Molecular profile and its clinical impact of IDH1 mutated versus IDH1 wild type intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma; MutationColangiocarcinoma intrahepático; MutaciónColangiocarcinoma intrahepàtic; MutacióIDH1-mutated cholangiocarcinomas (CCAs) are an interesting group of neoplasia with particular behavior and therapeutic implications. The aim of the present work is to highlight the differences characterizing IDH1m and IDH1wt CCAs in terms of genomic landscape. 284 patients with iCCA treated for resectable, locally advanced or metastatic disease were selected and studied with the FOUNDATION Cdx technology. A comparative genomic analysis and survival analyses for the most relevant altered genes were performed between IDH1m and IDH1wt patients. Overall, 125 patients were IDH1m and 122 IDH1wt. IDH1m patients showed higher mutation rates compared to IDH1wt in CDKN2B and lower mutation rates in several genes including TP53, FGFR2, BRCA2, ATM, MAP3K1, NOTCH2, ZNF703, CCND1, NBN, NF1, MAP3KI3, and RAD21. At the survival analysis, IDH1m and IDH1wt patients showed no statistically differences in terms of survival outcomes, but a trend in favor of IDH1wt patients was observed. Differences in prognostic values of the most common altered genes were reported. In surgical setting, in IDH1m group the presence of CDKN2A and CDKN2B mutations negatively impact DFS, whereas the presence of CDKN2A, CDKN2B, and PBRM1 mutations negatively impact OS. In advanced setting, in the IDH1m group, the presence of KRAS/NRAS and TP53 mutations negatively impact PFS, whereas the presence of TP53 and PIK3CA mutations negatively impact OS; in the IDH1wt group, only the presence of MTAP mutation negatively impact PFS, whereas the presence of TP53 mutation negatively impact OS. We highlighted several molecular differences with distinct prognostic implications between IDH1m and IDH1wt patients

Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumors

Gastrointestinal neoplasms; Oncolytic virotherapy; Tumor microenvironmentNeoplasias gastrointestinales; Viroterapia oncolítica; Microambiente tumoralNeoplàsies gastrointestinals; Viroteràpia oncolítica; Microambient tumoralBackground VCN-01 is an oncolytic adenovirus (Ad5 based) designed to replicate in cancer cells with dysfunctional RB1 pathway, express hyaluronidase to enhance virus intratumoral spread and facilitate chemotherapy and immune cells extravasation into the tumor. This phase I clinical trial was aimed to find the maximum tolerated dose/recommended phase II dose (RP2D) and dose-limiting toxicity (DLT) of the intravenous delivery of the replication-competent VCN-01 adenovirus in patients with advanced cancer. Methods Part I: patients with advanced refractory solid tumors received one single dose of VCN-01. Parts II and III: patients with pancreatic adenocarcinoma received VCN-01 (only in cycle 1) and nab-paclitaxel plus gemcitabine (VCN-concurrent on day 1 in Part II, and 7 days before chemotherapy in Part III). Patients were required to have anti-Ad5 neutralizing antibody (NAbs) titers lower than 1/350 dilution. Pharmacokinetic and pharmacodynamic analyses were performed. Results 26% of the patients initially screened were excluded based on high NAbs levels. Sixteen and 12 patients were enrolled in Part I and II, respectively: RP2D were 1×1013 viral particles (vp)/patient (Part I), and 3.3×1012 vp/patient (Part II). Fourteen patients were included in Part III: there were no DLTs and the RP2D was 1×1013 vp/patient. Observed DLTs were grade 4 aspartate aminotransferase increase in one patient (Part I, 1×1013 vp), grade 4 febrile neutropenia in one patient and grade 5 thrombocytopenia plus enterocolitis in another patient (Part II, 1×1013 vp). In patients with pancreatic adenocarcinoma overall response rate were 50% (Part II) and 50% (Part III). VCN-01 viral genomes were detected in tumor tissue in five out of six biopsies (day 8). A second viral plasmatic peak and increased hyaluronidase serum levels suggested replication after intravenous injection in all patients. Increased levels of immune biomarkers (interferon-γ, soluble lymphocyte activation gene-3, interleukin (IL)-6, IL-10) were found after VCN-01 administration. Conclusions Treatment with VCN-01 is feasible and has an acceptable safety. Encouraging biological and clinical activity was observed when administered in combination with nab-paclitaxel plus gemcitabine to patients with pancreatic adenocarcinoma.MB-P, EB, and MC were funded by CDTI (PANCATHER project IDI-20130759). The clinical study was supported by VCN Biosciences

Advances in the systemic treatment of therapeutic approaches in biliary tract cancer

Biliary tract cancer; Molecular testing; Next-generation sequencingCáncer del tracto biliar; Pruebas moleculares; Secuenciación de nueva generaciónCàncer del tracte biliar; Proves moleculars; Seqüenciació de nova generacióIntroduction Biliary tract cancers (BTCs) are a rare and heterogenous group with an increasing incidence and high mortality rate. The estimated new cases and deaths of BTC worldwide are increasing, but the incidence and mortality rates in South East Asia are the highest worldwide, representing a real public health problem in these regions. BTC has a poor prognosis with a median overall survival <12 months. Thus, an urgent unmet clinical need for BTC patients exists and must be addressed. Results The backbone treatment of these malignancies is chemotherapy in first- and second-line setting, but in the last decade a rich molecular landscape has been discovered, expanding conceivable treatment options. Some druggable molecular aberrations can be treated with new targeted therapies and have already demonstrated efficacy in patients with BTC, improving clinical outcomes, such as the FGFR2 or IDH1 inhibitors. Many other molecular alterations are being discovered and the treatment of BTC will change in the near future from our current clinical practice. Conclusions In this review we discuss the epidemiology, molecular characteristics, present treatment approaches, review the recent therapeutic advances, and explore future directions for patients with BTC. Due to the rich molecular landscape of BTC, molecular profiling should be carried out early. Ongoing research will bring new targeted treatments and immunotherapy in the near future

Human Metastatic Cholangiocarcinoma Patient-Derived Xenografts and Tumoroids for Preclinical Drug Evaluation

Human metastatic cholangiocarcinoma; Xenografts; TumoroidsColangiocarcinoma metastàtic humà; Xenoempelts; TumoroidesColangiocarcinoma metastásico humano; Xenoinjertos; TumoroidesPurpose: Cholangiocarcinoma (CCA) is usually diagnosed at advanced stages, with limited therapeutic options. Preclinical models focused on unresectable metastatic CCA are necessary to develop rational treatments. Pathogenic mutations in IDH1/2, ARID1A/B, BAP1, and BRCA1/2 have been identified in 30%–50% of patients with CCA. Several types of tumor cells harboring these mutations exhibit homologous recombination deficiency (HRD) phenotype with enhanced sensitivity to PARP inhibitors (PARPi). However, PARPi treatment has not yet been tested for effectiveness in patient-derived models of advanced CCA. Experimental Design: We have established a collection of patient-derived xenografts from patients with unresectable metastatic CCA (CCA_PDX). The CCA_PDXs were characterized at both histopathologic and genomic levels. We optimized a protocol to generate CCA tumoroids from CCA_PDXs. We tested the effects of PARPis in both CCA tumoroids and CCA_PDXs. Finally, we used the RAD51 assay to evaluate the HRD status of CCA tissues. Results: This collection of CCA_PDXs recapitulates the histopathologic and molecular features of their original tumors. PARPi treatments inhibited the growth of CCA tumoroids and CCA_PDXs with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1. In line with these findings, only CCA_PDX and CCA patient biopsy samples with mutations of BRCA2 showed RAD51 scores compatible with HRD. Conclusions: Our results suggest that patients with advanced CCA with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1, are likely to benefit from PARPi therapy. This collection of CCA_PDXs provides new opportunities for evaluating drug response and prioritizing clinical trials.This work was supported by grants from the Fundació Marató TV3 awarded to T. Macarulla, M. Melé, and S. Peiró; BeiGene research grant awarded to T. Macarulla and S. Peiró; AECC (INVES20036TIAN), Ramón y Cajal investigator program (RYC2020-029098-I), Proyecto de I+D+i (PID2019-108008RJ-I00), and FERO Foundation grant awarded to T.V. Tian; Proyecto de Investigación en Salud from the Instituto de Salud Carlos III (ISCIII) (PI20/00898) awarded to T. Macarulla; FIS/FEDER from the Instituto de Salud Carlos III (ISCIII) (PI12/01250; CP08/00223; PI16/00253 and CB16/12/00449) awarded to S. Peiró; and Ramón y Cajal investigator program (RYC-2017-22249) awarded to M. Melé. Q. Serra-Camprubí is a recipient of the Ph.D. fellowship from La Caixa Foundation (LCF/PR/PR12/51070001). A. Llop-Guevara was supported by the AECC (INVES20095LLOP) and V. Serra by the ISCIII (CPII19/00033). E.J. Arenas was funded by the AECC (POSTD211413AREN). J. Arribas is funded by the Instituto de Salud Carlos III (AC15/00062, CB16/12/00449, and PI22/00001). This publication is based upon the work of COST Action CA18122, European Cholangiocarcinoma Network, supported by the COST (European Cooperation in Science and Technology, www.cost.eu), a funding agency for research and innovation networks. The authors would like to thank Dr. V.A. Raker for manuscript editing and Drs. N. Herranz and J. Mateo for scientific discussions. The authors acknowledge the infrastructure and support of the FERO Foundation, La Caixa Foundation, and the Cellex Foundation

ICO-ICS Praxis para el tratamiento médico y con irradiación del adenocarcinoma del páncreas

Tractament mèdic; Tractament amb irradiació; Adenocarcinoma; Pàncrees; CàncerTratamiento médico; Tratamiento con irradiación; Adenocarcinoma; Páncreas; CáncerMedical treatment; Irradiation treatment; Adenocarcinoma; Pancreas; CancerEl càncer de pàncrees se situa com la tercera causa més freqüent de càncer en la forma d'adenocarcinoma ductal pancreàtic. És un dels càncers més agressius i amb un percentatge més baix de curació. Els objectius d'aquesta guia són: -Desenvolupar, difondre, implementar i avaluar resultats de la ICO-ICSPraxi de càncer de pàncrees. -Disminuir la variabilitat terapèutica entre els pacients tractats als diferents centres d'aquesta institució. -Implementar els resultats de la terapèutica en els pacients amb adenocarcinoma de pàncrees tractats d'acord amb les recomanacions d'aquesta guia

Análisis de un panel genîmico predictivo de respuesta en enfermos con adenocarcioma de páncreas tratados con quimioterapia basada en platino

Antecedents: L'adenocarcinoma de pàncrees és una neoplasia de mal pronòstic. Les alteracions en els gens DDR s'han descrit en aproximadament un 20% dels pacients. En aquesta tesi s'investiga el valor predictiu d'aquestes alteracions a la quimioteràpia basada en platins. Mètodes: S'ha realitzat un estudi retrospectiu de pacients amb adenocarcinoma de pàncrees que han rebut tractament basat en platins. S'han classificat els pacients en respondedors i no respondedors. S'han considerat respondedors aquells pacients amb resposta parcial, completa o supervivència lliure de progressió major a 6 mesos a la quimioteràpia basada en platins. S'han considerat no respondedors aquells pacients en progressió a la primera avaluació de resposta de la primera línia basada en platins. S'ha realitzat un estudi de NGS incloent gens DDR a tots els pacients. Resultats: S'han inclòs 78 pacients, amb una mitjana d'edat al diagnòstic de la malaltia oncològica de 54 anys. Hi va haver 44 pacients (58,97%) diagnosticats en estadi metastàtic. Hi va haver 25 pacients no respondedors, dels quals 4 (16%) presentaven alteracions en gens DDR. Dels 53 pacients respondedors, 28 (53%) presentaven alteracions en els gens de la reparació del ADN. Presentar una alteració en els gens de la reparació de l'ADN es va associar a ser respondedor, amb una ODDS rati de 5,8 (95% IC 1,6-26,2), sent estadísticament significatiu (p=0,003). La supervivència lliure de progressió a la teràpia basada en platí dels pacients amb alteracions en els gens DDR va ser de 10,27 mesos comparada amb 4,08 mesos en els pacients sense alteracions (HR 0,52, 95% IC 0,31-0,81, p=0,01). La supervivència global en els pacients amb alteracions en els gens DDR va ser de 31,9 mesos i 20,3 mesos en els pacients sense alteracions en DDR (HR 0,45, 95% IC 0,25-0,80, p=0,006). Conclusions: Existeix una major proporció de pacients amb alteracions en gens DDR en el grup de pacients respondedors a la quimioteràpia basada en platí, sent l'associació estadísticament significativa. Els pacients amb alteracions en els gens DDR tenen una major supervivència al rebre quimioteràpia basada en platins que aquells que no les presenten.Antecedentes: El adenocarcinoma de páncreas es una neoplasia de mal pronóstico. Las alteraciones en los genes DDR se han descrito en alrededor de un 20% de los pacientes. En esta tesis investigamos el valor predictivo de estas alteraciones a la quimioterapia basada en platinos. Métodos: Se ha realizado un estudio retrospectivo de pacientes con adenocarcinoma de páncreas que han recibido tratamiento basado en platinos. Se han clasificado los pacientes en respondedores y no respondedores. Se han considerado respondedores aquellos pacientes con respuesta parcial, completa o supervivencia libre de progresión mayor a 6 meses a la quimioterapia basada en platinos. Se han considerado no respondedores aquellos pacientes en progresión a la primera evaluación de respuesta de la primera línea basada en platinos. Se ha realizado un estudio de NGS incluyendo genes DDR a todos los pacientes. Resultados: Se han incluido 78 pacientes, con una mediana de edad al diagnóstico de la enfermedad oncológica de 54 años. Hubo 44 pacientes (58,97%) diagnosticados en estadio metastásico. Hubo 25 pacientes no respondedores, de los cuales 4 (16%) presentaban alteraciones en genes DDR. De los 53 pacientes respondedores, 28 (53%) presentaban alteraciones en los genes de la reparación del ADN. Presentar una alteración en los genes de la reparación del ADN se asoció a ser respondedor, con una ODDS ratio de 5,8 (95% IC 1,6-26,2), siendo estadísticamente significativo (p=0,003). La supervivencia libre de progresión a la terapia basada en platino de los pacientes con alteraciones en los genes DDR fue de 10,27 meses comparada con 4,08 meses en los pacientes sin alteraciones (HR 0,52, 95% IC 0,31-0,81, p=0,01). La supervivencia global en los pacientes con alteraciones en los genes DDR fue de 31,9 meses y 20,3 meses en los pacientes sin alteraciones en DDR (HR 0,45, 95% IC 0,25-0,80, p=0,006). Conclusiones: Existe una mayor proporción de pacientes con alteraciones en genes DDR en el grupo de pacientes respondedores a la quimioterapia basada en platino, siendo la asociación estadísticamente significativa. Los pacientes con alteraciones en los genes DDR tiene una mayor supervivencia al recibir quimioterapia basada en platinos que aquellos que no las presentan.Background: Pancreatic cancer is a poor prognosis cancer. DDR gene alterations are present in around 20% of the patients. In this thesis we investigate the predictive value of those alterations for response to platinum-based chemotherapy. Methods: This is a retrospective study of patients with pancreatic adenocarcinoma who have received a platin-based treatment as a first line treatment. We have classified patients in responder and non-responders. Responder patients are those with a partial, complete response or progression free survival longer than 6 months to platinum-based chemotherapy. Non-responder patients are those who have progressed to first response evaluation. Results: 78 patients have been included. Median age at diagnosis was 54 years. 44 patients (58.97%) were diagnosed at stage IV. There were 25 non-responder patients, 4 of them (16%) had alterations in DDR genes. From 53 responder patients, 28 (53%) had alterations in DDR genes. Having an alteration in DDR genes was associated with being responder, with an ODDS ratio of 5.8 (95% CI 1.6-26.2), p=0.03. Progression free survival to platinum-based chemotherapy of patients with DDR alterations was 10.27 months and 4.08 in patients without DDR alterations (HR 0.52, 95% CI 0.31-0.81, p=0.01). Overall survival in patients with DDR alterations treated with platinum-based chemotherapy was 31.9 months versus 20.3 months in patients without DDR alterations (HR 0.45, 95% CI 0.25-0.80, p=0.006). Conclusions: There is a greater proportion of patients with alterations in DDR genes in the group of patients with responses to platinum-based chemotherapy, being this associations statistically significative. Patients with DDR alterations have a longer survival with platinum-based chemotherapy than those who do not have those alterations

Quality of life of patients with metastatic pancreatic adenocarcinoma initiating first-line chemotherapy in routine practice

Quimioteràpia contra el càncer; Qualitat de vida relacionada amb la salut; Càncer de pàncreesQuimioterapia contra el cáncer; Calidad de vida relacionada con la salud; Cancer de pancreasCancer chemotherapy; Health-related quality of life; Pancreatic CancerBackground Despite advances in surgery, radiotherapy, and chemotherapy, pancreatic adenocarcinoma often progresses rapidly and causes death. The physical decline of these patients is expected to impact their quality of life (QoL). Therefore, in addition to objective measures of effectiveness, the evaluation of health-related QoL should be considered a matter of major concern when assessing therapy outcomes. Methods Observational, prospective, multicenter study including patients with metastatic pancreatic adenocarcinoma who started first-line chemotherapy in 12 Spanish centers. Treatment and clinical characteristics were recorded at baseline. Patients’ health-related quality of life, ECOG, and Karnofsky index were measured at baseline, at Days 15 and 30, and every four weeks up to 6 months of chemotherapy. Health-related quality of life was measured using the EORTC-QLQ-C30 and EQ-5D questionnaires. Other endpoints included overall survival and progression-free survival. Results The study sample included 116 patients (median age of 65 years). Mean (SD) scores for the QLQ-C30 global health status scale showed a significant increasing trend throughout the treatment (p = 0.005). Patients with either a Karnofsky index of 70–80 or ECOG 2 showed greater improvement in the QLQ-C30 global health status score than the corresponding groups with better performance status (p ≤ 0.010). Pain, appetite, sleep disturbance, nausea, and constipation significantly improved throughout the treatment (p < 0.005). Patients with QLQ-C30 global health status scores ≥50 at baseline had significantly greater overall survival and progression-free survival (p = 0.005 and p = 0.021, respectively). No significant associations were observed regarding the EQ-5D score. Conclusions Most metastatic pancreatic adenocarcinoma patients receiving first-line chemotherapy showed an increase in health-related quality of life scores throughout the treatment. Patients with lower performance status and health-related quality of life at baseline tended to greater improvement. The EORTC QLQ-C30 scale allowed us to measure the health-related quality of life of metastatic pancreatic adenocarcinoma patients receiving first-line chemotherapy.This study was promoted, sponsored, and funded (including statistical and medical writing support) by Celgene. The funding body contributed to study design, data analysis, and revision of the manuscript drafts; all members of the funding body involved in this work have been included in the author list

Phase 2 trial of bintrafusp alfa as second-line therapy for patients with locally advanced/metastatic biliary tract cancers

BACKGROUND AIMS: Biliary tract cancers are rare, heterogeneous cancers with poor prognosis. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β "trap") fused to a human IgG1 mAb blocking PD-L1, was evaluated in patients with locally advanced/metastatic chemorefractory biliary tract cancers. APPROACH RESULTS: This multicenter, single-arm, open-label, phase 2 study (NCT03833661) enrolled adults with locally advanced or metastatic biliary tract cancer that was intolerant to or had failed first-line systemic platinum-based chemotherapy. Patients received 1200 mg bintrafusp alfa intravenously Q2W. Primary endpoint was confirmed objective response according to RECIST 1.1 assessed by IRC. Secondary endpoints included DOR, durable response rate, safety, PFS, and OS.Between March 2019 and January 2020, 159 patients were enrolled. Median follow-up was 16.1 (range, 0.0-19.3) months; 17 patients (10.7%; 95% CI, 6.4% -16.6%) achieved objective response. Median DOR was 10.0 (range, 1.9-15.7) months; 10 patients (6.3%; 95% CI, 3.1%- 11.3%) had a durable response (≥6 mo). Median PFS was 1.8 months (95% CI, 1.7-1.8 mo); median OS was 7.6 months (95% CI, 5.8-9.7 mo). OS rates were 57.9% (6-month) and 38.8% (12-month). Grade ≥3 AEs occurred in 26.4% of patients, including one treatment-related death (hepatic failure). Frequent grade ≥3 adverse events included anemia (3.8%), pruritus (1.9%), and increased alanine aminotransferase (1.9%). CONCLUSIONS: Although this study did not meet its prespecified primary endpoint, bintrafusp alfa demonstrated clinical activity as second-line treatment in this hard-to-treat cancer, with durable responses and a manageable safety profile

Analysis of mutant allele fractions in driver genes in colorectal cancer - biological and clinical insights

Colorectal cancer; Driver gene; Mutant allele fractionCàncer colorectal; Gen conductor; Fracció d'al·lel mutantCáncer colorrectal; Gen conductor; Fracción de alelo mutanteSequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions (MAFs, or the 'mutation dose') of a driver gene may reveal the genomic structure of tumors and influence response to targeted therapies. We performed a comprehensive analysis of MAFs of driver alterations in unpaired primary and metastatic colorectal cancer (CRC) at our institution from 2010 to 2015 and studied their potential clinical relevance. Of 763 CRC samples, 622 had detailed annotation on overall survival in the metastatic setting (OSmet) and 89 received targeted agents matched to KRAS (MEK inhibitors), BRAF (BRAF inhibitors), or PIK3CA mutations (PI3K pathway inhibitors). MAFs of each variant were normalized for tumor purity in the sample (adjMAFs). We found lower adjMAFs for BRAFV600E and PIK3CA than for KRAS, NRAS, and BRAF non-V600 variants. TP53 and BRAFV600E adjMAFs were higher in metastases as compared to primary tumors, and high KRAS adjMAFs were found in CRC metastases of patients with KRAS wild-type primary tumors previously exposed to EGFR antibodies. Patients with RAS- or BRAFV600E -mutated tumors, irrespective of adjMAFs, had worse OSmet. There was no significant association between adjMAFs and time to progression on targeted therapies matched to KRAS, BRAF, or PIK3CA mutations, potentially related to the limited antitumor activity of the employed drugs (overall response rate of 4.5%). In conclusion, the lower BRAFV600E and PIK3CA adjMAFs in subsets of primary CRC tumors indicate subclonality of these driver genes. Differences in adjMAFs between metastases and primary tumors suggest that approved therapies may result in selection of BRAFV600E - and KRAS-resistant clones and an increase in genomic heterogeneity with acquired TP53 alterations. Despite significant differences in prognosis according to mutations in driver oncogenes, adjMAFs levels did not impact on survival and did not help predict benefit with matched targeted agents in the metastatic setting