Phase II study of high-sensitivity genotyping of KRAS, NRAS, BRAF and PIK3CA to ultra-select metastatic colorectal cancer patients for panitumumab plus FOLFIRI: the ULTRA trial

Background: Several studies show the importance of accurately quantifying not only KRAS and other low-abundant mutations because benefits of anti-EGFR therapies may depend on certain sensitivity thresholds. We assessed whether ultra-selection of patients using a high-sensitive digital PCR (dPCR) to determine KRAS, NRAS, BRAF and PIK3CA status can improve clinical outcomes of panitumumab plus FOLFIRI. Patients and methods: This was a single-arm phase II trial that analysed 38 KRAS, NRAS, BRAF and PIK3CA hotspots in tumour tissues of irinotecan-resistant metastatic colorectal cancer patients who received panitumumab plus FOLFIRI until disease progression or early withdrawal. Mutation profiles were identified by nanofluidic dPCR and correlated with clinical outcomes (ORR, overall response rate; PFS, progression-free survival; OS, overall survival) using cut-offs from 0% to 5%. A quantitative PCR (qPCR) analysis was also performed. Results: Seventy-two evaluable patients were enrolled. RAS (KRAS/NRAS) mutations were detected in 23 (32%) patients and RAS/BRAF mutations in 25 (35%) by dPCR, while they were detected in 7 (10%) and 11 (15%) patients, respectively, by qPCR. PIK3CA mutations were not considered in the analyses as they were only detected in 2 (3%) patients by dPCR and in 1 (1%) patient by qPCR. The use of different dPCR cut-offs for RAS (KRAS/NRAS) and RAS/BRAF analyses translated into differential clinical outcomes. The highest ORR, PFS and OS in wild-type patients with their lowest values in patients with mutations were achieved with a 5% cut-off. We observed similar outcomes in RAS/BRAF wild-type and mutant patients defined by qPCR. Conclusions: High-sensitive dPCR accurately identified patients with KRAS, NRAS, BRAF and PIK3CA mutations. The optimal RAS/BRAF mutational cut-off for outcome prediction is 5%, which explains that the predictive performance of qPCR was not improved by dPCR. The biological and clinical implications of low-frequent mutated alleles warrant further investigations

Colorectal cancer residual disease at maximal response to EGFR blockade displays a druggable Paneth cell–like phenotype

Blockade of epidermal growth factor receptor (EGFR) causes tumor regression in some patients with metastatic colorectal cancer (mCRC). However, residual disease reservoirs typically remain even after maximal response to therapy, leading to relapse. Using patient-derived xenografts (PDXs), we observed that mCRC cells surviving EGFR inhibition exhibited gene expression patterns similar to those of a quiescent subpopulation of normal intestinal secretory precursors with Paneth cell characteristics. Compared with untreated tumors, these pseudodifferentiated tumor remnants had reduced expression of genes encoding EGFR-activating ligands, enhanced activity of human epidermal growth factor receptor 2 (HER2) and HER3, and persistent signaling along the phosphatidylinositol 3-kinase (PI3K) pathway. Clinically, properties of residual disease cells from the PDX models were detected in lingering tumors of responsive patients and in tumors of individuals who had experienced early recurrence. Mechanistically, residual tumor reprogramming after EGFR neutralization was mediated by inactivation of Yes-associated protein (YAP), a master regulator of intestinal epithelium recovery from injury. In preclinical trials, Pan-HER antibodies minimized residual disease, blunted PI3K signaling, and induced long-term tumor control after treatment discontinuation. We found that tolerance to EGFR inhibition is characterized by inactivation of an intrinsic lineage program that drives both regenerative signaling during intestinal repair and EGFR-dependent tumorigenesis. Thus, our results shed light on CRC lineage plasticity as an adaptive escape mechanism from EGFR-targeted therapy and suggest opportunities to preemptively target residual disease

Estructuras de licuefacción sísmica en el yacimiento romano de La Magdalena, Complutum s. IV AD (Madrid, España)

la antigua ciudad romana de Complutum (Alcalá de Henares, Madrid) fue fundada en el s. I AD y fue una de las ciudades más importantes de Hispania. Complutum fue destruida, abandonada bruscamente, reubicada y reconstruida en una nueva localización en el s. IV AD. Las causas de la destrucción y la nueva localización de la ciudad son aún una incógnita para la arqueología. En este trabajo se muestran diferentes efectos arqueosismológicos de terremotos (EAEs) afectando al yacimiento de La Magdalena (una explotación agrícola situada a 4 km al NE del núcleo urbano de Complutum). El efecto geológico de origen sísmico que afectó al yacimiento es la licuefacción. Se pueden observar diques de arena y cráteres de gravas por explosión afectando a instalaciones romanas, como cisternas, casas o tumbas. Simultáneamente al abandono de La Magdalena también fueron abandonadas de forma brusca la ciudad de Complutum y varias villas romanas a lo largo del valle del Henares, en algunos casos con EAEs que pueden asociarse al mismo evento que destruyó el yacimiento de La Magdalena. Estos EAEs podrían estar generados por un terremoto de Mw = 5.0-6,6, utilizando los límites empíricos de licuefacción y ruptura cosísmica de la fallaInstituto Geológico y Minero de España, EspañaDepartamento de Geología, Escuela Politécnica Superior de Ávila, Universidad Salamanca, EspañaTrébede, Patrimonio Cultural, S.L., EspañaUniversidad de Salamanca, EspañaFacultad de Ciencias, Universidad Autónoma de Madrid, EspañaDepartamento de Ingeniería del Terreno, Escuela Politécnica Superior de Ávila, Universidad de Salamanca, EspañaDepartamento de Edafología, Escuela Técnica Superior de Ingenieros Agrónomos, Universidad Politécnica de Madrid, EspañaFacultad de Ciencias, Universidad Nacional de Educación a Distancia, EspañaDepartamento de Geología, Universidad de Alcalá de Henares, Españ

Análisis de la deformación en la Península Ibérica a partir del estudio de mecanismos focales, implicaciones en la peligrosidad sísmica

Reunión Ibérica sobre Fallas Activas y Paleosismología (3ª. 2018. Alicante). - Texto en inglés con resumen y palabras claves en inglés y españolSe han analizado 682 mecanismos focales de terremotos localizados en la Península Ibérica y zonas próximas. Aplicando métodos de determinación del tensor de deformación (Modelo de Deslizamiento), se han obtenido diferentes resultados para cada uno de los mecanismos focales: (1) plano de falla entre los dos planos nodales del mecanismo, (2) orientación de máximo acortamiento horizontal (ey), (3) factor de forma de tensor de deformación (k’) y (4) tipo de falla. Con estos datos se pueden realizar análisis regionales y locales de las características de la fracturación activa en el área considerada: (a) caracterización de la fracturación, (b) orientación de máximo acortamiento horizontal, (c) zonación en función del tipo de falla y del factor de forma del tensor de deformación. Este tipo de información puede ser muy útil a la hora de realizar tanto diferentes análisis locales de la peligrosidad sísmica, como para incorporar a los catálogos sísmicos terremotos históricos destructivos sin información de la fuente sísmica. = We analysed 682 earthquake focal mechanism solutions located in the Iberian Peninsula and nearby areas. We have obtained different parameters applying methods of determination of the strain tensor (Slip Model): (1) the fault plane between the nodal planes of the focal mechanism, (2) the orientation of the maximum horizontal shortening (ey), (3) the strain shape factor (k`) and (4) the type of fault. With these data, regional and local analysis of active faulting can be carried out in Spain: (a) fracture characterization, (b) the orientation of maximum horizontal shortening, (c) spatial zonation according to the type of fault and (d) the strain shape factor. These results can be useful for seismic hazards studies of local zones and for including destructive historical earthquakes in the seismic catalogs.Departamento de Geología y Geoquímica, Universidad Autónoma de Madrid, EspañaInstituto Geológico y Minero de España, EspañaDepartamento de Geología, Universidad de Salamanca, EspañaDepartamento de Geología, Geografía y Medio Ambiente, Universidad de Alcalá, EspañaDepartamento de Edafología, Universidad Politécnica de Madrid, Españ

Seismically induced liquefaction structures in La Magdalena archaeological site, the 4th century AD Roman Complutum (Madrid, Spain)

The ancient Roman city of Complutum(Alcalá deHenares,Madrid), founded in the 1st century AD,was one of the most important cities ofHispania. The old Roman citywas destroyed, abruptly abandoned, relocated close by and rebuilt during the late 4th century AD. Destruction of the city and its relocation has not yet been explained by archaeologists. In this paper,with ourmultidisciplinary approach, we identify and characterize earthquake archaeological effects (EAEs) affecting the archaeological site, the La Magdalena, an agricultural holding 4 km from the core of Complutum. The most important EAEs in the site are liquefactions (sand dikes and explosive sand-gravel craters) affecting Roman structures, such as water tanks (cisterns), houses and graves. Ground liquefaction generated significant ground cracks, explosive craters and folds in foundations of buildings. Several other Roman sites throughout the valleywere also abandoned abruptly during the 4th century AD, in some caseswith EAEs of similar origin. This suggests the occurrence of a 5.0–6.6 Mw seismic event in the zone, in accordance with the minimum empirical limit of seismically-induced liquefaction and the maximum surface rupture length of the Henares fault.Instituto Geológico y Minero de España, EspañaDepartamento de Geología, Escuela Politécnica Superior de Ávila, Universidad Salamanca, EspañaFacultad de Ciencias, Universidad Autónoma de Madrid, EspañaTrébede, Patrimonio Cultural, S.L., EspañaDepartamento de Ingeniería del Terreno, Escuela Politécnica Superior de Ávila, Universidad Salamanca, EspañaDepartamento de Edafología, Universidad Politécnica de Madrid, EspañaFacultad de Ciencias, Universidad Nacional de Educación a Distancia, EspañaDepartamento de Geología, Universidad de Alcalá de Henares, Españ

Análisis arqueosismológico del conjunto arqueológico romano de Mulva- Munigua (Sevilla, España). Resultados preliminares

El conjunto arqueológico romano de Mulva-Munigua (Sevilla, España) presenta daños en las edificaciones que pueden ser interpretadas como resultado de la ocurrencia de un evento sísmico (Efectos Arqueológicos de los Terremotos: EAEs) a finales del siglo III A.D., fecha coincidente con el inicio del periodo de declive económico de este asentamiento romano. Para intentar establecer el posible origen sísmico de las deformaciones, se ha procedido al inventario y análisis de las estructuras deformadas presentes en el yacimiento. No obstante, algunas de estas deformaciones también se pueden interpretar como resultado de procesos gravitaciones asociados a la ladera Este de la colina sobre la que se sitúa parte del yacimiento. Las direcciones de máxima deformación (ey) obtenidas del análisis de EAEs indica dos direcciones preferentes de la deformación (o movimiento preferente del terreno): NNO-SSE y ENEOSO. Aunque los datos presentan una dispersión importante, se puede establecer que la orientación principal NNO-SSE es compatible con un evento sísmico situado en el borde norte del Valle del Guadalquivir. La orientación ENE-OSO podría relacionarse con un evento posterior, o más seguramente con procesos de ladera de carácter cosísmico o no.Departamento de Geología y Geoquímica, Universidad Autónoma de Madrid, EspañaDepartamento de Geología, Universidad de Alcalá, EspañaInstituto Geológico y Minero de España, EspañaDepartamento de Geología, Escuela Politécnica Superior de Ávila, Universidad Salamanca, EspañaDepartamento de Edafología, Escuela Técnica Superior de Ingenieros Agrónomos, Universidad Politécnica de Madrid, EspañaDepartamento de Geografía Física, Universidad de Sevilla, Españ

Concordance of blood- and tumor-based detection of RAS mutations to guide anti-EGFR therapy in metastatic colorectal cancer

Circulating tumor DNA (ctDNA) is a potential source for tumor genome analysis. We explored the concordance between the mutational status of RAS in tumor tissue and ctDNA in metastatic colorectal cancer (mCRC) patients to establish eligibility for anti-epidermal growth factor receptor (EGFR) therapy. A prospective-retrospective cohort study was carried out. Tumor tissue from 146 mCRC patients was tested for RAS status with standard of care (SoC) PCR techniques, and Digital PCR (BEAMing) was used both in plasma and tumor tissue. ctDNA BEAMing RAS testing showed 89.7% agreement with SoC (Kappa index 0.80; 95% CI 0.71 − 0.90) and BEAMing in tissue showed 90.9% agreement with SoC (Kappa index 0.83; 95% CI 0.74 − 0.92). Fifteen cases (10.3%) showed discordant tissue-plasma results. ctDNA analysis identified nine cases of low frequency RAS mutations that were not detected in tissue, possibly due to technical sensitivity or heterogeneity. In six cases, RAS mutations were not detected in plasma, potentially explained by low tumor burden or ctDNA shedding. Prediction of treatment benefit in patients receiving anti-EGFR plus irinotecan in second- or third-line was equivalent if tested with SoC PCR and ctDNA. Forty-eight percent of the patients showed mutant allele fractions in plasma below 1%. Plasma RAS determination showed high overall agreement and captured a mCRC population responsive to anti-EGFR therapy with the same predictive level as SoC tissue testing. The feasibility and practicality of ctDNA analysis may translate into an alternative tool for anti-EGFR treatment selection

Controversies in the treatment of RAS wild-type metastatic colorectal cancer.

To provide guidance for the management of RAS wild-type (wt) metastatic colorectal cancer (mCRC) in daily practice. Nominal group and Delphi techniques were used. A steering committee of seven experts analyzed the current management of RAS wt mCRC, through which they identified controversies, critically analyzed the available evidence, and formulated several guiding statements for clinicians. Subsequently, a group of 30 experts (the expert panel) was selected to test agreement with the statements, through two Delphi rounds. The following response categories were established in both rounds: 1 = totally agree, 2 = basically agree, 3 = basically disagree, 4 = totally disagree. Agreement was defined if ≥ 75% of answers were in categories 1 and 2 (consensus with the agreement) or 3 and 4 (consensus with the disagreement). Overall, 71 statements were proposed, which incorporated the following areas: (1) overarching principles; (2) tumor location; (3) triplets; (4) maintenance; (5) second-line and beyond treatments; (6) Rechallenge and liquid biopsy. After the two Delphi rounds, only six statements maintained a lack of clear consensus. This document aims to describe the expert's attitude when dealing with several common clinical questions regarding patients with RAS wt mCRC

Efectos ambientales del terremoto de Arenas del Rey de 1884 (España): aplicación de la escala ESI07

Reunión Ibérica sobre Fallas Activas y Paleosismología (3ª. 2018. Alicante). - Texto en español con resumen y palabras claves en inglés y españolEl terremoto de Arenas del Rey de 1884 ha sido el último gran terremoto catastrófico que ha sufrido España (EMS98=IX-X; Mw=6,5-6,7). Generó una ruptura superficial de falla normal de más de 20 km de longitud. Así mismo produjo una gran cantidad de efectos geológicos, tanto primarios como secundarios. Los efectos segundarios más comunes fueron deslizamientos y caídas de rocas. La utilización de la escala macrosísmica de efectos ambientales ESI07 ha permitido acotar la zona epicentral de este terremoto en el polje de Zafarraya. A partir de la distribución de intensidades resultante y de la modelización de las dimensiones de la fuente sísmica, se ha elaborado un mapa de aceleraciones (Shake Map), obteniéndose aceleraciones máximas de 0,71g. = The Arenas del Rey earthquake of 1884 was the last major damaging earthquake in Spain (EMS98 = IX-X, Mw = 6.5- 6.7). It generated a normal fault surface rupture of more than 20 km in length. It also produced a large number of geological effects, both primary and secondary. The most common secondary effects were landslides and rock falls. The use of the macroseismic scale of environmental effects ESI07 has allowed to delimit the epicentral zone in the Zafarraya polje. From the resulting intensity distribution and modeling of the dimensions of the seismic source, an acceleration map (shake map) has been obtained which shows maximum accelerations of 0.71g.Instituto Geológico y Minero de España, EspañaDepartamento de Geología, Universidad de Salamanca, EspañaDepartamento de Geología, Universidad Autónoma de Madrid, EspañaDepartamento de Edafología, Universidad Politécnica de Madrid, Españ