (MeSO-CLICaP).

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive tumor, associated with poor prognosis. There is a lack of information about the clinical and pathological features related with survival in the Latin American population. METHODS: The MeSO-CLICaP registry identified 302 patients with advanced MPM diagnosed and treated between January 2008 and March 2016. The Cox model was applied to determine the variables associated with survival. A random forest tree model was built to predict the response to first-line chemotherapy among Latin American patients. RESULTS: The median age was 61.1 years (SD 10.6 years), 191 (63.2%) were men, 65.9% were ever smokers, and 38.7% had previous exposure to asbestos. A total of 237 (78.5%) had epithelioid tumors, and 188 (62.3%) and 114 (37.7%) cases had stage III or IV MPM, respectively. A total of 49 patients (16.2%) underwent pleurectomy, 57 (18.9%) received radiotherapy, and 279 patients received first-line platinum-based chemotherapy. The overall response rate to first-line chemotherapy was 40.4%, progression-free survival to first-line treatment was 5.7 months (95% CI 4.9-6.5), and 63 (20.8%) patients had pemetrexed maintenance. The median overall survival was 16.8 months (95% CI 13.0-20.5), and multivariate analysis found that stage (P = 0.013), and pleurodesis (P = 0.048), were independent prognostic factors for first-line overall survival. The model to predict response to first-line chemotherapy obtained a 0.98 area under the curve, a sensitivity of 93%, and a specificity of 95% for detecting responders and non-responders. CONCLUSION: This study identifies factors associated with clinical benefit from chemotherapy among advanced MPM Latin American patients, emphasizing the impact of histology and the clinical benefit of chemotherapy on outcomes.

EGFR Amplification and Sensitizing Mutations Correlate with Survival in Lung Adenocarcinoma Patients Treated with Erlotinib (MutP-CLICaP).

BACKGROUND: Non-small cell lung cancer (NSCLC) has a 5-year survival of 5-16%. Epidermal growth factor receptor (EGFR) mutations, in most cases, confer sensitivity to EGFR tyrosine kinase inhibitor (TKI) therapy. Nonetheless, it is still unclear why clinical outcomes vary among patients with identical EGFR mutations. The amplification of the EGFR gene (EGFRamp) may play a significant role. OBJECTIVE: Compare the complete (CR) and partial response (PR) rates, overall survival (OS), and progression-free survival (PFS) in Hispanic patients with lung adenocarcinoma treated with erlotinib with EGFR mutations (L858R or exon 19 deletion [Del19]) with and without concomitant EGFRamp. PATIENTS AND METHODS: Seventy-two EGFR-positive lung adenocarcinoma patients of Hispanic origin, who underwent first-line treatment with erlotinib, were evaluated for EGFRamp by fluorescence in situ hybridization (FISH). The clinical outcomes were analyzed according to EGFR mutations and EGFRamp status. RESULTS: 30.6% of samples showed EGFRamp, more frequently present in patients with Del19 (p = 0.05). Patients with EGFRamp had a longer PFS (in months) [(28.5, 95% CI 22.3-34.6) vs. (11.0, 95% CI 8.2-16.7); p = 0.002] and OS [(37.8, 95% CI 30.9-44.7) vs. (27.1, 95% CI 12.8-41.3); p = 0.009] than those without. EGFRamp significantly influenced the response to erlotinib (p = 0.0001). EGFRamp+/Del19 had a longer OS, 37.8 (95% CI 31.0-44.6), compared to EGFRamp+/L8585R, 27.5 (95% CI 12.4-42.5) (p < 0.001) and longer PFS (p = 0.043). CONCLUSION: Among Hispanic patients, EGFRamp was present in 30% of patients with EGFR mutations. EGFR mutations and EGFRamp are associated with better OS, PFS, CR, and PR to erlotinib and, hence, could aid in the correct selection of patients that benefit from EGFR TKI treatment.

Acquired Resistance to Erlotinib in EGFR Mutation-Positive Lung Adenocarcinoma among Hispanics (CLICaP).

BACKGROUND: Lung cancer harboring epidermal growth factor receptor (EGFR) mutations and treated with EGFR tyrosine kinase inhibitors (TKIs) all eventually develop acquired resistance to the treatment, with half of the patients developing EGFR T790M resistance mutations. OBJECTIVE: The purpose of this study was to assess histological and clinical characteristics and survival outcomes in Hispanic EGFR mutated lung cancer patients after disease progression. PATIENTS AND METHODS: EGFR mutation-positive lung cancer patients (n = 34) with acquired resistance to the EGFR-TKI erlotinib were identified from 2011 to 2015. Post-progression tumor specimens were collected for molecular analysis. Post-progression interventions, response to treatment, and survival were assessed and compared among all patients and those with and without T790M mutations. RESULTS: Mean age was 59.4 ± 13.9 years, 65% were never-smokers, and 53% had a performance status 0-1. All patients received erlotinib as first-line treatment. Identified mutations included: 60% DelE19 (Del746-750) and 40% L858R. First-line erlotinib overall response rate (ORR) was 61.8% and progression free survival (PFS) was 16.8 months (95% CI: 13.7-19.9). Acquired resistance mutations identified were T790M mutation (47.1%); PI3K mutations (14.7%); EGFR amplification (14.7%); KRAS mutation (5.9%); MET amplification (8.8%); HER2 alterations (5.9%, deletions/insertions in e20); and SCLC transformation (2.9%). Of patients, 79.4% received treatment after progression. ORR for post-erlotinib treatment was 47.1% (CR 2/PR 14) and median PFS was 8.3 months (95% CI: 2.2-36.6). Median overall survival (OS) from treatment initiation was 32.9 months (95% CI: 30.4-35.3), and only the use of post-progression therapy affected OS in a multivariate analysis (p = 0.05). CONCLUSIONS: Hispanic patients with acquired resistance to erlotinib continued to be sensitive to other treatments after progression. The proportion of T790M+ patients appears to be similar to that previously reported in Caucasians.

Cáncer de mama: Hallazgos en la resonancia magnética según tipo histológico y modificación de la conducta terapéutica / Role of Magnetic Resonance in Modifying the Therapeutic Approach in Patients with Diagnosis of Breast Cancer and MRI Findings According to the Histological Subtype

Introducción: La resonancia magnética (RM) es importante en el proceso de diagnóstico, estadificación y tratamiento del cáncer de mama, aporta información valiosa del tamaño tumoral y el grado de extensión local. Objetivo: Describir el porcentaje de cambio de conducta terapéutica en relación con los hallazgos de la RM en pacientes con cáncer de mama confirmado. Métodos: Estudio observacional de corte transversal en pacientes con diagnóstico confirmado. Se clasificaron las variables en datos demográficos, clínicos y resultados de pruebas diagnósticas. La principal variable fue la intención terapéutica, medida antes y después de cada estudio. El análisis descriptivo de las variables cuantitativas se realizó con medidas de tendencia central y dispersión; y en las cualitativas, con distribuciones de frecuencias absolutas y relativas. Resultados: Se analizaron 107 pacientes con diagnóstico confirmado de cáncer de mama (edad promedio de 50,6 años [±10,4]). El subtipo histológico más frecuente fue el cáncer ductal infiltrante (69,1 %) seguido por el lobulillar infiltrante (13 %). La estadificación tumoral fue la indicación más común de la RM (74,7 %). Se encontró cambio de actitud terapéutica en el 21,5 % de los casos. Conclusión: Se confirma la importancia de la RM para la toma de decisiones, demuestra cambio en una de cada cuatro pacientes de esta serie. Se debería contemplar como un estudio indispensable en todas las mujeres que requieran estadificación de su patología previo a la toma de una conducta terapéutica

Introduction: MRI is important in diagnosis and staging of breast cancer, providing information on tumor size and degree of local extension, key findings when defining a therapeutic approach. Objective: To describe the percentage of change in the therapeutic conduct in relation to imaging findings in MRI. Methods: Observational cross-sectional study in patients with a confirmed diagnosis of breast cancer who underwent MRI. The variables were classified into demographic and clinical data and diagnostic test results. The main variable was the therapeutic intent, measured before and after each study. The descriptive analysis of quantitative variables was performed with measures of central tendency and dispersion; and qualitative distributions of absolute and relative frequencies. Results: 107 patients with confirmed breast cancer were analyzed, (average age of 50.6 years(± 10.4)). The most common histological subtype was infiltrating ductal cancer (69.1 %) followed by infiltrating lobular cancer (13 %). The most common indication for MRI was tumor staging (74.7 %). Of the total number of patients included, a change in therapeutic approach was found in 21.5 % of cases. Conclusions: The importance of MRI in modifying the therapeutic approach is confirmed, demonstrating this shift in one of every four patients. MRI should be seen as an indispensable study in all women requiring staging of their pathology previous to deciding a therapeutic approach.

BIM deletion polymorphisms in Hispanic patients with non-small cell lung cancer carriers of EGFR mutations.

BACKGROUND: Germline alterations in the proapoptotic protein Bcl-2-like 11 (BIM) can have a crucial role in diverse tumors. To determine the clinical utility of detecting BIM deletion polymorphisms (par4226 bp/ par363 bp) in EGFR positive non-small-cell lung cancer (NSCLC) we examined the outcomes of patients with and without BIM alterations. RESULTS: BIM deletion was present in 14 patients (15.7%). There were no significant differences between patients with and without BIM-del in clinical characteristics or EGFR mutation type; however, those with BIM-del had a worse overall response rate (ORR) to erlotinib (42.9% vs. 73.3% in patients without BIM-del; p=0.024) as well as a significantly shorter progression-free survival (PFS) (10.8 BIM-del+ vs. 21.7 months for patients without BIM-del; p=0.029) and overall survival (OS) (15.5 BIM-del+ vs. 34.0 months for patients without BIM-del; p=0.035). Multivariate Cox regression analysis showed that BIM-del+ was an independent indicator of shorter PFS (HR 3.0; 95%CI 1.2-7.6; p=0.01) and OS (HR 3.4; 95%CI 1.4-8.3; p=0.006). METHODS: We studied 89 NSCLC Hispanic patients with EGFR mutation who were treated with erlotinib between January 2009 and November 2014. BIM deletion polymorphisms (BIM-del) was analyzed by PCR in formalin-fixed paraffin-embedded (FFPE) tissues of tumor biopsies. We retrospectively analyzed clinical characteristics, response rate, toxicity, and outcomes among patients with and without BIM-del. CONCLUSIONS: The incidence of BIM-del found in Hispanic patients is similar to that previously described in Asia. This alteration is associated with a poor clinical response to erlotinib and represents an independent prognostic factor for patients who had NSCLC with an EGFR mutation.

Valor pronóstico de la densidad microvascular y de la expresión del VEGF, EGFR y HIF-1α en pacientes con cáncer de cérvix localmente avanzado tratados con quimiorradiación (ONCOLGroup)§ / Prognostic value of microvascular density and expression of VEGF, EGFR and HIF-1α in patients with locally advanced cervical cancer treated with chemoradiation (ONCOLGroup)§

Introducción: en Colombia el carcinoma de cuello uterino representa la segunda causa de muerte por cáncer entre las mujeres. Objetivo: describir el valor pronóstico de la densidad microvascular (DMV) y de la expresión proteica de varios genes relacionados con la supervivencia y proliferación del cáncer de cérvix localmente avanzado tratado con quimiorradiación/braquiterapia intracavitaria. Se estimaron la tasa de respuesta global (TRG), la supervivencia libre de progresión (SLP) y la supervivencia global (SG). Resultados: se incluyeron 61 mujeres con una edad media de 52 ± 10 años; todas tenían diagnóstico de cáncer de cérvix localmente avanzado (IIA 2.3%/IIB 47.5%/IIIA 4.9%/IIIB 37.7%/IVA 3.3%/no definido 3.3%), con un volumen tumoral promedio de 6.4cm (DE± 1.8cm) e infección por VPH en 46% de los casos; 58 sujetos (95%) tenían un patrón escamoso, dos fueron adenocarcinomas y >50% presentaba neoplasias moderada o pobremente diferenciadas. Todas fueron tratadas con quimiorradiación (interrupción transitoria de la teleterapia por toxicidad y otras causas en 19 y 21.4%, respectivamente/media de ciclos de platino concomitante 4.8 series ± 1.0) y braquiterapia (77% completaron el tratamiento intracavitario). La mediana para la SLP y global fue de 6.6 meses (4.0-9.1) y 30 meses (1148), respectivamente. Ninguna de las variables tuvo efecto sobre la SLP, mientras el análisis multivariado demostró que los niveles de expresión del VEGF (p=0.026), EGFR (p=0.030), y el volumen tumoral <6 cm (p=0.02) influyeron sobre este desenlace. Conclusión: la tipificación de genes relacionados con angiogénesis y proliferación celular en el cáncer de cérvix localmente avanzado tratado con quimiorradiación basada en platino tiene una influencia positiva sobre el pronóstico. (Acta Med Colomb 2012; 37: 106-117).

Introduction: cervical carcinoma is the second leading cause of cancer death among women in Colombia. Objective: to describe the prognostic value of microvascular density (MVD) and protein expression of several genes related to survival and proliferation of locally advanced cervical cancer (LACC) treated with chemoradiation / intracavitary brachytherapy. We estimated the overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: we included 61 women with a mean age of 52 ± 10 years; all were diagnosed with locally advanced cervical cancer (IIA 2.3% / IIB 47.5% / IIIA 4.9% / IIIB 37.7% / IVA 3.3% / 3.3% undefined ), with an average tumor volume of 6.4cm (SD ± 1.8cm) and HPV infection in 46% of cases. 58 subjects (95%) had a squamous pattern; two were adenocarcinomas and >50% had moderate or poorly differentiated neoplasms. All were treated with chemoradiation (temporary interruption of teletherapy due to toxicity, and other causes was documented in 19% and 21.4% respectively / mean of concomitant platinum cycles 4.8 ± 1.0) and brachytherapy (77% completed intracavitary treatment). The median PFS and OS was 6.6 months (4.0-9.1) and 30 months (11-48), respectively. None of the variables had an effect on the PFS, while multivariate analysis demonstrated that the levels of VEGF expression (p = 0.026), EGFR (p = 0.030), and tumor volume <6 cm (p = 0.02) influenced this outcome. Conclusion: the characterization of genes related to angiogenesis and cell proliferation in locally advanced cervical cancer treated with platinum-based chemoradiation had a positive influence on the prognosis. (Acta Med Colomb 2012; 37: 106-117).

Características histológicas de la gastritis crónica reportadas en las biopsias gástricas de niños de 1 a 16 años de edad en el Hospital Infantil de San José, durante el período comprendido entre septiembre de 2008 a septiembre de 2010 / Histological characteristics of chronic gastritis reported in gastric biopsies from children aged 1 to 16 years at the Hospital Infantil de San José from september 2008 to september 2010

La gastritis es una inflamación del revestimiento de la mucosa gástrica en respuesta a una lesión. Puede ser aguda, crónica o mixta y estar asociada con metaplasia intestinal y atrofia. Los factores etiológicos son múltiples y varían desde irritantes, químicos, inmunológicos y genéticos, hasta infecciosos; dentro de estos últimos se destaca el bacilo Helicobacter pylori como el agente causal más común. Objetivo: Caracterizar los hallazgos histológicos de la gastritis crónica en niños de 1 a 16 años de edad internados en el Hospital Infantil de San José, durante el período comprendido entre septiembre de 2008 a septiembre de 2010. Materiales y métodos: Se realizó un estudio observacional descriptivo, de corte transversal. La información se obtuvo de los reportes de biopsias gástricas de niños entre 1 a 16 años de edad, evaluados en el Hospital Infantil de San José entre septiembre de 2008 y septiembre de 2010. Resultados: Se revisaron 826 reportes de biopsias gástricas de niños con gastritis crónica, y se pudo observar que el 59,2% de la muestra eran niñas y el promedio de edad fue de 9 años. El Helicobacter pylori estuvo presente en el 58,96% de la población, la atrofia gástrica en el 0,7% y la metaplasia intestinal en el 1%. Se identificó que la presencia de este microorganismo estuvo relacionada con el grado de inflamación crónica y el grado de actividad neutrofílica polimorfonuclear. Conclusiones: La infección por Helicobacter pylori es frecuente en la gastritis crónica en la infancia y su presencia se relaciona con el grado de inflamación crónica y de actividad neutrofílica polimorfonuclear.

Gastritis is an inflammation of the lining of the gastric mucosa which occurs in response to an injury. It can be acute, chronic or mixed, and it can be associated with intestinal metaplasia and atrophy. There are multiple etiologic factors including irritation, chemical, immunological, genetic and infectious factors. Among the latter, Helicobacter pylori is the most common causative agent. Objective: The objective of this study was to characterize histologic findings of chronic gastritis in children aged 1-16 years at the Hospital Infantil de San José from September 2008 to September 2010. Materials and methods: This was an observational and descriptive cross sectional study. Information was obtained from gastric biopsy reports from children between 1 and 16 years of age who had been evaluated at the Hospital Infantil de San José from September 2008 to September 2010. Results: We reviewed 826 reports of gastric biopsies from children with chronic gastritis. 59.2% of the sample was female, and the mean age was 9 years. Helicobacter pylori was present in 58.96% of this population, gastric atrophy was present in 0.7% and intestinal metaplasia in 1%. It was found that the presence of Helicobacter pylori was related to the degree of chronic inflammation and polymorphonuclear neutrophil activity levels. Conclusions: Helicobacter pylori infection is common in chronic gastritis in children and its presence is related to the degree of chronic inflammation and polymorphonuclear neutrophil activity.