Monitoring of RAS mutant clones in plasma of patients with RAS mutant metastatic colorectal cancer

Circulating tumor DNA; Liquid biopsy; Metastatic colorectal cancerADN tumoral circulante; Biopsia liquida; Cáncer colorrectal metastásicoADN tumoral circulant; Biòpsia líquida; Càncer colorectal metastàticPurpose Some patients with histologically confirmed primary mCRC and mutated RAS reported undetectable RAS mutant clones in plasma after receiving anti-VEGF treatment. The aim was to prospectively assess it with its potential therapeutic implications. Methods RAS mutant genes in solid biopsy (before first-line treatment: FOLFOX/CAPOX + bevacizumab) were compared in liquid biopsy (before second-line treatment: panitumumab + FOLFIRI), using Idylla™ system. Discordant results between solid/liquid biopsies were assessed by the next-generation sequencing (NGS) test (solid/liquid biopsies). Results Twenty-three patients were assessed (seven had RAS mutant discrepancies between solid/liquid biopsies). The NGS test confirmed that 3/23 (13%) patients had undetectable RAS mutant clones in liquid biopsy and 3/23 (13%) presented discrepancies in solid biopsy (Idylla™ system vs. NGS test). Conclusion Thirteen percentage of patients had undetectable RAS mutant clones in liquid biopsy after first-line treatment. However, some discrepancies between solid and liquid biopsies have been observed. These results suggest a need to improve accuracy of RAS analyses, especially in solid biopsies.This work was supported by Amgen S.A. Amgen did not have any role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication

Crustal Imbrication in an Alpine Intraplate Mountain Range: A Wide-Angle Cross-Section Across the Spanish-Portuguese Central System

Intraplate ranges are topographic features that can occur far from plate boundaries, the expected position of orogens as described in the plate tectonics theory. To understand the lithospheric structure of intraplate ranges, we focused on the Spanish-Portuguese Central System (SPCS), the most outstanding topographic feature in the central Iberian Peninsula. The SPCS is an Alpine range that exhumes Precambrian-Paleozoic rocks and is located at >200 km from the northern border of the Iberian microplate. Here, we provide a P-wave velocity model based on wide-angle seismic reflection/refraction data of the central SPCS (Gredos sector). Our results show: (a) a layered lithosphere characterized by three major interfaces: Conrad, Mohorovicic, and Hales discontinuities, (b) an asymmetry of the crust-mantle boundary under the SPCS, (c) the extent of the Variscan batholith forming the main outcrops of Gredos, and (d) the thinning of the lower crust toward the south. This model suggests that the exhumation of the SPCS basement was driven by a south-vergent thick-skinned thrust system, developed in the southern part of the SPCS and that promoted crustal imbrication and a Mohorovicic discontinuity's offset under the SPCS. Thus, the deformation mechanisms of the crust seem to be controlled by the presence of the late- to post-Variscan granitoids that assimilated the Variscan mid-crustal detachment creating a new rheological boundary. This tectonic structure allowed the formation of Alpine crustal-scale thrust systems that eased coupled deformation of the upper and lower crust, leading to limited underthrusting of both crustal layers.This study has been funded by the Ministry of Science, Innovation and Competitiveness through the Project CIMDEF (CGL2014-56548-P). IP is funded by the Spanish Government and the University of Salamanca (Beatriz Galindo grant BEGAL 18/00090). JA is funded by grant IJC2018-036074-I, funded by MCIN/AEI/10.13039/501100011033. DMP and FGL are also funded by grants CGL2015-71692 (MINECO/ FEDER) and PID2020-118822GB-I00 (MCIN/AEI/10.13039/501100011033).Peer reviewe

Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer

Cetuximab is a standard-of-care treatment for RAS wild-type metastatic colorectal cancer (mCRC) but not for those harbor a KRAS mutation since MAPK pathway is constitutively activated. Nevertheless, cetuximab also exerts its effect by its immunomodulatory activity despite the presence of RAS mutation. The aim of this study was to determine the impact of polymorphism FcγRIIIa V158F and killer immunoglobulin-like receptor (KIR) genes on the outcome of mCRC patients with KRAS mutations treated with cetuximab. This multicenter Phase II clinical trial included 70 mCRC patients with KRAS mutated. We found KIR2DS4 gene was significantly associated with OS (HR 2.27; 95% CI, 1.08–4.77; P = 0.03). In non-functional receptor homozygotes the median OS was 2.6 months longer than in carriers of one copy of full receptor. Multivariate analysis confirmed KIR2DS4 as a favorable prognostic marker for OS (HR 6.71) in mCRC patients with KRAS mutation treated with cetuximab. These data support the potential therapeutic of cetuximab in KRAS mutated mCRC carrying non-functional receptor KIR2DS4 since these patients significantly prolong their OS even after heavily treatment. KIR2DS4 typing could be used as predictive marker for identifying RAS mutated patients that could benefit from combination approaches of anti-EGFR monoclonal antibodies and other immunotherapies to overcome the resistance mediated by mutation in RAS.This clinical trial was approved and supported by Merck S.L., an affiliate of Merck KGaA, Darmstadt. Germany [research project number 2010-023580-18, date: 05-06-2014

Compensación isostática en la Cordillera Bética Occidental (Sur de España) causada por descarga erosiva desde el Messiniense hasta la actualidad: la emersión de un orógeno

In the Western-Central Betic Cordillera (WCBC), the Messinian Salinity Crisistriggered and important fluvial denudation, removing millions cubic meters of rocks from the Mediterranean slope of the emergent orogen. We offer an evaluation of the subsequent isostatic response calculating in a GIS environment the geophysical relief (gr ) values (denudation plate and continuous models) and also surface uplift (Airy isostasy) for 48 drainage basins (spatial isostatic units). Higher gr (major denudation) values are obtained consistently at the Mediterranean side of the ancient water divide (328-465 m) and noticeable lower (<235 m) in the Atlantic slope. The obtained gr models show a similar asymmetric distribution. Comparison with published uplift models based on stratigraphic markers and landforms in the zone confirms that near the 45-50% of the total uplift of the WCBC was triggered during the MSC. Calculated surface uplift for the Mediterranean (291 ±20 m) and Atlantic (179 ±20 m) slopes indicate uplift rates during the MSC of 0.18 mm/yr in the Mediterranean (practically null in the Atlantic). Consequently, isostatic uplift caused by fluvial erosional unloading can be identified as one of the main proces controlling the landscape evolution in the zone during and after the MSCEn la Cordillera Bética Centro Occidental (CBCO), la MSC desencadenó una importante denudación fluvial, retirando millones de metros cúbicos de roca de la vertiente mediterránea del orógeno emergente. En este trabajo evaluamos la respuesta isostática subsiguiente calculando (en SIG) el relieve geofísico (rg , valores y modelos continuos de la placa de denudación) y la elevación superficial (isostasia de Airy) para 48 cuencas de drenaje (unidades isostáticas espaciales). Los valores más altos de rg (mayor denudación) se han obtenido sistemáticamente en la antigua vertiente mediterránea (328-465 m), claramente menores en la vertiente Atlántica (<235 m). Los modelos continuos de rg presentan la misma distribución asimétrica. La comparación con modelos de elevación publicados para la zona confirma que el 45-50% de la elevación total de la CBCO se produjo durante la MSC y las elevaciones isostáticas calculadas para la antigua vertiente mediterránea (c. 291 ±20 m) y Atlántica (c.179 ±20 m) ofrecen tasas de elevación vertical de 0,18 mm/año durante la MSC en la mediterránea (y prácticamente cero en la atlántica). Por tanto, el rebote isostático producido por la denudación fluvial durante la MSC es uno de los procesos principales que controla la evolución vertical del relieve y el paisaje durante y después de la MS