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Colorectal cancer; Predictive markers; Tumour biomarkers Cáncer colorrectal; Marcadores predictivos; Biomarcadores tumorales Càncer colorrectal; Marcadors predictius; Biomarcadors tumorals Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600E colorectal cancer (mCRCBRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCBRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12–0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10–0.71; P = 0.008), in patients with MSS-RNF43mutated versus MSS-RNF43wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients. VHIO would like to acknowledge the Cellex Foundation for providing research facilities and equipment, the FERO Foundation for their funding support, the Consorcio Centro de Investigación Biomédica en Red de Cáncer (CIBERONC, CB16/12/00259) from the Institute of Health Carlos III (ISCIII), Ministry of Science and Innovation, and the Department of Health (Generalitat de Catalunya, SLT008/18/00198 and SLT008/18/00205) for their support on this research. Authors acknowledge financial support from the State Agency for Research (Agencia Estatal de Investigación) (CEX2020-001024-S / AEI / 10.13039 /501100011033). This research is funded by the SCITRON program; Novartis funded the genomics characterization by WES of samples from 28 patients from the discovery cohort and had no influence on data analysis/interpretation or writing of the paper (3003145512 to R.A.T.). S.Li. is financially supported by a Chinese Scholarship Council PhD fellowship (201909370083 to S. Li). R.P.-L. is supported by a CRIS Foundation Talent Award (TALENT19-05), the FERO Foundation, the Instituto de Salud Carlos III-Investigación en Salud (PI18/01395 and PI21/01019 to R.P.-L.) and the Prostate Cancer Foundation (Young Investigator Award). This work was supported by the Miguel Servet-I Research Award from ISCIII of the Ministry of Economy (CP17/00199 to R.A.T.), the Olga Torres Foundation Award to emerging researchers (2601 to R.A.T.), the ISCIII-FEDER (PI17/00947 and PI20/00968 to E.E.), and the Fundación AECC (CLSEN19001ELEZ to E.E.) and Ministry of Science and Innovation (Europa Redes y Gestores, ECT2020-000827 to E.E.).

Several uncommon genomic alterations beyondA prospective data set at three Italian Academic Hospitals included 650 patients with mCRC with comprehensive genomic profiling by FoundationOne CDx and treated with anti-EGFRs. PRESSING2 panel alterations were selected on the basis of previous clinico-biologic studies and includedAmong 162 hyperselected patients, 24 (15%) had PRESSING2 alterations, which were mutually exclusive except in two samples and were numerically higher in right-sided versus left-sided cancers (28%Negative ultraselection warrants further investigation with the aim of maximizing the benefit of EGFR blockade strategies in patients with

Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFsupV600E/supcolorectal cancer (mCRCsupBRAF-V600E/sup). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCsupBRAF-V600E/suptreated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12-0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10-0.71; P = 0.008), in patients with MSS-RNF43supmutated/supversus MSS-RNF43supwild-type/suptumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCsupBRAF-V600E/suptumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients.

PURPOSE Several uncommon genomic alterations beyond RAS and BRAFV600E mutations drive primary resistance to anti–epidermal growth factor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer (mCRC). Our PRESSING panel (including PIK3CA exon 20/ AKT1/ PTEN mutations, ERBB2/ MET amplifications, gene fusions, and microsatellite instability-high status) represented a paradigm of negative hyperselection with more precise tailoring of EGFR blockade. However, a modest proportion of hyperselected mCRC has intrinsic resistance potentially driven by even rarer genomic alterations. MATERIALS AND METHODS A prospective data set at three Italian Academic Hospitals included 650 patients with mCRC with comprehensive genomic profiling by FoundationOne CDx and treated with anti-EGFRs. PRESSING2 panel alterations were selected on the basis of previous clinico-biologic studies and included NTRKs, ERBB3, NF1, MAP2K1/ 2/ 4, AKT2 pathogenic mutations; PTEN/ NF1 loss; ERBB3, FGFR2, IGF1R, KRAS, ARAF, and AKT1-2 amplification; and EGFR rearrangements. These were collectively associated with outcomes in patients with hyperselected disease, ie, RAS/ BRAF wild-type, PRESSING-negative, and microsatellite stable. RESULTS Among 162 hyperselected patients, 24 (15%) had PRESSING2 alterations, which were mutually exclusive except in two samples and were numerically higher in right-sided versus left-sided cancers (28% v 13%; P = .149). Independently of sidedness and other factors, patients with PRESSING2-positive status had significantly worse progression-free survival and overall survival compared with PRESSING2-negative ones (median progression-free survival: 6.4 v 12.8 months, adjusted hazard ratio 4.19 [95% CI, 2.58 to 6.79]; median overall survival: 22.6 v 49.9 months, adjusted hazard ratio 2.98 [95% CI, 1.49 to 5.96]). The combined analysis of primary tumor sidedness and PRESSING2 status allowed us to better stratify outcomes. CONCLUSION Negative ultraselection warrants further investigation with the aim of maximizing the benefit of EGFR blockade strategies in patients with RAS and BRAF wild-type, microsatellite stable mCRC.

218 Background: Immune checkpoint inhibitors (ICI) showed high efficacy in both first and subsequent lines in metastatic colorectal cancer with mismatch repair deficiency (dMMR-mCRC); however, they still fail in a minority of patients (pts). In non-preplanned analyses from previous studies, RAS mutations ( RASm) have been related to limited activity of ICI monotherapy (ICIm) as compared to ICI doublets (ICId) in dMMR-mCRC. Emerging data suggest different immunological features in presence of RASm, resulting in lower immunogenicity. Methods: NERDY is a retrospective, monocentric study designed to investigate the effect of ICIm and ICId on dMMR-mCRC basing on RASm. Pts with dMMR-mCRC treated with ICIm/ICId at our Institute were included. Clinical-pathological features for each patient were collected. On primary tumor specimens, proinflammatory pathways and CMS subgroup will be assessed by Nanostring and RNA-Seq respectively. The study is exploratory and no formal hypothesis has been postulated. Both PFS and OS were calculated with Kaplan-Meier. Cox proportional hazard model was adopted in the interaction tests. Primary objective was to assess OS and PFS according to RAS in dMMR-mCRC pts treated with ICIm or ICId. Secondary objectives were to describe the inflammatory infiltrate and TMB in dMMR-mCRC according to RAS status. Results: From June 2015 to January 2022, a total of 126 consecutive dMMR-mCRC pts treated with ICI were included, 33 RASm/93 RASwt. RASm pts were more frequently males (p=0.015) and younger (median age 47 vs 65). An imbalance was observed in sidedness (more right-CRC in RASwt than in RASm as BRAF effect, p=0.001) and timing of ICI (administered in later lines in RASm, p=0.013). No differences in ECOG-PS, histotype, disease burden, stage at diagnosis, treatment with ICIm vs ICId and best response. At a median follow up of 53.5 months (95%CI 34.7-56.9), a trend toward longer PFS in pts treated with ICId over ICIm was found in the overall population (HR 0.62; 95%CI 0.36-1.05; p=0.055), being significantly longer in RASm-only pts (HR 0.41; 95%CI 0.13-1.28; p=0.047) but not in RASwt-only pts (HR 0.64; 95%CI 0.34-1.20; p=0.139). No difference was observed in OS between ICId and ICIm in the overall population (HR 0.64; 95%CI 0.36-1.16; p=0.121), in RASwt (HR 0.59; 95%CI 0.29-1.20; p=0.132) nor in RASm pts (HR 0.59; 95%CI 0.19-1.78; p=0.275). Interaction test for RAS and ICI treatment type was not significant for PFS (HR 0.63; 95%CI 0.21-1.94; p=0.423) nor for OS (HR=1.00; 95%CI 0.29-3.41; p=0.999). Conclusions: Preliminary clinical results of the NERDY study suggest enhanced activity of ICId compared to ICIm in pts with RASm dMMR-mCRC. Further data are expected from pending translational analyses and a pre-planned adjunctive cohort from two other Italian centers will be used for external validation.

The endoplasmic reticulum (ER) is a continuous cell-wide membrane network. Network formation has been associated with proteins producing membrane curvature and fusion, such as reticulons and atlastin. Regulated network fragmentation, occurring in different physiological contexts, is less understood. Here we find that the ER has an embedded fragmentation mechanism based upon the ability of reticulon to produce fission of elongating network branches. In Drosophila, Rtnl1-facilitated fission is counterbalanced by atlastin-driven fusion, with the prevalence of Rtnl1 leading to ER fragmentation. Ectopic expression of Drosophila reticulon in COS-7 cells reveals individual fission events in dynamic ER tubules. Consistently, in vitro analyses show that reticulon produces velocity-dependent constriction of lipid nanotubes leading to stochastic fission via a hemifission mechanism. Fission occurs at elongation rates and pulling force ranges intrinsic to the ER, thus suggesting a principle whereby the dynamic balance between fusion and fission controlling organelle morphology depends on membrane motility., The endoplasmic reticulum (ER) is an intracellular network characterized by highly dynamic behavior whose control mechanisms are unclear. Here, the authors show that the ER-membrane protein Reticulon (Rtnl1) can constrict ER bilayers and lead to ER fission.

Background: Several genomic alterations beyond RAS and BRAFV600E mutations have been preclinically validated as primary resistance drivers to EGFR inhibition in mCRC. We showed that our PRESSING panel (including PIK3CA exon 20/AKT1/PTEN mutations, ERBB2/MET amplification and ALK/ROS1/RET/NTRKs fusions) is useful to promote a new paradigm of negative hyper-selection, since patients with RAS/BRAF wt MSS mCRC and PRESSING alterations achieve significantly worse survival upon anti-EGFRs. With the aim of further refining molecular selection (negative ultra-selection), we investigated the clinical impact of candidate resistance alterations with even lower frequency (PRESSING2 panel) in a cohort of hyper-selected patients. Methods: A prospective dataset was developed at 3 Italian Academic Hospitals and included 650 mCRC patients with comprehensive genomic profiling of FFPE tumor tissue by means of FoundationOne CDx. We selected those with RAS/BRAF wt, MSS and PRESSING negative treated with anti-EGFRs. Alterations of the PRESSING2 panel were selected based on their actionability and biological value, as follows: ALK, ROS1, NTRKs, ERBB2/3/4, NF1, ARAF, MAP2K1 pathogenic mutations, PTEN loss, KRAS and AKT1-2 amplification, FGFR2 amplification/fusions, EGFR fusions. PRESSING2 status was correlated with progression-free survival (PFS) and overall survival (OS). Results: 163 molecularly hyper-selected patients with PRESSING negative status were identified; 30 (18%) had PRESSING2 alterations, which were mutually exclusive in 26 (87%) samples. No significant differences in baseline clinical and pathological characteristics - including sidedness - were found in PRESSING2 positive vs negative patients. The median follow-up was 34.6 months (IQR 23.5-49.3). Patients with PRESSING2 positive status had significantly worse PFS and OS vs those with PRESSING2 negative disease (median PFS 7.0 and 13.0 months; HR 3.54, 95%CI 2.26-5.52, P Conclusions: In the era of comprehensive genomic profiling, several resistance alterations with extremely low prevalence may be detected, especially in CRCs that do not bear other genomic drivers. Negative ultra-selection may represent a relevant step forward in precision medicine in patients with RAS/BRAF wt MSS mCRC potentially eligible for EGFR blockade. Citation Format: Giovanni Randon, Giulia Maddalena, Marco Maria Germani, Filippo Pagani, Francesca Bergamo, Mirella Giordano, Chiara Pircher, Caterina Sposetti, Luca Zambelli, Francesca Corti, Marta Bini, Alessandro Rametta, Andrea Spagnoletti, Aldo Montagna, Matteo Fassan, Alessandra Boccaccino, Guglielmo Vetere, Silvia Damian, Massimo Milione, Filippo de Braud, Chiara Cremolini, Sara Lonardi, Filippo Pietrantonio. Negative ultra-selection of patients with RAS/BRAF wild-type (wt), microsatellite stable (MSS) metastatic colorectal cancer (mCRC) receiving anti-EGFR-based therapy: The PRESSING2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1269.

2025 Background: Brain metastases (BM) from primary colorectal cancer (prCRC) are rare (1-3%); few is known about CRC BM predictive factors, prognosticators and molecular pathways. High rate of HER2 amplification ( HER2+) in CRC with BM was previously described, being HER2+ overall rare in CRC (

A 3D integrated saturation model was built for the Sierras Blancas Formation of the Neuquén Basin, Argentina. The saturation model was based on core, logs and seismic data. History match of reservoir pressure and well productivities were taken into account to accurately determine the gas in place and productive reservoir boundaries, specifically using 3D seismic water saturation in the gas condensate formation. The Sierras Blancas Formation is an eolian deposit. In tight, wet and diagenetically altered regions, the seismic inversion porosity and acoustic impedance based models were not adequate to describe the gas in place distribution. Further, the effective gas permeabilities in the tighter part of the reservoir are a strong function of the initial water saturation as evidenced by fewer condensate and water blocking problems of horizontal wells that navigated through low water saturation, high permeability regions. Any relationship between seismic impedance and porosity correlation degraded in areas affected by secondary diagenetic processes therefore necessitating the use of a saturation parameter. 30 vertical wells that had DT curves were selected based on their production and spatial location in order to establish a correlation between log saturation and seismic attributes. Seismic saturation cubes were generated by multiattribute seismic analysis and resampled into the simulation scale model. Log saturations were then co-kriged with the 3D seismic saturation. Water saturations obtained from the initialized simulation scale model were compared with the 2D saturation logs, the 3D seismic and the geological model scales. An objective function was defined to match the 3D seismic water saturation with the initialized simulation model water saturation. Model parameters were iterated until a satisfactory match with the initialized simulation model was obtained. By focusing the saturation match at the initialization stage, seismic, geological, petrophysical and SCAL models were ensured to be consistent prior to the full history match. Well history matching was consequently achieved much more simply and quickly. This paper presents a new detailed methodology of 3D pseudo-seismic water saturation generation, modeling and simulation used to accurately define OGIP, the productive boundaries of the reservoir, and to design trajectories for new horizontal wells.

The object of this work was to optimize a waterflood project in a highly complex structural-stratigraphic area. A geophysicist, two waterflood-monitoring engineers and a numerical simulation specialist made up the multidisciplinary team created for the project. The goal was to explain the low response to water injection in the subject area, i.e. the injection well behavior (variation in the admitted volume, overpressurization, etc.), and the corresponding shortage in production wells. The information used for this study consisted in 3D seismic data, interpreted well logs, correlation, transient pressure tests, production and injection history, hydraulic connectivity analysis and previous structural interpretations. A radioactive tracer test was also conducted. Seismic cross-section were developed between wells in order to detect structural and stratigraphic lineaments. Then, a seismic attribute analysis was performed. The reflection strength and the amplitude attribute reflected clearly the thickness loss northward and the deterioration of the petrophysical properties toward the east. The instantaneous phase attribute was used to interpret the structural frame but no significant results were obtained. A reliable correlation between petrophysical information and seismic data was achieved. After defining the structural – stratigraphic frame, the information above was related to the production and injection history of the area. Some old build up and fall off tests were reviewed in order to confirm the existence of faults and petrophysical changes. Based on this analysis, some proposals were drawn to improve 1the production and injection behavior of the pattern, namely, horizontal drilling from existing vertical wells, acid treatment, hydraulic fracturing and the drilling of a horizontal well in an unswept area. The reservoir water saturation distribution was evaluated for each proposal using a numerical simulation model and a cost-effective analysis of the proposals was carried out.