Author: "Tabernero J." / Topic: colorectal cancer - Searchworks@Jio Institute Digital Library Search Results

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106 results on '"Tabernero J."'

1. 515MO Encorafenib + cetuximab (EC) + FOLFIRI for BRAF V600E-mutant metastatic colorectal cancer (mCRC): Updated results from the BREAKWATER safety lead-in (SLI).

Author: Tabernero, J., Yoshino, T., Kim, T.W., Yaeger, R., Desai, J., Wasan, H.S., Van Cutsem, E., Ciardiello, F., Maughan, T., Eng, C., Tie, J., Fernandez, M.E. Elez, Lonardi, S., Usari, T., Hahn, E., Dychter, S., Ferrier, G., Zhang, X., and Kopetz, S.
Subjects: *COLORECTAL cancer, *CANCER chemotherapy, *METASTASIS, *BRAF genes, *CETUXIMAB
Published: 2024
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2. Quality of life with encorafenib plus cetuximab with or without binimetinib treatment in patients with BRAF V600E-mutant metastatic colorectal cancer: patient-reported outcomes from BEACON CRC

Author: Kopetz, S, Grothey, A, Van Cutsem, E, Yaeger, R, Wasan, H, Yoshino, T, Desai, J, Ciardiello, F, Loupakis, F, Hong, YS, Steeghs, N, Guren, TK, Arkenau, H-T, Garcia-Alfonso, P, Belani, A, Zhang, X, Tabernero, J, Institut Català de la Salut, [Kopetz S] University of Texas MD Anderson Cancer Center, Houston, USA. [Grothey A] West Cancer Center and Research Institute, OneOncology, Germantown, USA. [Van Cutsem E] University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium. [Yaeger R] Memorial Sloan-Kettering Cancer Center, New York, USA. [Wasan H] Hammersmith Hospital, Department of Cancer Medicine, London, UK. [Yoshino T] National Cancer Center Hospital East, Kashiwa, Japan. [Tabernero J] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. IOB-Quiron, UVic-UCC, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Proto-Oncogene Proteins B-raf, Cancer Research, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Cetuximab, colorectal cancer, encorafenib, Antineoplastic Agents, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Còlon - Càncer - Tractament, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES], Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], BEACON CRC, Recte - Càncer - Tractament, Antineoplastic Combined Chemotherapy Protocols, Humans, Investigative Techniques::Epidemiologic Methods::Data Collection::Surveys and Questionnaires::Health Care Surveys::Patient Reported Outcome Measures [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Patient Reported Outcome Measures, Sulfonamides, técnicas de investigación::métodos epidemiológicos::recopilación de datos::encuestas y cuestionarios::encuestas sobre atención a la salud::medidas de resultados percibidos por los pacientes [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES], quality of life, Oncology, patient-reported outcomes, Mutation, Avaluació de resultats (Assistència sanitària), Quality of Life, Benzimidazoles, Carbamates, Colorectal Neoplasms
Abstract: Colorectal cancer; Encorafenib; Quality of life Cáncer colorrectal; Encorafenib; Calidad de vida Càncer colorectal; Encorafenib; Qualitat de vida Background In the BEACON CRC study (NCT02928224), encorafenib plus cetuximab with binimetinib {9.3 versus 5.9 months; hazard ratio (HR) [95% confidence interval (CI)]: 0.60 [0.47-0.75]} or without binimetinib [9.3 versus 5.9 months; HR (95% CI): 0.61 (0.48-0.77)] significantly improved overall survival (OS) compared with the previous standard of care (control) in patients with BRAF V600E metastatic colorectal cancer (mCRC). Quality of life (QoL) was a secondary endpoint, assessed using validated instruments. Patients and methods BEACON CRC was a randomized, open-label, phase III study comparing encorafenib plus cetuximab with or without binimetinib and the investigator’s choice of irinotecan plus cetuximab or FOLFIRI plus cetuximab (chemotherapy control) in patients with previously treated BRAF V600E mCRC. Patient-reported QoL assessments included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC) and Functional Assessment of Cancer Therapy—Colorectal (FACT-C). The primary outcome for these tools was time to definitive 10% deterioration. Results Encorafenib plus cetuximab, both with and without binimetinib, was associated with longer median times to definitive 10% deterioration versus the control group in the EORTC Global Health Status scale [HR (95% CI): 0.65 (0.52-0.80) versus 0.61 (0.49-0.75), respectively] and the FACT-C functional well-being subscale [HR (95% CI): 0.62 (0.50-0.76) versus 0.58 (0.47-0.72), respectively]. Consistent results were observed across all subscales of the EORTC and FACT-C instruments. QoL was generally maintained during treatment for the global EORTC and FACT-C scales. Conclusions In addition to improving OS, encorafenib plus cetuximab with or without binimetinib delays QoL decline in previously treated patients with BRAF V600E-mutant mCRC. This study was sponsored by Array BioPharma Inc, which was acquired by Pfizer, United States; National Cancer Institute, United States in July 2019. This work was also supported by the Cancer Center Core Grant [grant number P30 CA 008748] to Memorial Sloan-Kettering Cancer Center.
Published: 2022
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3. ME2 Current insights of chemotherapy in colorectal cancer.

Author: Tabernero, J., Elez, E., and Castells, M.R.
Subjects: *CANCER chemotherapy, *COLORECTAL cancer
Published: 2024
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4. SY14-1 Unveiling BRAFV600E metastatic colorectal cancer as an entity of its own.

Author: Tabernero, J., Elez, E., and Ros, J.
Subjects: *COLORECTAL cancer, *METASTASIS
Published: 2024
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5. AXL is a predictor of poor survival and of resistance to anti-EGFR therapy in RAS wild-type metastatic colorectal cancer

Author: Cardone C., Blauensteiner B., Moreno-Viedma V., Martini G., Simeon V., Vitiello P. P., Ciardiello D., Belli V., Matrone N., Troiani T., Morgillo F., Zito Marino F., Dentice M., Nappi A., Boccaccino A., Antoniotti C., Cremolini C., Pietrantonio F., Prager G. W., Normanno N., Maiello E., Argiles G., Elez E., Signoriello G., Franco R., Falcone A., Tabernero J., Sibilia M., Ciardiello F., Martinelli E., ZITO MARINO, Federica, Cardone, Claudia, Blauensteiner, Bernadette, Moreno-Viedma, Veronica, Martini, Giulia, Simeon, Vittorio, Vitiello, Pietro P, Ciardiello, Davide, Belli, Valentina, Matrone, Nunzia, Troiani, Teresa, Morgillo, Floriana, Zito Marino, Federica, Dentice, Monica, Nappi, Annarita, Boccaccino, Alessandra, Antoniotti, Carlotta, Cremolini, Chiara, Pietrantonio, Filippo, Prager, Gerald W, Normanno, Nicola, Maiello, Evaristo, Argiles, Guillem, Elez, Elena, Signoriello, Giuseppe, Franco, Renato, Falcone, Alfredo, Tabernero, Josep, Sibilia, Maria, Ciardiello, Fortunato, Martinelli, Erika, Cardone, C., Blauensteiner, B., Moreno-Viedma, V., Martini, G., Simeon, V., Vitiello, P. P., Ciardiello, D., Belli, V., Matrone, N., Troiani, T., Morgillo, F., Zito Marino, F., Dentice, M., Nappi, A., Boccaccino, A., Antoniotti, C., Cremolini, C., Pietrantonio, F., Prager, G. W., Normanno, N., Maiello, E., Argiles, G., Elez, E., Signoriello, G., Franco, R., Falcone, A., Tabernero, J., Sibilia, M., Ciardiello, F., Martinelli, E., and ZITO MARINO, Federica
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, Population, 03 medical and health sciences, Mice, 0302 clinical medicine, Growth factor receptor, Internal medicine, Cell Line, Tumor, Proto-Oncogene Proteins, Medicine, Animals, Humans, Epithelial–mesenchymal transition, Neoplasm Metastasis, education, education.field_of_study, Cetuximab, business.industry, AXL, EGFR resistance, RAS WT, Receptor Protein-Tyrosine Kinases, Transfection, medicine.disease, Xenograft Model Antitumor Assays, Axl Receptor Tyrosine Kinase, Blockade, ErbB Receptors, 030104 developmental biology, Genes, ras, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Immunohistochemistry, business, Colorectal Neoplasms, Biomarkers, medicine.drug
Abstract: Background RAS mutations are the only validated biomarkers in metastatic colorectal cancer (mCRC) for anti-epidermal growth factor receptor (EGFR) therapy. Limited clinical information is available on AXL expression, marker of epithelial to mesenchymal transition, in mCRC. Methods AXL was retrospectively assessed by immunohistochemistry in 307 patients. RAS wild-type (WT) patients (N = 136) received first-line anti-EGFR–based therapy; RAS mutant patients (N = 171) received anti-angiogenic–based regimens. Preclinical experiments were performed using human RAS WT CRC cell lines and xenograft models. AXL RNA levels were assessed in a cohort of patients with available samples at baseline and at progression to anti-EGFR treatment and in the GSE5851 dataset. Results AXL was expressed in 55/307 tumour tissues, correlating with worse survival in the overall population (AXL-positive, 23.7 months; AXL-negative, 30.8 months; HR, 1.455, P = 0.032) and in RAS WT patients (AXL-positive, 23.0 months; AXL-negative, 35.8 months; HR,1.780, P = 0.032). Progression-free survival (PFS) in the RAS WT cohort was shorter in the AXL-positive cohort (6.2 months versus 12.1 months; HR, 1.796, P = 0.013). Three-dimensional cultures obtained from a patient following anti-EGFR therapy resulted AXL-positive, showing resistance to anti-EGFR drugs and sensitivity to AXL inhibition. AXL transfection in CRC cell lines induced AXL overexpression and resistance to the EGFR blockade. At progression to cetuximab, 2/10 SW48-tumour xenograft mice showed AXL expression. Consistently, AXL RNA levels increased in 5/7 patients following anti-EGFR therapy. Moreover, in the GSE5851 dataset higher AXL RNA levels correlated with worse PFS with cetuximab in KRAS-exon2 WT chemorefractory patients. Conclusions AXL is a marker of poor prognosis in mCRC with consistent clinical and preclinical evidences of involvement in primary and acquired resistance to anti-EGFR drugs in RAS WT patients.
Published: 2020

6. Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE—a global phase III study

Author: Yoshino, Takayuki, Portnoy, D. C., Obermannová, R., Bodoky, G., Prausová, J., García-Carbonero, Rocío, Ciuleanu, Tudor Eliade, García-Alfonso, Pilar, Cohn, A. L., Van Cutsem, E., Yamazaki, K., Lonardi, Sara, Muro, K., Kim, T. W., Yamaguchi, K., Grothey, A., O'Connor, J., Taieb, J., Wijayawardana, S. R., Hozak, R. R., Nasroulah, F., Tabernero, J., Vall d'Hebron Institut d'Oncologia, Institut Català de la Salut, [Yoshino T] National Cancer Center Hospital East, Kashiwa, Japan. [Portnoy DC] The West Clinic, Memphis, USA. [Obermannová R] Masarykuv Onkologicky Ustav, Brno, Czech Republic. [Bodoky G] St. Laszlo Hospital, Budapest, Hungary. [Prausová J] Fakultni Nemocnice v MOTOLE, Prague, Czech Republic. [Garcia-Carbonero R] Hospital Hospital Universitario Doce de Octubre, IIS imas12, UCM, CNIO, CIBERONC, Madrid, Spain. [Tabernero J] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. CIBERONC, Barcelona, Spain, Hospital Universitari Vall d'Hebron, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, Oncology, Male, IRINOTECAN, Colorectal cancer, Left, Leucovorin, factores biológicos::biomarcadores::marcadores tumorales [COMPUESTOS QUÍMICOS Y DROGAS], Cetuximab, Other subheadings::/analysis [Other subheadings], GUIDELINES, medicine.disease_cause, DOUBLE-BLIND, 0302 clinical medicine, Còlon - Càncer, Antineoplastic Combined Chemotherapy Protocols, OXALIPLATIN, Neoplasm Metastasis, Neovascularization, Pathologic, Otros calificadores::/análisis [Otros calificadores], COLON-CANCER, Hazard ratio, Neoplasms::Neoplastic Processes::Neoplasm Metastasis [DISEASES], Hematology, CHEMOTHERAPY, neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES], Prognosis, KRAS WILD-TYPE, Survival Rate, Colorectal carcinoma, 030220 oncology & carcinogenesis, FOLFIRI, Recte - Càncer, Female, KRAS, Fluorouracil, Colorectal Neoplasms, Life Sciences & Biomedicine, medicine.medical_specialty, ramucirumab, BEVACIZUMAB, NRAS, Antibodies, Monoclonal, Humanized, Ramucirumab, BRAF, 03 medical and health sciences, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES], colorectal carcinoma, left, Internal medicine, Gastrointestinal Tumors, medicine, Biomarkers, Tumor, Humans, Biological Factors::Biomarkers::Biomarkers, Tumor [CHEMICALS AND DRUGS], Survival rate, Aged, Splenic flexure, Science & Technology, business.industry, Marcadors tumorals, Original Articles, medicine.disease, FLUOROURACIL, digestive system diseases, Proto-Oncogene Proteins c-raf, 030104 developmental biology, neoplasias::procesos neoplásicos::metástasis neoplásica [ENFERMEDADES], ANTIBODIES, Mutation, ras Proteins, Camptothecin, business, Follow-Up Studies
Abstract: Carcinoma colorrectal; Ramucirumab; BRAF Carcinoma colorrectal; Ramucirumab; BRAF Colorectal carcinoma; Ramucirumab; BRAF Background Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC) [hazard ratio (HR)=0.84, 95% CI 0.73–0.98, P = 0.022]. Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters. Patients and methods Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS (RAS) mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon, and cecum. Results RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95% CI 0.71–1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95% CI 0.64–1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95% CI 0.25–1.13), although, as with the other genetic sub-group analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P = 0.523, PFS P = 0.655) indicated that the ramucirumab benefit was not statistically different among the mutation sub-groups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95% CI 0.68–0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95% CI 0.75–1.26). The treatment-by-sub-group interaction was not statistically significant for tumour sidedness (P = 0.276). Conclusions In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the P-values were not statistically significant. This work was supported by Eli Lilly and Company. No grant number is applicable.
Published: 2018

7. Feasibility of cetuximab given with a simplified schedule every 2 weeks in advanced colorectal cancer: a multicenter, retrospective analysis

Author: Bouchahda, M., Macarulla, T., LIedo, G., Lévi, F., Elez, M. E., Paule, B., Karaboué, A., Artru, P., Tabernero, J., Machover, D., Innominato, P., Goldschmidt, E., Bonnet, D., Ducreux, M., Castagne, V., and Guimbaud, R.
Published: 2011
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8. 91P Clinical outcomes of patients (Pts) with BRAF V600E-mutant metastatic colorectal cancer (mCRC) treated with first-line (1L) chemotherapy regimens.

Author: Parikh, A., Tabernero, J., Vieira, M.C., Kponee-Shovein, K., Li, B., Cheng, M., Liu, J., Kang, H., and Zhang, X.
Subjects: *COLORECTAL cancer, *METASTASIS, *BRAF genes, *TREATMENT effectiveness, *CANCER chemotherapy
Published: 2024
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9. 614P Effect of KRASG12 mutations on overall survival in patients with refractory metastatic colorectal cancer: A post-hoc analysis of the phase III SUNLIGHT trial.

Author: Tabernero, J., Prager, G., Fakih, M., Ciardiello, F., Van Cutsem, E., Elez Fernandez, M.E., Cruz, F.J.S.M., Wyrwicz, L.S., Stroyakovskiy, D., Pápai, Z., Martinelli, E., Salvatore, L., Poureau, P.G., Liposits, G., Cremolini, C., Modest, D.P., Causse-Amellal, N., Roby, L., Skanji, D., and Taieb, J.
Subjects: *CLINICAL trials, *OVERALL survival, *COLORECTAL cancer, *METASTASIS, *BRAF genes, *METASTATIC breast cancer
Published: 2023
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10. P-35 Zanzalintinib (XL092) in combination with atezolizumab for previously treated metastatic colorectal cancer.

Author: Tabernero, J., Saeed, A., Parikh, A., Wang, Y., Wang, Z., Schwickart, M., Curran, D., and Hecht, J.
Subjects: *COLORECTAL cancer, *ATEZOLIZUMAB, *METASTASIS
Published: 2023
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11. Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study.

Author: Tabernero, J, Hozak, R R, Yoshino, T, Cohn, A L, Obermannova, R, Bodoky, G, Garcia-Carbonero, R, Ciuleanu, T -E, Portnoy, D C, and Prausová, J
Subjects: *VASCULAR endothelial growth factors, *IMMUNOGLOBULINS, *DRUG therapy, *CANCER patients, *CANCER treatment, *HEALTH outcome assessment
Abstract: Background: The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo+FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most fromVEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Patients and methods: Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Results: Biomarker results were available from>80% (n=894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME+MC populations found that the median OS in the ramucirumab+FOLFIRI arm compared with placebo+FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5-15.6) versus 11.5 months (95% CI 10.1-12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7-14.0) versus 13.1 months (95% CI 11.8-17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. Conclusions: The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. [ABSTRACT FROM AUTHOR]
Published: 2018
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12. Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel

Author: Nordlinger, B, Van Cutsem, E, Gruenberger, T, Glimelius, B, Poston, G, Rougier, P, Sobrero, A, Ychou, M, Carrato, A, Chiang, Jm, De Hemptinne, B, Falcone, A, Figueras, J, Gigot, Jf, Georgoulias, V, Giuliante, Felice, Glynne Jones, R, Köhne, Ch, Papamichael, D, Pozzo, Carmelo, Tabernero, J, Wasan, H, and Wilson, R.
Subjects: medicine.medical_specialty, Bevacizumab, Colorectal cancer, Settore MED/18 - CHIRURGIA GENERALE, medicine.medical_treatment, Targeted therapy, Liver metastases, Liver disease, Colorectal metastases, Antineoplastic Combined Chemotherapy Protocols, medicine, Chemotherapy, Hepatectomy, Humans, Combination therapy, Neoadjuvant therapy, Targeted agents, Expert panel, Liver resection, business.industry, General surgery, Liver Neoplasms, Cancer, Hematology, medicine.disease, Chemotherapy regimen, Combined Modality Therapy, Neoadjuvant Therapy, Surgery, Oncology, Chemical and Drug Induced Liver Injury, business, Colorectal Neoplasms, medicine.drug
Abstract: The past 5 years have seen the clear recognition that the administration of chemotherapy to patients with initially unresectable colorectal liver metastases can increase the number of patients who can undergo potentially curative secondary liver resection. Coupled with this, recent data have emerged that show that perioperative chemotherapy confers a disease-free survival advantage over surgery alone in colorectal cancer (CRC) patients with initially resectable liver disease. The purpose of this paper is to build on the existing knowledge and review the issues surrounding the use of chemotherapy +/- targeted agents combined with surgery in the treatment of CRC patients with liver metastases, with a view to providing clinical recommendations. An international panel of 21 experts in colorectal oncology comprising liver surgeons and medical oncologists reviewed the available evidence. In a major change to clinical practice, the panel's recommendation was that the majority of patients with CRC liver metastases should be treated up front with chemotherapy, irrespective of the initial resectability status of their metastases.
Published: 2009

13. LBA26 BREAKWATER safety lead-in (SLI): Encorafenib (E) + cetuximab (C) + chemotherapy (chemo) for BRAFV600E metastatic colorectal cancer (mCRC).

Author: Tabernero, J., Yoshino, T., Kim, T.W., Yaeger, R., Desai, J., Wasan, H.S., Van Cutsem, E., Ciardiello, F., Maughan, T., Eng, C., Tie, J., Fernandez, M.E. Elez, Lonardi, S., Zhang, X., Chavira, R., Usari, T., Hahn, E., and Kopetz, S.
Subjects: *COLORECTAL cancer, *CETUXIMAB, *METASTASIS, *BREAKWATERS, *CANCER chemotherapy
Published: 2022
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14. P-111 PERSPECTIVE: Tepotinib plus cetuximab in patients with RAS/BRAF wild-type left-sided metastatic colorectal cancer and acquired resistance to anti-EGFR antibody therapy due to MET amplification.

Author: Tabernero, J., Bekaii-Saab, T., Safont Aguilera, M., Cubillo, A., Garcia-Carbonero, R., Limon, L., Rodríguez-Salas, N., Tournigand, C., Borg, C., Raghav, K., Finley, G., Strickler, J., Beier, F., Salim, S., Esser, R., Liu, E., Adrian, S., and López-López, C.
Subjects: *CETUXIMAB, *COLORECTAL cancer, *EPIDERMAL growth factor receptors
Published: 2021
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15. O-9 5-FU/LV + cetuximab + vemurafenib as maintenance therapy for BRAF-mutant (BRAFmut) metastatic colorectal cancer: Efficacy, safety, and exploratory biomarker findings from Cohort 1 of the MODUL trial.

Author: Ducreux, M., Tabernero, J., Grothey, A., Arnold, D., O'Dwyer, P., Perdicchio, M., Assaf, Z., Das Thakur, M., Irahara, N., Tahiri, A., Schmoll, H., Van Cutsem, E., and de Gramont, A.
Subjects: *CETUXIMAB, *BRAF genes, *COLORECTAL cancer
Published: 2021
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16. Microsatellite instability due to hMLH1 deficiency is associated with increased cytotoxicity to irinotecan in human colorectal cancer cell lines.

Author: Vilar, E, Scaltriti, M, Balmaña, J, Saura, C, Guzman, M, Arribas, J, Baselga, J, Tabernero, J, and Balmaña, J
Subjects: MICROSATELLITE repeats, CANCER cells, CELL lines, COLON cancer, NUCLEOTIDES, ANTINEOPLASTIC agents, CAMPTOTHECIN, CARRIER proteins, COLON tumors, COMPARATIVE studies, DEGENERATION (Pathology), ENZYMES, RESEARCH methodology, MEDICAL cooperation, RECTUM tumors, RESEARCH, DNA-binding proteins, EVALUATION research, NUCLEAR proteins, CYTOTOXINS, PHARMACODYNAMICS
Abstract: Around 15% of colorectal cancers (CRCs) show microsatellite instability (MSI) due to dysfunction of the mismatch repair system (MMR). As a consequence of this, MSI tumours tend to accumulate errors in mononucleotide repeats as those in genes implicated in repairing double-strand breaks (DSBs). Previous studies have shown that irinotecan (CPT-11), a chemotherapy agent inducing DSB, is more active in MSI than in microsatellite stable (MSS) CRC. The purpose of this study was to compare the sensitivity to CPT-11 in a series of CRC cell lines with either proficient or deficient MMR and to assess the mutational status of two DSB repair genes, MRE11 and RAD50, in these cell lines. hMLH1-deficient cell lines due to either epigenetic silencing or mutation showed very similar IC(50) and were four- to nine-fold more sensitive to CPT-11 than the MSS line. Cell lines harbouring mutations in both MRE11 and RAD50 were most sensitive to CPT-11. We conclude that MSI cell lines display higher sensitivity to CPT-11 than MSS cells. Mutation of MRE11 and RAD50 could account for this difference in response to CPT-11. Future clinical trials tailoring chemotherapy regimens based on microsatellite status are warranted. [ABSTRACT FROM AUTHOR]
Published: 2008
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17. LBA-5 ANCHOR CRC: a single-arm, phase 2 study of encorafenib, binimetinib plus cetuximab in previously untreated BRAF V600E-mutant metastatic colorectal cancer.

Author: Grothey, A., Tabernero, J., Taieb, J., Yaeger, R., Yoshino, T., Maiello, E., Fernandez, E. Elez, Casado, A. Ruiz, Ross, P., André, T., Kato, T., Ruffinelli, J., Graham, J., den Eynde, M. Van, Vera, R., Jean, B., Roussel, E. Carriere, Cahuzac, C., Issiakhem, Z., and Vedovato, J.
Subjects: *CETUXIMAB, *COLORECTAL cancer, *BRAF genes
Published: 2020
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18. P-71 KRYSTAL-10: A randomized phase 3 study of adagrasib (MRTX849) in combination with cetuximab vs chemotherapy in patients with previously treated advanced colorectal cancer with KRASG12C mutation.

Author: Tabernero, J., Bendell, J., Corcoran, R., Kopetz, S., Lee, J., Davis, M., Christensen, J., Chi, A., Kheoh, T., and Yaeger, R.
Subjects: *CETUXIMAB, *CANCER chemotherapy, *COLORECTAL cancer
Published: 2021
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19. P-79 C-PRECISE-01 study: A phase Ib/II trial of MEN1611, a PI3K inhibitor, and cetuximab in patients with PIK3CA mutated metastatic colorectal cancer failing irinotecan, oxaliplatin, 5-FU and anti-EGFR containing regimens.

Author: Tabernero, J., Fernandez, E. Elez, Ghiringhelli, F., Folprecht, G., Curigliano, G., Siena, S., Cremolini, C., Sobrero, A., Kwiatek, M., Keränen, S. Roselló, Ahn, D., Punt, C., Laurent, D., Ferrara, M., Pellacani, A., and Capriati, A.
Subjects: *CETUXIMAB, *COLORECTAL cancer, *CANCER treatment
Published: 2020
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20. Circulating tumor DNA, and clinical features to guide rechallenge with BRAF inhibitors in BRAF-V600E mutated metastatic colorectal cancer.

Author: Ros, J., Vivancos, A., Tabernero, J., and Élez, E.
Subjects: *CIRCULATING tumor DNA, *COLORECTAL cancer, *METASTASIS, *REGORAFENIB, *BRAF genes
Published: 2024
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21. LBA19Fluoropyrimidine (FP) + bevacizumab (BEV) + atezolizumab vs FP/BEV in BRAFwt metastatic colorectal cancer (mCRC): Findings from Cohort 2 of MODUL – a multicentre, randomized trial of biomarker-driven maintenance treatment following first-line induction therapy

Author: Grothey, A, Tabernero, J, Arnold, D, Gramont, A De, Ducreux, M P, O'Dwyer, P J, Cutsem, E Van, Bosanac, I, Srock, S, and Mancao, C
Subjects: *COLORECTAL cancer, *METASTASIS, *CANCER genetics
Published: 2018
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22. Plasmatic BRAF-V600E allele fraction as a prognostic factor in metastatic colorectal cancer treated with BRAF combinatorial treatments

Author: J. Ros, J. Matito, G. Villacampa, R. Comas, A. Garcia, G. Martini, I. Baraibar, N. Saoudi, F. Salvà, Á. Martin, M. Antista, R. Toledo, E. Martinelli, F. Pietrantonio, A. Boccaccino, C. Cremolini, R. Dientsmann, J. Tabernero, A. Vivancos, E. Elez, Ros, J, Matito, J, Villacampa, G, Comas, R, Garcia, A, Martini, G, Baraibar, I, Saoudi, N, Salvà, F, Martin, Á, Antista, M, Toledo, R, Martinelli, E, Pietrantonio, F, Boccaccino, A, Cremolini, C, Dientsmann, R, Tabernero, J, Vivancos, A, Elez, E, Institut Català de la Salut, [Ros J] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Matito J, Comas R, Garcia A, Toledo R, Dientsmann R, Vivancos A] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Villacampa G] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. The Institute of Cancer Research, London, UK. [Martini G] Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy. [Baraibar I, Saoudi N, Salvà F, Tabernero J, Elez E] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Martin Á] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: BRAF inhibitor, MEK inhibitor, Recte - Càncer - Aspectes genètics, Prognosi, Otros calificadores::Otros calificadores::/genética [Otros calificadores], Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES], Còlon - Càncer - Aspectes genètics, colorectal cancer, Hematology, fenómenos genéticos::estructuras genéticas::genoma::componentes genómicos::genes::alelos [FENÓMENOS Y PROCESOS], neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES], anti-EGFR, mutant allele fraction, Anomalies cromosòmiques, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES], Oncology, Other subheadings::Other subheadings::/genetics [Other subheadings], BRAF-V600E mutation, Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Alleles [PHENOMENA AND PROCESSES], Diagnosis::Prognosis [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], diagnóstico::pronóstico [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS]
Abstract: BRAF inhibitor; Colorectal cancer Inhibidor de BRAF; Cáncer colorrectal Inhibidor de BRAF; Càncer colorectal Background Combination of a BRAF inhibitor (BRAFi) and an anti-epidermal growth factor receptor (EGFR), with or without a MEK inhibitor (MEKi), improves survival in BRAF-V600E-mutant metastatic colorectal cancer (mCRC) over standard chemotherapy. However, responses are heterogeneous and there are no available biomarkers to assess patient prognosis or guide doublet- or triplet-based regimens. In order to better characterize the clinical heterogeneity observed, we assessed the prognostic and predictive role of the plasmatic BRAF allele fraction (AF) for these combinations. Patients and methods A prospective discovery cohort including 47 BRAF-V600E-mutant patients treated with BRAFi–anti-EGFR ± MEKi in clinical trials and real-world practice was evaluated. Results were validated in an independent multicenter cohort (n = 29). Plasmatic BRAF-V600E AF cut-off at baseline was defined in the discovery cohort with droplet digital PCR (ddPCR). All patients had tissue-confirmed BRAF-V600E mutations. Results Patients with high AF have major frequency of liver metastases and more metastatic sites. In the discovery cohort, median progression-free survival (PFS) and overall survival (OS) were 4.4 and 10.1 months, respectively. Patients with high BRAF AF (≥2%, n = 23) showed worse PFS [hazard ratio (HR) 2.97, 95% confidence interval (CI) 1.55-5.69; P = 0.001] and worse OS (HR 3.28, 95% CI 1.58-6.81; P = 0.001) than low-BRAF AF patients (
Published: 2023

23. 490P Safety and efficacy of tusamitamab ravtansine in patients with colorectal or gastric cancer expressing carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5).

Author: Italiano, A., Gazzah, A., Tabernero, J., Kang, Y-K., Calvo, E., Provencio Pulla, M., Bang, Y-J., Barlesi, F., Bedard, P.L., Park, J.O., Kim, J-S., Chadjaa, M., Yoruk, S., and Delord, J-P.
Subjects: *CELL adhesion molecules, *STOMACH cancer, *COLORECTAL cancer
Published: 2022
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24. 438TiP MOUNTAINEER-03: Phase III study of tucatinib, trastuzumab, and mFOLFOX6 as first-line treatment in HER2+ metastatic colorectal cancer (trial in progress).

Author: André, T., Bekaii-Saab, T., Tabernero, J., Siena, S., Yoshino, T., Norwood, K.G., Adelberg, D.E., Ward, J., Yang, S., Strickler, J.H., and Van Cutsem, E.
Subjects: *COLORECTAL cancer, *METASTASIS, *TRASTUZUMAB, *THERAPEUTICS
Published: 2022
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25. Plasmatic BRAF-V600E allele fraction as a prognostic factor in metastatic colorectal cancer treated with BRAF combinatorial treatments.

Author: Ros, J., Matito, J., Villacampa, G., Comas, R., Garcia, A., Martini, G., Baraibar, I., Saoudi, N., Salvà, F., Martin, Á., Antista, M., Toledo, R., Martinelli, E., Pietrantonio, F., Boccaccino, A., Cremolini, C., Dientsmann, R., Tabernero, J., Vivancos, A., and Elez, E.
Subjects: *BRAF genes, *COLORECTAL cancer, *CIRCULATING tumor DNA, *METASTASIS, *PROGNOSIS
Abstract: Combination of a BRAF inhibitor (BRAFi) and an anti-epidermal growth factor receptor (EGFR), with or without a MEK inhibitor (MEKi), improves survival in BRAF - V600E-mutant metastatic colorectal cancer (mCRC) over standard chemotherapy. However, responses are heterogeneous and there are no available biomarkers to assess patient prognosis or guide doublet- or triplet-based regimens. In order to better characterize the clinical heterogeneity observed, we assessed the prognostic and predictive role of the plasmatic BRAF allele fraction (AF) for these combinations. A prospective discovery cohort including 47 BRAF- V600E-mutant patients treated with BRAFi–anti-EGFR ± MEKi in clinical trials and real-world practice was evaluated. Results were validated in an independent multicenter cohort (n = 29). Plasmatic BRAF- V600E AF cut-off at baseline was defined in the discovery cohort with droplet digital PCR (ddPCR). All patients had tissue-confirmed BRAF- V600E mutations. Patients with high AF have major frequency of liver metastases and more metastatic sites. In the discovery cohort, median progression-free survival (PFS) and overall survival (OS) were 4.4 and 10.1 months, respectively. Patients with high BRAF AF (≥2%, n = 23) showed worse PFS [hazard ratio (HR) 2.97, 95% confidence interval (CI) 1.55-5.69; P = 0.001] and worse OS (HR 3.28, 95% CI 1.58-6.81; P = 0.001) than low- BRAF AF patients (<2%, n = 24). In the multivariable analysis, BRAF AF levels maintained independent significance. In the validation cohort, high BRAF AF was associated with worse PFS (HR 3.83, 95% CI 1.60-9.17; P = 0.002) and a trend toward worse OS was observed (HR 1.86, 95% CI 0.80-4.34; P = 0.15). An exploratory analysis of predictive value showed that high-BRAF AF patients (n = 35) benefited more from triplet therapy than low-BRAF AF patients (n = 41; PFS and OS interaction tests, P < 0.01). Plasmatic BRAF AF determined by ddPCR is a reliable surrogate of tumor burden and aggressiveness in BRAF- V600E-mutant mCRC treated with a BRAFi plus an anti-EGFR with or without a MEKi and identifies patients who may benefit from treatment intensification. Our results warrant further validation of plasmatic BRAF AF to refine clinical stratification and guide treatment strategies. • Plasmatic BRAF AF has a prognostic role for survival in mCRC treated with BRAF inhibitors. • ddPCR, applied in a cohort including a real-world population, mirrored those of the BEACON clinical trial using next-generation sequencing (NGS). • ddPCR detects BRAF AF in circulating tumor DNA (ctDNA) with high reproducibility and sensitivity, offering a validated alternative to NGS. • Identifying prognostic factors in BRAF-mutant mCRC is crucial to stratify patients and guide treatment strategies. [ABSTRACT FROM AUTHOR]
Published: 2023
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26. Monoclonal antibodies in the treatment of advanced colorectal cancer.

Author: Capdevila, J., Saura, C., Macarulla, T., Casado, E., Ramos, F.J., and Tabernero, J.
Subjects: CANCER treatment, IMMUNOGLOBULINS, CANCER patients, MONOCLONAL antibodies
Abstract: Abstract: Despite the advances obtained in recent years in the treatment of metastatic colorectal cancer, the prognosis remains poor. An emerging understanding of the molecular pathways has provided novel targets in cancer therapy to improve these results. Emerging data from the clinical development of new drugs against these targets is providing novel opportunities in the treatment of patients with colorectal cancer. There is a need to optimize and define the best use of these new approaches. In this review, the authors examine the current development status of monoclonal antibodies in the treatment of advanced colorectal cancer. [Copyright &y& Elsevier]
Published: 2007
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27. 600TiP A randomized blinded phase II study of ompenaclid (RGX-202-01) vs placebo in combination with FOLFIRI plus bevacizumab (BEV) in patients (pts) with previously treated RAS mutated (RASmt) advanced/metastatic colorectal cancer (mCRC).

Author: Elez Fernandez, M.E., Rosello Keranen, S., Paez, D., Jiménez Castro, J., Rivera Herrero, F., Ruiz-Casado, A., Riesco Martinez, M.C., Montagut Viladot, C., Coupez, D., Ducreux, M.P., Loly, C., Martin-Babau, J., Prenen, H., van den Eynde, M., Borg, C., Cuyle, P-J., de Haar-Holleman, A., Raimbourg, J., Bechar, N., and Tabernero, J.
Subjects: *COLORECTAL cancer, *METASTASIS, *CANCER chemotherapy, *BEVACIZUMAB, *PLACEBOS
Published: 2024
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28. 588P Genomic landscape of acquired resistance to first-line (1L) anti-EGFR treatment in metastatic colorectal cancer (mCRC) beyond the classical EGFR pathway: Findings from the PLATFORM-B study.

Author: Martelli, V., Barrull, J. Vidal, Rodriguez, C. Fernandez, Toledo, R.D.A., Gibert, J., Alfonso, P. García, Paez, D., Alonso-Orduna, V., Gomez España, M.A., Vivas, C. Santos, Ogaya, G. Duran, Fernandez, M.E. Elez, Garcia-Carbonero, R., Monteagudo, R. Ferreiro, Mozo, J.L. Manzano, Paricio, B. Bellosillo, Tabernero, J., Soler, R. Salazar, Aguilar, E. Aranda, and Viladot, C. Montagut
Subjects: *COLORECTAL cancer, *METASTASIS, *EPIDERMAL growth factor receptors
Published: 2024
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29. 526P Efficacy and safety of fruquintinib in refractory metastatic colorectal cancer: A FRESCO-2 subgroup analysis by age.

Author: Fernandez, M.E. Elez, Dasari, N.A., Lonardi, S., Eng, C., Garcia-Carbonero, R., Yoshino, T., Sobrero, A., Yao, J.C., Alfonso, P. García, Kocsis, J., Gracian, A. Cubillo, Bianchi, A. Sartore, Satoh, T., Randrian, V., Cremolini, C., Yang, Z., Schelman, W., Zhu, H., Chen, L., and Tabernero, J.
Subjects: *COLORECTAL cancer, *METASTASIS, *SUBGROUP analysis (Experimental design), *AGE, *SAFETY
Published: 2024
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30. Corrigendum to "Plasmatic BRAF-V600E allele fraction as a prognostic factor in metastatic colorectal cancer treated with BRAF combinatorial treatments": [Annals of Oncology 34 (2023) 543-552].

Author: Ros, J., Matito, J., Villacampa, G., Comas, R., Garcia, A., Martini, G., Baraibar, I., Saoudi, N., Salvà, F., Martin, Á., Antista, M., Toledo, R., Martinelli, E., Pietrantonio, F., Boccaccino, A., Cremolini, C., Dienstmann, R., Tabernero, J., Vivancos, A., and Elez, E.
Subjects: *COLORECTAL cancer, *PROGNOSIS, *METASTASIS, *BRAF genes, *ALLELES
Published: 2024
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31. Trifluridine/tipiracil plus bevacizumab for third-line management of metastatic colorectal cancer: SUNLIGHT study design

Author: Gerald W. Prager, Josep Tabernero, Nadia Amellal, Eric Van Cutsem, Julien Taieb, Catherine Leger, Fortunato Ciardiello, Marwan Fakih, Ronan Fougeray, Tabernero, J., Taieb, J., Prager, G. W., Ciardiello, F., Fakih, M., Leger, C., Fougeray, R., Amellal, N., Van Cutsem, E., Institut Català de la Salut, [Tabernero J] Vall d'Hebron Hospital Universitari, Barcelona, Spain. Institute of Oncology (VHIO), Barcelona, Spain. [Taieb J] Service d'hépatogastroentérologie et d'oncologie digestive, Université de Paris, Paris Descartes University, Georges Pompidou European Hospital, 20 rue Leblanc, Paris, France. [Prager GW] Department of Medicine I, Comprehensive Cancer Centre Vienna, Medical University Vienna, Josefstaedter Str. 23/15, Vienna, Austria. [Ciardiello F] Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Via S. Pansini, Naples, Italy. [Fakih M] Briskin Center for Clinical Research, Section Head and GI Medical Oncology, City of Hope Comprehensive Cancer Center, 1500 E Duarte St, Duarte, CA, USA. [Leger C] Institut de Recherches Internationales Servier, 50 rue Carnot, Suresnes Cedex, France, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Oncology, Male, Cancer Research, Pyrrolidines, genetic structures, Colorectal cancer, Medicaments antineoplàstics - Ús terapèutic, Trifluridine, law.invention, trifluridine/tipiracil, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Còlon - Càncer, Antineoplastic Combined Chemotherapy Protocols, Multicenter Studies as Topic, Other subheadings::/therapeutic use [Other subheadings], 030212 general & internal medicine, Neoplasm Metastasis, third line, Randomized Controlled Trials as Topic, third-line, Aged, 80 and over, metastatic colorectal cancer, General Medicine, Middle Aged, neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES], Bevacizumab, Drug Combinations, 030220 oncology & carcinogenesis, Recte - Càncer, Female, Colorectal Neoplasms, Life Sciences & Biomedicine, medicine.drug, Adult, medicine.medical_specialty, bevacizumab, 03 medical and health sciences, Young Adult, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES], Phase III, Refractory, Internal medicine, mental disorders, parasitic diseases, medicine, Humans, Thymidine phosphorylase, terapéutica::protocolos clínicos::protocolos antineoplásicos::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Tipiracil, Aged, Science & Technology, Otros calificadores::/uso terapéutico [Otros calificadores], business.industry, nutritional and metabolic diseases, Therapeutics::Clinical Protocols::Antineoplastic Protocols::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], medicine.disease, eye diseases, nervous system diseases, refractory, chemistry, Third line, Clinical Trials, Phase III as Topic, randomized controlled trial, FTD/TPI, business, Thymine
Abstract: Bevacizumab; Càncer colorectal metastàtic; Trifluridine/tipiracil Bevacizumab; Cáncer colorrectal metastásico; Trifluridine/tipiracil Bevacizumab; Metastatic colorectal cancer; Trifluridine/tipiracil Trifluridine/tipiracil (FTD/TPI) is an orally active formulation of trifluridine, a thymidine-based nucleoside analog, and tipiracil hydrochloride, a thymidine phosphorylase inhibitor that increases the bioavailability of trifluridine. Preliminary studies of FTD/TPI plus bevacizumab have produced encouraging results in the treatment of refractory metastatic colorectal cancer. Here, we describe the design of the multinational Phase III SUNLIGHT, an open-label study of FTD/TPI plus bevacizumab as third-line treatment for patients with unresectable metastatic colorectal cancer. A total of 490 patients will be randomized 1:1 to receive either FTD/TPI plus bevacizumab, or FTD/TPI monotherapy. The primary objective is to significantly improve overall survival with FTD/TPI plus bevacizumab compared with FTD/TPI monotherapy. The first patient was enrolled in November 2020.
Published: 2021

32. Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E–Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study

Author: Takayuki Yoshino, Ashwin Gollerkeri, Tormod Kyrre Guren, K. Maharry, Hendrik Tobias Arkenau, Fortunato Ciardiello, Neeltje Steeghs, Pilar García-Alfonso, Josep Tabernero, Eric Van Cutsem, Jayesh Desai, Scott Kopetz, Fotios Loupakis, Janna Christy-Bittel, Rona Yaeger, Elena Elez, Yong Sang Hong, Harpreet Wasan, Axel Grothey, Institut Català de la Salut, [Tabernero J] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. UVic-UCC, IOB-Quiron, Barcelona, Spain. [Grothey A] West Cancer Center, OneOncology, Germantown, TN. [Van Cutsem E] University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium. [Yaeger R] Memorial Sloan-Kettering Cancer Center, New York, NY. [Wasan H] Hammersmith Hospital, Department of Cancer Medicine, Imperial College London, London, United Kingdom. [Yoshino T] National Cancer Center Hospital East, Kashiwa, Japan, Vall d'Hebron Barcelona Hospital Campus, Tabernero, J., Grothey, A., van Cutsem, E., Yaeger, R., Wasan, H., Yoshino, T., Desai, J., Ciardiello, F., Loupakis, F., Hong, Y. S., Steeghs, N., Guren, T. K., Arkenau, H. -T., Garcia-Alfonso, P., Elez, E., Gollerkeri, A., Maharry, K., Christy-Bittel, J., and Kopetz, S.
Subjects: 0301 basic medicine, Oncology, Male, Cancer Research, Intestí gros - Càncer, Colorectal cancer, Cetuximab, chemistry.chemical_compound, 0302 clinical medicine, Encorafenib, Gastrointestinal Cancer, Antineoplastic Combined Chemotherapy Protocols, Neoplasm Metastasis, Aged, 80 and over, Sulfonamides, Binimetinib, Standard of Care, Middle Aged, Prognosis, neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES], Survival Rate, 030220 oncology & carcinogenesis, FOLFIRI, Female, Colorectal Neoplasms, medicine.drug, Adult, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, 03 medical and health sciences, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES], Internal medicine, RAPID COMMUNICATIONS, medicine, Humans, terapéutica::protocolos clínicos::protocolos antineoplásicos::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Survival rate, Aged, Medicaments antineoplàstics - Ús terapèutic - Eficàcia, business.industry, diagnóstico::pronóstico::resultado del tratamiento [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Therapeutics::Clinical Protocols::Antineoplastic Protocols::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], medicine.disease, Diagnosis::Prognosis::Treatment Outcome [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], digestive system diseases, Clinical trial, Irinotecan, 030104 developmental biology, chemistry, Mutation, Carbamates, business, Follow-Up Studies
Abstract: PURPOSE BEACON CRC evaluated encorafenib plus cetuximab with or without binimetinib versus investigators' choice of irinotecan or FOLFIRI plus cetuximab in patients with BRAFV600E–mutant metastatic colorectal cancer (mCRC), after progression on 1-2 prior regimens. In the previously reported primary analysis, encorafenib, binimetinib plus cetuximab (ENCO/BINI/CETUX; triplet) and encorafenib plus cetuximab (ENCO/CETUX; doublet) regimens improved overall survival (OS) and objective response rate (ORR; by blinded central review) versus standard of care. The purpose of this analysis was to report updated efficacy and safety data. METHODS In this open-label, phase III trial, 665 patients with BRAF V600E–mutant mCRC were randomly assigned 1:1:1 to receive triplet, doublet, or control. Primary end points were OS and independently reviewed ORR comparing triplet to control. OS for doublet versus control was a key secondary end point. Updated analyses include 6 months of additional follow-up and ORR for all randomized patients. RESULTS Patients received triplet (n = 224), doublet (n = 220), or control (n = 221). Median OS was 9.3 months (95% CI, 8.2 to 10.8) for triplet and 5.9 months (95% CI, 5.1 to 7.1) for control (hazard ratio [HR], 0.60 [95% CI, 0.47 to 0.75]). Median OS for doublet was 9.3 months (95% CI, 8.0 to 11.3) (HR v control, 0.61 [95% CI, 0.48 to 0.77]). Confirmed ORR was 26.8% (95% CI, 21.1% to 33.1%) for triplet, 19.5% (95% CI, 14.5% to 25.4%) for doublet, and 1.8% (95% CI, 0.5% to 4.6%) for control. Adverse events were consistent with the prior primary analysis, with grade ≥ 3 adverse events in 65.8%, 57.4%, and 64.2% for triplet, doublet, and control, respectively. CONCLUSION In the BEACON CRC study, encorafenib plus cetuximab improved OS, ORR, and progression-free survival in previously treated patients in the metastatic setting compared with standard chemotherapy. Based on the primary and updated analyses, encorafenib plus cetuximab is a new standard care regimen for previously treated patients with BRAF V600E mCRC.
Published: 2021

33. 76P Association of clinicopathological (C-P) features and tumor (tum) immune contexture with dissemination pattern in metastatic colorectal cancer (mCRC).

Author: Salvà Ballabrera, F., Garcia-Galea, E., Comas, R., Salva de Torres, C., Rodriguez Castells, M., Saoudi Gonzalez, N., Baraibar Argota, I., Ros Montana, F.J., Vaghi, C., Garcia Rodriguez, A., Alcaraz, A., Dopazo, C., Calixto, Z., Querol, R., Macias Declara, I., Hernandez Yague, J., Cuadra-Urteaga, J., Vivancos, A., Tabernero, J., and Elez Fernandez, M.E.
Subjects: *COLORECTAL cancer, *METASTASIS, *CLINICAL pathology, *TUMORS
Published: 2024
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34. Molecular subtypes and the evolution of treatment management in metastatic colorectal cancer

Author: Francesc Salvà, Iosune Baraibar, Nuria Mulet, Josep Tabernero, Rodrigo Dienstmann, Davide Ciardiello, Giulia Martini, Guillem Argiles, Javier Ros, Elena Elez, Jose Luis Cuadra-Urteaga, Institut Català de la Salut, [Martini G] Università della Campania L. Vanvitelli, Naples. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Dienstmann R, Elez E] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Ros J, Baraibar I, Cuadra-Urteaga JL, Salva F, Mulet N, Argiles G, Tabernero J] Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Ciardiello D] Università della Campania L. Vanvitelli, Naples. Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Martini, G., Dienstmann, R., Ros, J., Baraibar, I., Cuadra-Urteaga, J. L., Salva, F., Ciardiello, D., Mulet, N., Argiles, G., Tabernero, J., and Elez, E.
Subjects: Oncology, medicine.medical_specialty, Colorectal cancer, EGFR, colorectal cancer, Disease, Review, lcsh:RC254-282, Còlon - Càncer - Tractament, Molecular classification, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES], Metàstasi, Internal medicine, Recte - Càncer - Tractament, medicine, Otros calificadores::/terapia [Otros calificadores], molecular classification, business.industry, Neoplasms::Neoplastic Processes::Neoplasm Metastasis [DISEASES], biomarkers, Other subheadings::/therapy [Other subheadings], lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES], Treatment management, neoplasias::procesos neoplásicos::metástasis neoplásica [ENFERMEDADES], biomarker, business, RAS
Abstract: Biomarcadors; Càncer colorectal; Classificació molecular Biomarcadores; Cáncer colorrectal; Clasificación molecular Biomarkers; Colorectal cancer; Molecular classification Colorectal cancer (CRC) is a heterogeneous disease representing a therapeutic challenge, which is further complicated by the common occurrence of several molecular alterations that confer resistance to standard chemotherapy and targeted agents. Mechanisms of resistance have been identified at multiple levels in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAFV600E, and in the HER2 and MET receptors. These alterations represent oncogenic drivers that may co-exist in the same tumor with other primary and acquired alterations via a clonal selection process. Other molecular alterations include DNA damage repair mechanisms and rare kinase fusions, potentially offering a rationale for new therapeutic strategies. In recent years, genomic analysis has been expanded by a more complex study of epigenomic, transcriptomic, and microenvironment features. The Consensus Molecular Subtype (CMS) classification describes four CRC subtypes with distinct biological characteristics that show prognostic and potential predictive value in the clinical setting. Here, we review the panorama of actionable targets in CRC, and the developments in more recent molecular tests, such as liquid biopsy analysis, which are increasingly offering clinicians a means of ensuring optimal tailored treatments for patients with metastatic CRC according to their evolving molecular profile and treatment history
Published: 2020

35. 580P Impact of RAS and BRAFV600E mutations on tumor immune microenvironment and associated genomic alterations in patients with microsatellite instability (MSI) or DNA mismatch repair deficient (dMMR) colorectal cancers.

Author: Puccini, A., Foureau, D., Mauer, E., André, T., Zhang, W., El-Refai, S.M., George, T.J., Tabernero, J., Sinicrope, F.A., Tie, J., Kopetz, S., Van Cutsem, E., Lonardi, S., Overman, M.J., and Salem, M.E.
Subjects: *DNA mismatch repair, *COLORECTAL cancer, *TUMOR microenvironment, *MICROSATELLITE repeats, *GENETIC mutation
Published: 2024
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36. Impact of circulating tumor DNA mutant allele fraction on prognosis in RAS-mutant metastatic colorectal cancer

Author: Ramon Salazar, Chiara Chianese, Evaristo Maiello, Alba Noguerido, Josep Tabernero, Ana Vivancos, Erica Martinelli, Judit Matito, Guillem Argiles, Cristina Santos, Giulia Martini, Ginevra Caratu, Jaume Capdevila, Ariadna Garcia, Francesco M. Mancuso, Julieta Grasselli, Nuria Mulet, Nicola Normanno, Fortunato Ciardello, Enrique Sanz-Garcia, Claudia Cardone, Elena Elez, Frederick S. Jones, Riziero Esposito Abate, Teresa Macarulla, [Elez E, Sanz-García E, Noguerido A, Martini G, Macarulla T, Argilés G, Capdevila J, Garcia A, Tabernero J] Servei d’Oncologia Mèdica, Hospital Universitari Vall d'Hebron, Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d'Hebron Institut d'Oncologia, Barcelona, Spain. [Chianese C, Mancuso FM, Caratù G, Matito J, Vivancos A] Grup de Genòmica del Càncer, Vall d'Hebron Institut d'Oncologia, Barcelona, Spain. [Martinelli E] Medical Oncology, Department of Clinical and Experimental Medicine ‘F. Magrassi’, Università della Campania ‘L. Vanvitelli’, Napoli, Italy. [Grasselli J] Servei d’Oncologia Mèdica, Hospital Universitari Vall d'Hebron, Barcelona, Spain. Servei d’Oncologia Mèdica, Institut Català d’Oncologia, L'Hospitalet, Spain. Universitat de Barcelona, L'Hospitalet, Spain. [Mulet N] Servei d’Oncologia Mèdica, Hospital Universitari Vall d'Hebron, Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d'Hebron Institut d'Oncologia, Barcelona, Spain. Servei d’Oncologia Mèdica, Institut Català d’Oncologia, L'Hospitalet, Spain. Universitat de Barcelona, L'Hospitalet, Spain., Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Elez, E., Chianese, C., Sanz-Garcia, E., Martinelli, E., Noguerido, A., Mancuso, F. M., Caratu, G., Matito, J., Grasselli, J., Cardone, C., Esposito Abate, R., Martini, G., Santos, C., Macarulla, T., Argiles, G., Capdevila, J., Garcia, A., Mulet, N., Maiello, E., Normanno, N., Jones, F., Tabernero, J., Ciardello, F., Salazar, R., and Vivancos, A.
Subjects: 0301 basic medicine, Oncology, Male, Pathological Conditions, Signs and Symptoms::Pathologic Processes::Neoplastic Processes::Neoplasm Metastasis [DISEASES], Cancer Research, Colorectal cancer, Sang, técnicas de investigación::técnicas de laboratorio clínico::técnicas citológicas::citodiagnóstico::biopsia::técnicas de investigación::técnicas de laboratorio clínico::técnicas de investigación::biopsia líquida [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], 0302 clinical medicine, Carcinoembryonic antigen, Medicine, Prospective Studies, Prospective cohort study, prognostic biomarker, Diagnosis::Prognosis::Neoplasm Staging [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Research Articles, circulating tumor DNA, biology, Metastatic colorectal cancer, neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES], metastatic colorectal cancer, Hazard ratio, General Medicine, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, MAF, Survival Rate, Blood, 030220 oncology & carcinogenesis, Cohort, Molecular Medicine, Female, diagnóstico::pronóstico::estadificación de neoplasias [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Colorectal Neoplasms, Neoplasias::Neoplasias por Localización::Neoplasias del Sistema Digestivo::Neoplasias Gastrointestinales::Neoplasias Intestinales::Neoplasias Colorrectales [ENFERMEDADES], Research Article, medicine.medical_specialty, Citodiagnòstic, Prognostic biomarker, Investigative Techniques::Clinical Laboratory Techniques::Cytological Techniques::Cytodiagnosis::Biopsy::Investigative Techniques::Clinical Laboratory Techniques::Investigative Techniques::Liquid Biopsy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Oncogene Protein p21(ras), lcsh:RC254-282, Disease-Free Survival, 03 medical and health sciences, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES], Metàstasi, Càncer colorectal, Internal medicine, Mortalitat, Genetics, Humans, RAS analysis, Mortality, Allele, Survival rate, Alleles, Aged, Retrospective Studies, Circulating tumor DNA, business.industry, Mutació (Biologia), Recte - Càncer - Prognosi, Mutation (Biology), medicine.disease, Confidence interval, 030104 developmental biology, afecciones patológicas, signos y síntomas::procesos patológicos::procesos neoplásicos::metástasis neoplásica [ENFERMEDADES], Mutation, biology.protein, business, Genètica
Abstract: Metastatic colorectal cancer; RAS analysis; Prognostic biomarker Cáncer colorrectal en metástasis; Análisis RAS; Biomarcador como pronóstico Càncer colorectal en metàstasi; Anàlisi RAS; Biomarcador com a pronòstic Despite major advances in the treatment of metastatic colorectal cancer (mCRC), the survival rate remains very poor. This study aims at exploring the prognostic value of RAS‐mutant allele fraction (MAF) in plasma in mCRC. Forty‐seven plasma samples from 37 RAS‐mutated patients with nonresectable metastases were tested for RAS in circulating tumor DNA using BEAMing before first‐ and/or second‐line treatment. RAS MAF was correlated with several clinical parameters (number of metastatic sites, hepatic volume, carcinoembryonic antigen, CA19‐9 levels, primary site location, and treatment line) and clinical outcome [progression‐free survival (PFS) and overall survival (OS)]. An independent cohort of 32 patients from the CAPRI‐GOIM trial was assessed for clinical outcome based on plasma baseline MAF. RAS MAF analysis at baseline revealed a significant correlation with longer OS [Hazard ratios (HR) = 3.514; P = 0.00066]. Patients with lower MAF also showed a tendency to longer PFS, although not statistically significant. Multivariate analysis showed RAS MAFs as an independent prognostic factor in both OS (HR = 2.73; P = 0.006) and first‐line PFS (HR = 3.74; P = 0.049). Tumor response to treatment in patients with higher MAF was progression disease (P = 0.007). Patients with low MAFs at baseline in the CAPRI‐GOIM group also showed better OS [HR = 3.84; 95% confidence intervals (CI) 1.5–9.6; P = 0.004] and better PFS (HR = 2.5; 95% CI: 1.07–5.62; P = 0.033). This minimally invasive test may help in adding an independent factor to better estimate outcomes before initiating treatment. Further prospective studies using MAF as a stratification factor could further validate its utility in clinical practice. This work was supported partially by the Instituto de Salud Carlos III (Ministerio de Economia y Competitividad) and `Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa' grants [FIS PI12-01589 to RS] and RETICC Cancer.
Published: 2018

37. 613P Effect of prior use of anti-VEGF agents on overall survival in patients with refractory metastatic colorectal cancer: A post-hoc analysis of the phase III SUNLIGHT trial.

Author: Prager, G., Taieb, J., Fakih, M., Ciardiello, F., Van Cutsem, E., Elez Fernandez, M.E., Cruz, F.J.S.M., Wyrwicz, L.S., Pápai, Z., Poureau, P.G., Liposits, G., Cremolini, C., Bondarenko, I., Modest, D.P., Calleja, E.M., Roby, L., Barboux, V., Causse-Amellal, N., and Tabernero, J.
Subjects: *CLINICAL trials, *OVERALL survival, *COLORECTAL cancer, *METASTASIS, *VASCULAR endothelial growth factor antagonists
Published: 2023
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38. A Phase Ib/II Study of WNT974 + Encorafenib + Cetuximab in Patients With BRAF V600E-Mutant KRAS Wild-Type Metastatic Colorectal Cancer

Author: Josep Tabernero, Eric Van Cutsem, Elena Garralda, David Tai, Filippo De Braud, Ravit Geva, Mark T J van Bussel, Katia Fiorella Dotti, Elena Elez, María J de Miguel, Kevin Litwiler, Danielle Murphy, Michelle Edwards, Van Karlyle Morris, Institut Català de la Salut, [Tabernero J] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. UVic-UCC, IOB-Quiron, Barcelona, Spain. [Van Cutsem E] University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium. [Garralda E] START Madrid, Hospital Universitario HM Sanchinarro, Madrid, Spain. [Tai D] Division of Medical Oncology, National Cancer Centre Singapore, Singapore. [De Braud F] Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. [Geva R] Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel. [Elez E] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Cancer Research, Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES], terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Medicaments antineoplàstics - Ús terapèutic, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], colorectal cancer, encorafenib, Other subheadings::Other subheadings::/drug therapy [Other subheadings], neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES], metastatic, Còlon - Càncer - Tractament, Anomalies cromosòmiques, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES], Oncology, Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Recte - Càncer - Tractament, cetuximab, WNT974, fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS]
Abstract: Background WNT974 is a small molecule inhibitor of Wnt signaling that specifically inhibits porcupine O-acyltransferase. This phase Ib dose-escalation study evaluated the maximum tolerated dose of WNT974 in combination with encorafenib and cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer with RNF43 mutations or RSPO fusions. Patients and Methods Patients received once-daily encorafenib and weekly cetuximab, in addition to once-daily WNT974, in sequential dosing cohorts. In the first cohort, patients received 10-mg WNT974 (COMBO10), which was reduced in subsequent cohorts to 7.5-mg (COMBO7.5) or 5-mg (COMBO5) after dose–limiting toxicities (DLTs) were observed. Primary endpoints were incidence of DLTs and exposure to WNT974 and encorafenib. Secondary endpoints were anti-tumor activity and safety. Results Twenty patients were enrolled (COMBO10, n = 4; COMBO7.5, n = 6; COMBO5, n = 10). DLTs were observed in 4 patients, including grade 3 hypercalcemia (COMBO10, n = 1; COMBO7.5, n = 1), grade 2 dysgeusia (COMBO10, n = 1), and lipase increased (COMBO10, n = 1). A high incidence of bone toxicities (n = 9) was reported, including rib fracture, spinal compression fracture, pathological fracture, foot fracture, hip fracture, and lumbar vertebral fracture. Serious adverse events were reported in 15 patients, most frequently bone fracture, hypercalcemia, and pleural effusion. The overall response rate was 10% and disease control rate 85%; most patients achieved stable disease as their best response. Conclusion Concerns surrounding the safety and lack of preliminary evidence of improved anti-tumor activity of WNT974 + encorafenib + cetuximab, compared with previous encorafenib + cetuximab data, ultimately led to study discontinuation. Phase II was not initiated. Trial registration ClinicalTrials.gov, NCT02278133
Published: 2023
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39. Prospective validation of a lymphocyte infiltration prognostic test in stage III colon cancer patients treated with adjuvant FOLFOX

Author: Jean-François Emile, Catherine Julié, Karine Le Malicot, Come Lepage, Josep Tabernero, Enrico Mini, Gunnar Folprecht, Jean-Luc Van Laethem, Stéphanie Dimet, Camille Boulagnon-Rombi, Marc-Antoine Allard, Frédérique Penault-Llorca, Jaafar Bennouna, Pierre Laurent-Puig, Julien Taieb, Josef Thaler, Richard Greil, Johannes Gaenzer, Wolfgang Eisterer, Joerg Tschmelitsch, Felix Keil, Hellmut Samonigg, August Zabernigg, Franz Schmid, Günther Steger, Robert Steinacher, Johannes Andel, Björn Jagdt, Alois Lang, Michael Fridrik, Reinhold Függer, Friedrich Hofbauer, Ewald Woell, Dietmar Geissler, Alfred Lenauer, Manfred Prager, Geert D'Haens, Gauthier Demolin, Joseph Kerger, Guido Deboever, Gilbert Ghillebert, Marc Polus, Eric Van Cutsem, Hassan Rezaie Kalantari, Thierry Delaunoit, Jean Charles Goeminne, Marc Peeters, Philippe Vergauwe, Ghislain Houbiers, Yves Humblet, Jos Janssens, Dirk Schrijvers, Erik Vanderstraeten, Jan Vermorken, Daniel Van Daele, Michel Ferrante, Frederic Forget, Alain Hendlisz, Mette Yilmaz, Svend Erik Nielsen, Lene Vestermark, Jim Larsen, Mohamed-Ayman Zawadi, Olivier Bouche, Laurent Mineur, Jaafar Bennouna-Louridi, Louis Marie Dourthe, Marc Ychou, Eveline Boucher, Denis Pezet, Francoise Desseigne, Michel Ducreux, Patrick Texereau, Laurent Miglianico, Philippe Rougier, Serge Fratte, Charles-Briac Levache, Yacine Merrouche, Stephen Ellis, Christophe Locher, Jean-Francois Ramee, Claire Garnier, Frederic Viret, Bruno Chauffert, Isabelle Cojean-Zelek, Pierre Michel, Cedric Lecaille, Christian Borel, Jean-Francois Seitz, Denis Smith, Catherine Lombard-Bohas, Thierry Andre, Jean-Marc Gornet, Francine Fein, Marie-Aude Coulon-Sfairi, Marie-Christine Kaminsky, Jean-Paul Lagasse, Dominique Luet, Pierre-Luc Etienne, Mohamed Gasmi, Andre Vanoli, Suzanne Nguyen, Thomas Aparicio, Hervé Perrier, Noel Stremsdoerfer, Philippe Laplaige, Dominique Arsene, Dominique Auby, Laurent Bedenne, Romain Coriat, Bernard Denis, Patrick Geoffroy, Gilles Piot, Yves Becouarn, Gilbert Bordes, Gael Deplanque, Olivier Dupuis, Frederic Fruge, Rosine Guimbaud, Thierry Lecomte, Gérard Lledo, Iradej Sobhani, Amani Asnacios, Ahmed Azzedine, Christophe Desauw, Marie-Pierre Galais, Dany Gargot, You-Heng Lam, Abakar Abakar-Mahamat, Jean-Francois Berdah, Sylviane Catteau, Marie-Christine Clavero-Fabri, Jean-Francois Codoul, Jean-Louis Legoux, Denis Goldfain, Pierre Guichard, Denis Pere Verge, Jocelyne Provencal, Bruno Vedrenne, Catherine Brezault-Bonnet, Denis Cleau, Jean-Paul Desir, David Fallik, Bruno Garcia, Marie-Hélène Gaspard, Dominique Genet, Johannes Hartwig, Yves Krummel, Tamara Matysiak Budnik, Vanessa Palascak-Juif, Harizo Randrianarivelo, Yves Rinaldi, Albert Aleba, Ariane Darut-Jouve, Aimery de Gramont, Herve Hamon, Frederic Wendehenne, Axel Matzdorff, Michael Konrad Stahl, Wolfgang Schepp, Martin Burk, Lothar Mueller, Michael Geissler, Luisa Mantovani-Loeffler, Thomas Hoehler, Walter Asperger, Hendrik Kroening, Ludwig Fischer von Weikersthal, Stefan Fuxius, Matthias Groschek, Johannes Meiler, Tanja Trarbach, Jacqueline Rauh, Nicolas Ziegenhagen, Albrecht Kretzschmar, Ullrich Graeven, Arnd Nusch, Goetz von Wichert, Ralf-Dieter Hofheinz, Gerhard Kleber, Karl-Heinz Schmidt, Ursula Vehling-Kaiser, Claudia Baum, Jochen Schuette, Georg Martin Haag, Wilhelm Holtkamp, Jochen Potenberg, Tobias Reiber, Georg Schliesser, Hans-Joachim Schmoll, Wolfgang Schneider-Kappus, Wolfgang Abenhardt, Claudio Denzlinger, Jan Henning, Bartscht Marxsen, Hans Guenter Derigs, Helmut Lambertz, Ingulf Becker-Boost, Karel Caca, Christian Constantin, Thomas Decker, Henning Eschenburg, Sigrun Gabius, Holger Hebart, Albrecht Hoffmeister, Heinz-August Horst, Stephan Kremers, Malte Leithaeuser, Sebastian Mueller, Siegfried Wagner, Severin Daum, Frank Schlegel, Martina Stauch, Volker Heinemann, Evaristo Maiello, Luciano Latini, Alberto Zaniboni, Dino Amadori, Giuseppe Aprile, Sandro Barni, Rodolfo Mattioli, Andrea Martoni, Rodolfo Passalacqua, Mario Nicolini, Enzo Pasquini, Carla Rabbi, Enrico Aitini, Alberto Ravaioli, Carlo Barone, Guido Biasco, Stefano Tamberi, Angelo Gambi, Claudio Verusio, Marina Marzola, Giorgio Lelli, Corrado Boni, Stefano Cascinu, Paolo Bidoli, Massimo Vaghi, Giorgio Cruciani, Francesco Di Costanzo, Alberto Sobrero, Roberto Petrioli, Massimo Aglietta, Oscar Alabiso, Federico Capuzzo, Alfredo Falcone, Domenico Cristi Corsi, Roberto Labianca, Stefania Salvagni, Silvana Chiara, Libero Ciuffreda, Francesco Ferraù, Francesco Giuliani, Sara Lonardi, Nicola Gebbia, Giovanni Mantovani, Evaristo Sanches, Juan Carlos Mellidez, Pedro Santos, Joao Freire, Cristina Sarmento, Luis Costa, Antonio Moreira Pinto, Sergio Barroso, Jorge Espirito Santo, Fátima Guedes, Amélia Monteiro, Anabela Sa, Irene Furtado, Ramon Salazar, Enrique Aranda Aguilar, Fernando Rivera Herrero, Javier Sastre Valera, Manuel Valladares Ayerbes, Jaime Feliu Batlle, Silvia Gil, Albert Abad Esteve, Carlos Garcia-Giron, Guillermo Lopez Vivanco, Antonia Salud Salvia, Vicente Alonso Orduña, Ruth Vera Garcia, Javier Gallego, Bartomeu Massuti Sureda, Jordi Remon, Maria Jose Safont Aguilera, Luis Cirera Nogueras, Bernado Queralt Merino, Cristina Gravalos Castro, Purificacion Martinez de Prado, Carlos Pijaume Pericay, Manuel Constenla Figueiras, Inmaculada Guasch Jordan, Maria Jose Gome Reina, Amelia Lopez-Ladron Garcia, Antonio Arrivi Garcia-Ramos, Andres Cervantes, Carlos Fernandez Martos, Eugenio Marcuello Gaspar, Ines Cabezas Montero, Pilar Escudero Emperador, Ana Leon Carbonero, Manuel Gallen Castillo, Teresa Garcia Garcia, Jose Garcia Lopez, Encarnacion Gonzalez Flores, Monica Guillot Morales, Marta Llanos Muñoz, Ana López Martín, Joan Maurel, Juan Carlos Camara, Rosario Dueñas Garcia, Mercedes Salgado, Isabel Hernandez Busquier, Teresa Checa Ruiz, Adelaida Lacasta Muñoa, Miquel Nogue Aliguer, Amalia Velasco Ortiz de Taranco, Miguel Mendez Ureña, Ferran Losa Gaspa, Jose Juan Ponce, Carlos Bosch Roig, Pedro Valero Jimenez, Antonio Galan Brotons, Santiago Albiol Rodriguez, Jose Ales Martinez, Liliana Canosa Ruiz, Margarita Centelles Ruiz, John Bridgewater, Rob Glynne-Jones, Saad Tahir, Tamas Hickish, Jim Cassidy, Leslie Samuel, UE 1373 Fourrages Environnement Ruminants Lusignan, Institut National de la Recherche Agronomique ( INRA ) -Physiologie Animale et Systèmes d'Elevage ( PHASE ) -Environnement et Agronomie ( E.A. ) -Biologie et Amélioration des Plantes ( BAP ) -Fourrages Environnement Ruminants Lusignan ( FERLUS ), Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Service de Biostatistique, Fédération Francophone de la Cancérologie Digestive, FFCD, Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'hépato-gastroentérologie et cancérologie digestive (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Vall d'Hebron University Hospital [Barcelona], Dpt of Internal Medicine, Section of Immunoallergology and Respiratory [Florence] Diseases, University of Florence, Carl Gustav Carus University Hospital, Erasme Hospital, Brussels, Centre Hepato-Biliaire, AP-HP Hôpital Paul Brousse, Modèles de Cellules Souches Malignes et Thérapeutiques, Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne ( IMoST ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ), Institut de cancérologie de l'Ouest - Nantes ( ICO Nantes ), CRLCC Paul Papin-CRLCC René Gauducheau, Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université de Nantes ( UN ), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique ( MEPPOT - U1147 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Klinikum Wels Grieskirchen, Oncology department [Salzburg], Salzburger Landesklinikum - Uniklinikum Salzburg ( SALK ), Institute of Chemical Reaction Engineering, Hamburg University of Technology, Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar- und Meeresforschung ( AWI ), Department of Medical Oncology, Medical University Vienna, Department of Internal Medicine, Hospital of Steyr, Department Internal Medicine 3, Centre for Hematology and Medical Oncology, General Hospital Linz, Department Medicine LKH, Institut für Festköperfirschung, Institut des Sciences Moléculaires de Marseille ( ISM2 ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Centrale de Marseille ( ECM ) -Aix Marseille Université ( AMU ), University Hospitals Leuven [Leuven], Katholieke Universiteit Leuven ( KU Leuven ), Pharmacology and Toxicology, Ahvaz Jundishapur University of Medical Sciences, Institut de Biologie Computationnelle ( IBC ), Centre de Coopération Internationale en Recherche Agronomique pour le Développement ( CIRAD ) -Institut National de la Recherche Agronomique ( INRA ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Sciences Moléculaires ( ISM ), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique ( CNRS ), Faculty of Veterinary Medicine, Ghent University [Belgium] ( UGENT ), Medical Oncology, Antwerp University Hospital [Edegem], Recombinaison et Expression Génétique, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier de L'Ardenne (Libramont), Department of Cardiology [Sivas, Turkey], Cumhuriyet University [Sivas, Turkey], Department of Earth Sciences, Durham University, Department of Oncology, Rigshospitalet [Copenhagen], Odense Hospital, CP Kelco ApS, Centre Hospitalier Universitaire de Reims ( CHU Reims ), Institut de Recherche en Cancérologie de Montpellier ( IRCM - U1194 Inserm - UM ), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Université du Québec à Montréal ( UQAM ), Université Panthéon-Sorbonne ( UP1 ), École nationale supérieure d'architecture de Nantes ( ENSA Nantes ), Department of Hepatogastroenterology and Oncology, Hopital Ambroise Pare, 9, Avenue Charles de Gaulle, 92104, Boulogne Cedex, France., Hôpital Ambroise Paré, CH Belfort-Montbéliard, Polyclinique Francheville, Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne ( CHU de Saint-Etienne ), Centre Hospitalier de Meaux, Service d'hématologie, Clinique Catherine de Sienne, Unité de recherche sur les Biopolymères, Interactions Assemblages ( BIA ), Institut National de la Recherche Agronomique ( INRA ), Université de la Méditerranée - Aix-Marseille 2, Centre hospitalier universitaire d'Amiens ( CHU Amiens-Picardie ), CHU Amiens-Picardie, Pôle oncologie médicale, Hôpital des Diaconesses, Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bretagne Occidentale - École de sages-femmes ( UBO UFR MSS ESF ), Université de Brest ( UBO ) -Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Service Gastro-Entérologie, CHU Besançon, Université de Franche-Comté ( UFC ) -Université de Franche-Comté ( UFC ), Centre Alexis Vautrin ( CAV ), Ecophysiologie Végétale, Agronomie et Nutritions ( EVA ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Recherche Agronomique ( INRA ), Image et ville ( IV ), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Département informatique ( INFO ), Université européenne de Bretagne ( UEB ) -Télécom Bretagne-Institut Mines-Télécom [Paris], Service de Gastro-entérologie [Avicenne], Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Agence de l'Environnement et de la Maîtrise de l'Energie - ADEME, Service d'hépato-gastroentérologie, CHU Caen-Hôpital côte de nacre, Département de Médecine, Centre hospitalier de Libourne, Service d'Hépato-Gastro-Entérologie (CHU de Dijon), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Fondation FondaMental, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor, Variabilité de réponse aux psychotropes ( VariaPsy - U1144 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ), Département d'oncologie digestive, Institut Bergonié - CRLCC Bordeaux, Hôpital St Joseph, Service de Gynécologie et d'Obstétrique ( CHU Lyon ), Hospices Civils de Lyon ( HCL ), Gastro - Entérologie et Nutrition, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Génétique, Immunothérapie, Chimie et Cancer ( GICC ), Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Université Montpellier 1 ( UM1 ), Service de gastro-entérologie - Hôpital Henri Mondor, Laboratoire Matière et Systèmes Complexes ( Laboratoire MSC ), Université Paris Diderot - Paris 7 ( UPD7 ) -UFR de Physique, France, Amériques, Espagne – Sociétés, pouvoirs, acteurs ( FRAMESPA ), Université Toulouse - Jean Jaurès ( UT2J ) -Centre National de la Recherche Scientifique ( CNRS ), Regional Hospital of Orleans, Histoire, Archéologie et littératures des Mondes chrétiens et musulmans médiévaux ( CIHAM ), École normale supérieure - Lyon ( ENS Lyon ) -Université Lumière - Lyon 2 ( UL2 ) -École des hautes études en sciences sociales ( EHESS ) -Université Jean Moulin - Lyon III ( UJML ) -Université d'Avignon et des Pays de Vaucluse ( UAPV ) -Centre National de la Recherche Scientifique ( CNRS ), Neurobiologie des signaux intercellulaires ( NSI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Dept Med Genet, Hôpital Erasme (Bruxelles), Polyclinique de Limoges - site François Chénieux [Limoges], Clinique Médicale B, CHU Strasbourg, Service de gastro-entérologie, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Hôpital Européen [Fondation Ambroise Paré - Marseille], Asklepios Klinikum Uckermark GmbH, DESY, Notkestr 85, D-22607 Hamburg, Germany, NASA Ames Research Center ( ARC ), Department of Chemistry, Center for Structural Biology, Vanderbilt University [Nashville], Biostatistique et Processus Spatiaux ( BIOSP ), Institute of Ecology [Jena], Friedrich-Schiller-Universität Jena, University of Rostock [Germany], Universität Stuttgart [Stuttgart], Oneonta, Zentrum für Innere Medizin, Klinikum Schwäbisch Gmünd/Stauferklinik, Physiopathologie du stress pancréatique, Institut Armand Frappier ( INRS-IAF ), Institut National de la Recherche Scientifique [Québec] ( INRS ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut Armand Frappier, Institut de Mathématiques de Marseille ( I2M ), Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Department of Computer Science [Freiburg], University of Freiburg [Freiburg], Institut für Mathematik [Berlin], Technische Universität Berlin ( TUB ), Department of Information Engineering, Computer Science and Mathematics, Università degli Studi dell'Aquila [L'Aquila] ( UNIVAQ.IT ), Department of Animal Sciences, North Carolina Agricultural and Technical State University, FEEM, Romagna Cancer Registry, IRST, Luigi Pierantoni Hospital, Observatoire sociologique du changement ( OSC ), Sciences Po-Centre National de la Recherche Scientifique ( CNRS ), Dipartimento di Chimica, Fisica e Ambiente, Università degli Studi di Udine - University of Udine [Italie], Department of Nuclear Medicine, PET/CT Centre, Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Clinica di Oncologia Medica, AO Ospedali Riuniti, Università Politecnica delle Marche [Ancona] ( UNIVPM ), Universidade Nova de Lisboa ( UNINOVA ), Ottawa Hospital Research Institute [Ottawa] ( OHRI ), Oncologia Medica, Ospedali Riuniti, Ospedale 'San Vincenzo', NIPE, CIPES, European Synchrotron Radiation Facility ( ESRF ), Departamento de Engenharia Informática, Faculdade de Engenharia [Porto] ( FEUP ), Universidade do Porto [Porto]-Universidade do Porto [Porto], 3Decide, Unité de recherche Amélioration, Génétique et Physiologie Forestières ( UAGPF ), Universidade Federal de Campina Grande [Campina Grande] ( UFCG ), Instituto de Engenharia de Sistemas e Computadores ( INESC ), Departamento de Ciências Biológicas, Universidade Regional do Cariri ( URCA Brasil ), Department of Biochemistry and Molecular Biology [Barcelona, Spain], Universitat de Barcelona ( UB ), Associated Unit to Consejo Superior de Investigaciones Científicas - CSIC [Barcelona, Spain], University of Barcelona-Institute of Biomedicine - IBUB [Barcelona, Spain], IRCELYON-Caractérisation et remédiation des polluants dans l'air et l'eau ( CARE ), Institut de recherches sur la catalyse et l'environnement de Lyon ( IRCELYON ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'analyse et d'architecture des systèmes [Toulouse] ( LAAS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse ( INSA Toulouse ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Institut National Polytechnique [Toulouse] ( INP ), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier ( ICGM ICMMM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Instituto de Ciencia de Materiales de Madrid [Madrid] ( ICMM ), Interactions, Corpus, Apprentissages, Représentations ( ICAR ), École normale supérieure - Lyon ( ENS Lyon ) -Université Lumière - Lyon 2 ( UL2 ) -INRP-Ecole Normale Supérieure Lettres et Sciences Humaines-Centre National de la Recherche Scientifique ( CNRS ), Institut d'Investigacions Biomèdiques August Pi i Sunyer ( IDIBAPS ), North Region Cancer Registry of Portugal, UMR 5805 Environnements et Paléoenvironnements Océaniques et Continentaux ( EPOC ), Observatoire aquitain des sciences de l'univers ( OASU ), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Paediatrics and Intensive Care, Hospital Universitari Sant Joan de Deu, Laboratoire de Psychologie Sociale ( LPS ), Aix Marseille Université ( AMU ), Universitat de València ( UV ), Instituto de Cienca de Materiales de Madrid [Madrid] ( ICMM ), Biology, New Mexico State University, New Mexico State University, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Centre de recherche sur les Ions, les MAtériaux et la Photonique ( CIMAP - UMR 6252 ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Nationale Supérieure d'Ingénieurs de Caen ( ENSICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ), Institut d'Electronique et de Télécommunications de Rennes ( IETR ), Université de Nantes ( UN ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National des Sciences Appliquées - Rennes ( INSA Rennes ) -CentraleSupélec-Centre National de la Recherche Scientifique ( CNRS ), Computer Science Department - Carnegie Mellon University, University of Pittsburgh, Laboratoire de Sciences Actuarielle et Financière ( SAF ), Université de Lyon-Université de Lyon, Instituto de Oncologia Corachan ( IDOC ), Laboratoire d'informatique de l'école normale supérieure ( LIENS ), École normale supérieure - Paris ( ENS Paris ) -Centre National de la Recherche Scientifique ( CNRS ), Experimental Quantum Optics and Photonics Group, University of Strathclyde, Institut de recherches Asiatiques ( IrAsia ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Européen de Réalité Virtuelle ( CERV ), École Nationale d'Ingénieurs de Brest ( ENIB ), Sol Agro et hydrosystème Spatialisation ( SAS ), Institut National de la Recherche Agronomique ( INRA ) -AGROCAMPUS OUEST, Grenoble Institut des Neurosciences ( GIN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Grenoble-Université Joseph Fourier - Grenoble 1 ( UJF ), Centre de recherche cerveau et cognition ( CERCO ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire Géomatériaux et Environnement ( LGE ), Université Paris-Est Marne-la-Vallée ( UPEM ), Hôpital Ambroise Paré [AP-HP], Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre hépato-biliaire (CHB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Université de Nantes (UN), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Salzburger Landesklinikum - Uniklinikum Salzburg (SALK), Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar- und Meeresforschung (AWI), Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institut de Biologie Computationnelle (IBC), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Moléculaires (ISM), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University [Belgium] (UGENT), Antwerp University Hospital [Edegem] (UZA), Hillerød Hospital, Copenhagen University Hospital-Copenhagen University Hospital, Centre Hospitalier Universitaire de Reims (CHU Reims), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Université Paris 1 Panthéon-Sorbonne (UP1), École nationale supérieure d'architecture de Nantes (ENSA Nantes), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), Institut National de la Recherche Agronomique (INRA), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bretagne Occidentale - École de sages-femmes (UBO UFR MSS ESF), Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Alexis Vautrin (CAV), Ecophysiologie Végétale, Agronomie et Nutritions (EVA), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Recherche Agronomique (INRA), Image et ville (IV), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Département informatique (INFO), Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Agence de l'Environnement et de la Maîtrise de l'Energie (ADEME), Service d'Hépato-Gastro-Enterologie et Nutrition [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Libourne, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation FondaMental [Créteil], Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Service de Gynécologie et d'Obstétrique (CHU Lyon), Hospices Civils de Lyon (HCL), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1), Service de gastro-entérologie [Henri Mondor AP-HP, Créteil], Hôpital Henri Mondor-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Hôpital privé Toulon Hyères : Sainte Marguerite, Clinique des Quatre Pavillons, Lormont, France, Neurobiologie des signaux intercellulaires (NSI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), NASA Ames Research Center (ARC), Biostatistique et Processus Spatiaux (BioSP), Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], University of Rostock, State University of New York at Oneonta (SUNY Oneonta), State University of New York (SUNY), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Institut de Mathématiques de Marseille (I2M), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Klinikum Deggendorf, Technische Universität Berlin (TU), Università degli Studi dell'Aquila (UNIVAQ), North Carolina A&T State University, University of North Carolina System (UNC)-University of North Carolina System (UNC), Observatoire sociologique du changement (OSC), Sciences Po (Sciences Po)-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Università Politecnica delle Marche [Ancona] (UNIVPM), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Ottawa Hospital Research Institute [Ottawa] (OHRI), European Synchrotron Radiation Facility (ESRF), Departamento de Engenharia Informática [Porto], Faculdade de Engenharia da Universidade do Porto (FEUP), Universidade do Porto-Universidade do Porto, Universidade Federal de Campina Grande [Campina Grande] (UFCG), Instituto de Engenharia de Sistemas e Computadores (INESC), Universidade Regional do Cariri (URCA Brasil), Universitat de Barcelona (UB), IRCELYON-Catalytic and Atmospheric Reactivity for the Environment (CARE), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Interactions, Corpus, Apprentissages, Représentations (ICAR), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-INRP-Ecole Normale Supérieure Lettres et Sciences Humaines (ENS LSH)-Centre National de la Recherche Scientifique (CNRS), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), UMR 5805 Environnements et Paléoenvironnements Océaniques et Continentaux (EPOC), Observatoire aquitain des sciences de l'univers (OASU), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Hospital Universitario de Valme, Anenida de Bellavista s/n, Sevilla 41014, Spain, Hospital Son Llatzer, Universitat de València (UV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hospital Universitari Son Espases, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Instituto de Oncologia Corachan (IDOC), Laboratoire d'informatique de l'école normale supérieure (LIENS), École normale supérieure - Paris (ENS Paris), Institut de recherches Asiatiques (IrAsia), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre Européen de Réalité Virtuelle (CERV), École Nationale d'Ingénieurs de Brest (ENIB), Sol Agro et hydrosystème Spatialisation (SAS), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche cerveau et cognition (CERCO), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Géomatériaux et Environnement (LGE), Université Paris-Est Marne-la-Vallée (UPEM), Fédération Francophone de Cancérologie Digestive (FFCD), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Recherche Agronomique (INRA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Department of Information Engineering, Computer Science and Mathematics = Dipartimento di Ingegneria e Scienze dell'Informazione e Matematica [L'Aquila] (DISIM), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département d'informatique - ENS Paris (DI-ENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU), Institute of Biomedicine - IBUB [Barcelona, Spain]-University of Barcelona, Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC), AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de la Recherche Agronomique (INRA)-Environnement et Agronomie (E.A.)-Biologie et Amélioration des Plantes (BAP)-Fourrages Environnement Ruminants Lusignan (FERLUS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, University of Florence (UNIFI), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut de cancérologie de l'Ouest - Nantes (ICO Nantes), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique (CNRS), Ghent University [Belgium] (UGENT), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université du Québec à Montréal (UQAM), Université Panthéon-Sorbonne (UP1), Centre hospitalier universitaire d'Amiens (CHU Amiens-Picardie), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université de Franche-Comté (UFC)-Université de Franche-Comté (UFC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Avicenne, Optimisation Thérapeutique en Neuropsychopharmacologie (VariaPsy - U1144), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Biostatistique et Processus Spatiaux (BIOSP), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Technische Universität Berlin (TUB), Università degli Studi dell'Aquila [L'Aquila] (UNIVAQ.IT), Universidade Nova de Lisboa (NOVA), Faculdade de Engenharia [Porto] (FEUP), Unité de recherche Amélioration, Génétique et Physiologie Forestières (UAGPF), IRCELYON-Caractérisation et remédiation des polluants dans l'air et l'eau (CARE), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Consejo Superior de Investigaciones Científicas [Spain] (CSIC), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-INRP-Ecole Normale Supérieure Lettres et Sciences Humaines-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM), Emile, J, Julie, C, Le Malicot, K, Lepage, C, Tabernero, J, Mini, E, Folprecht, G, Van Laethem, J, Dimet, S, Boulagnon-Rombi, C, Allard, M, Penault-Llorca, F, Bennouna, J, Laurent-Puig, P, Taieb, J, Bidoli, P, Emile, J. -F., Julie, C., Le Malicot, K., Lepage, C., Tabernero, J., Mini, E., Folprecht, G., Van Laethem, J. -L., Dimet, S., Boulagnon-Rombi, C., Allard, M. -A., Penault-Llorca, F., Bennouna, J., Laurent-Puig, P., Taieb, J., Thaler, J., Greil, R., Gaenzer, J., Eisterer, W., Tschmelitsch, J., Keil, F., Samonigg, H., Zabernigg, A., Schmid, F., Steger, G., Steinacher, R., Andel, J., Jagdt, B., Lang, A., Fridrik, M., Fugger, R., Hofbauer, F., Woell, E., Geissler, D., Lenauer, A., Prager, M., D'Haens, G., Demolin, G., Kerger, J., Deboever, G., Ghillebert, G., Polus, M., Van Cutsem, E., Kalantari, H. R., Delaunoit, T., Goeminne, J. C., Peeters, M., Vergauwe, P., Houbiers, G., Humblet, Y., Janssens, J., Schrijvers, D., Vanderstraeten, E., Vermorken, J., Van Daele, D., Ferrante, M., Forget, F., Hendlisz, A., Yilmaz, M., Nielsen, S. E., Vestermark, L., Larsen, J., Zawadi, M. -A., Bouche, O., Mineur, L., Bennouna-Louridi, J., Dourthe, L. M., Ychou, M., Boucher, E., Pezet, D., Desseigne, F., Ducreux, M., Texereau, P., Miglianico, L., Rougier, P., Fratte, S., Levache, C. -B., Merrouche, Y., Ellis, S., Locher, C., Ramee, J. -F., Garnier, C., Viret, F., Chauffert, B., Cojean-Zelek, I., Michel, P., Lecaille, C., Borel, C., Seitz, J. -F., Smith, D., Lombard-Bohas, C., Andre, T., Gornet, J. -M., Fein, F., Coulon-Sfairi, M. -A., Kaminsky, M. -C., Lagasse, J. -P., Luet, D., Etienne, P. -L., Gasmi, M., Vanoli, A., Nguyen, S., Aparicio, T., Perrier, H., Stremsdoerfer, N., Laplaige, P., Arsene, D., Auby, D., Bedenne, L., Coriat, R., Denis, B., Geoffroy, P., Piot, G., Becouarn, Y., Bordes, G., Deplanque, G., Dupuis, O., Fruge, F., Guimbaud, R., Lecomte, T., Lledo, G., Sobhani, I., Asnacios, A., Azzedine, A., Desauw, C., Galais, M. -P., Gargot, D., Lam, Y. -H., Abakar-Mahamat, A., Berdah, J. -F., Catteau, S., Clavero-Fabri, M. -C., Codoul, J. -F., Legoux, J. -L., Goldfain, D., Guichard, P., Verge, D. P., Provencal, J., Vedrenne, B., Brezault-Bonnet, C., Cleau, D., Desir, J. -P., Fallik, D., Garcia, B., Gaspard, M. -H., Genet, D., Hartwig, J., Krummel, Y., Budnik, T. M., Palascak-Juif, V., Randrianarivelo, H., Rinaldi, Y., Aleba, A., Darut-Jouve, A., de Gramont, A., Hamon, H., Wendehenne, F., Matzdorff, A., Stahl, M. K., Schepp, W., Burk, M., Mueller, L., Geissler, M., Mantovani-Loeffler, L., Hoehler, T., Asperger, W., Kroening, H., von Weikersthal, L. F., Fuxius, S., Groschek, M., Meiler, J., Trarbach, T., Rauh, J., Ziegenhagen, N., Kretzschmar, A., Graeven, U., Nusch, A., von Wichert, G., Hofheinz, R. -D., Kleber, G., Schmidt, K. -H., Vehling-Kaiser, U., Baum, C., Schuette, J., Haag, G. M., Holtkamp, W., Potenberg, J., Reiber, T., Schliesser, G., Schmoll, H. -J., Schneider-Kappus, W., Abenhardt, W., Denzlinger, C., Henning, J., Marxsen, B., Derigs, H. G., Lambertz, H., Becker-Boost, I., Caca, K., Constantin, C., Decker, T., Eschenburg, H., Gabius, S., Hebart, H., Hoffmeister, A., Horst, H. -A., Kremers, S., Leithaeuser, M., Mueller, S., Wagner, S., Daum, S., Schlegel, F., Stauch, M., Heinemann, V., Maiello, E., Latini, L., Zaniboni, A., Amadori, D., Aprile, G., Barni, S., Mattioli, R., Martoni, A., Passalacqua, R., Nicolini, M., Pasquini, E., Rabbi, C., Aitini, E., Ravaioli, A., Barone, C., Biasco, G., Tamberi, S., Gambi, A., Verusio, C., Marzola, M., Lelli, G., Boni, C., Cascinu, S., Bidoli, P., Vaghi, M., Cruciani, G., Di Costanzo, F., Sobrero, A., Petrioli, R., Aglietta, M., Alabiso, O., Capuzzo, F., Falcone, A., Corsi, D. C., Labianca, R., Salvagni, S., Chiara, S., Ciuffreda, L., Ferrau, F., Giuliani, F., Lonardi, S., Gebbia, N., Mantovani, G., Sanches, E., Mellidez, J. C., Santos, P., Freire, J., Sarmento, C., Costa, L., Pinto, A. M., Barroso, S., Santo, J. E., Guedes, F., Monteiro, A., Sa, A., Furtado, I., Salazar, R., Aguilar, E. A., Herrero, F. R., Valera, J. S., Ayerbes, M. V., Batlle, J. F., Gil, S., Esteve, A. A., Garcia-Giron, C., Vivanco, G. L., Salvia, A. S., Orduna, V. A., Garcia, R. V., Gallego, J., Sureda, B. M., Remon, J., Safont Aguilera, M. J., Nogueras, L. C., Merino, B. Q., Castro, C. G., de Prado, P. M., Pericay, C. P., Figueiras, M. C., Jordan, I. G., Gome Reina, M. J., Garcia, A. L. -L., Garcia-Ramos, A. A., Cervantes, A., Martos, C. F., Gaspar, E. M., Montero, I. C., Emperador, P. E., Carbonero, A. L., Castillo, M. G., Garcia, T. G., Lopez, J. G., Flores, E. G., Morales, M. G., Munoz, M. L., Martin, A. L., Maurel, J., Camara, J. C., Garcia, R. D., Salgado, M., Busquier, I. H., Ruiz, T. C., Munoa, A. L., Aliguer, M. N., de Taranco, A. V. O., Urena, M. M., Gaspa, F. L., Ponce, J. J., Roig, C. B., Jimenez, P. V., Brotons, A. G., Rodriguez, S. A., Martinez, J. A., Ruiz, L. C., Ruiz, M. C., Bridgewater, J., Glynne-Jones, R., Tahir, S., Hickish, T., Cassidy, J., and Samuel, L.
Subjects: 0301 basic medicine, Oncology, Male, Cancer Research, Organoplatinum Compounds, Colorectal cancer, medicine.medical_treatment, Medizin, Leucovorin, Prospective cohort study, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, FOLFOX, Organoplatinum Compounds/therapeutic use, Antineoplastic Combined Chemotherapy Protocols, tudy, Lymphocytes, Prospective Studies, Leucovorin/therapeutic use, Middle Aged, Prognosis, 3. Good health, Colorectal carcinoma, Fluorouracil, 030220 oncology & carcinogenesis, Predictive value of tests, Colonic Neoplasms, Biomarker (medicine), Lymphocytes/pathology, Female, Adjuvant, medicine.drug, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Fluorouracil/therapeutic use, Biomarkers, Tumor/analysis, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Predictive Value of Tests, Biomarker, Immune response, Internal medicine, medicine, Biomarkers, Tumor, Humans, Survival analysis, Aged, business.industry, medicine.disease, Survival Analysis, Surgery, 030104 developmental biology, Prospective cohort&nbsp, Multivariate Analysis, Colonic Neoplasms/diagnosis, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, business
Abstract: IF 6.029; International audience; BackgroundThe prognostic value of lymphocyte infiltration (LI) of colorectal carcinoma (CC) has been demonstrated by several groups. However, no validated test is currently available for clinical practice. We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use.Patients and methodsAccording to National Institutes of Health criteria, we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study. Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI (#NCT02364024). Associations of LI with patient recurrence and survival were analysed, and multivariable models were adjusted for treatment and relevant factors. Automated testing of LI was performed on virtual slides without access to clinical data.ResultsAmong the 1220 CC patients enrolled, LI was high, low and not evaluable in 241 (19.8%), 790 (64.8%) and 189 (15.5%), respectively. Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in patients with high and low LI, respectively (p = 0.02). Patients with high LI also had better disease free survival (DFS) and overall survival (OS). Tumour stage, grade, RAS status and BRAF status were with LI the only prognostic markers in multivariable analysis for OS. Subgroup analyses revealed that high LI had better DFS and OS in mismatch repair (MMR) proficient patients, and in patients without RAS mutation, but not in MMR deficient and RAS mutated patients.ConclusionAlthough this is the first validation with high level of evidence (IIB) of the prognostic value of a LI test in colon cancers, it still needs to be confirmed in independent series of colon cancer patients.
Published: 2017
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40. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial

Author: John Bridgewater, Eric Van Cutsem, Josef Thaler, Côme Lepage, Lone Petersen, Jean-Luc Van Laethem, Fabien Subtil, Josep Tabernero, Julien Taieb, Laurence Collette, Philippe Rougier, Pierre Laurent-Puig, Enrico Mini, Jean-François Emile, Hélène Blons, Laurent Bedenne, Ramon Salazar, Gunnar Folprecht, Taieb, J, Tabernero, J, Mini, E, Subtil, F, Folprecht, G, Van Laethem, J, Thaler, J, Bridgewater, J, Petersen, L, Blons, H, Collette, L, Van Cutsem, E, Rougier, P, Salazar, R, Bedenne, L, Emile, J, Laurent-Puig, P, Lepage, C, Bidoli, P, Meiler, Johannes (Beitragende*r), Trarbach, Tanya (Beitragende*r), Taieb J, Tabernero J, Mini E, Subtil F, Folprecht G, Van Laethem JL, Thaler J, Bridgewater J, Petersen LN, Blons H, Collette L, Van Cutsem E, Rougier P, Salazar R, Bedenne L, Emile JF, Laurent-Puig P, Lepage C, PETACC-8 Study Investigator, and Biasco G
Subjects: Male, Oncology, Organoplatinum Compounds, Colorectal cancer, stage III, Medizin, medicine.disease_cause, Antineoplastic Combined Chemotherapy Protocols, cetuximab, Infusions, Intravenous, oxaliplatinum, education.field_of_study, Cetuximab, Exons, Middle Aged, Intention to Treat Analysis, 3. Good health, Oxaliplatin, colon cancer, Chemotherapy, Adjuvant, Colonic Neoplasms, 5-FLUOROURACIL, Female, Drug Eruptions, Fluorouracil, KRAS, medicine.drug, Adult, Diarrhea, Mucositis, medicine.medical_specialty, phase 3 trial, Bevacizumab, Perforation (oil well), Population, Adenocarcinoma, open-label, Antibodies, Monoclonal, Humanized, Disease-Free Survival, Proto-Oncogene Proteins p21(ras), Proto-Oncogene Proteins, Internal medicine, medicine, Humans, education, neoplasms, Aged, Neoplasm Staging, fluouracil, leucovorin, (PETACC-8), business.industry, medicine.disease, digestive system diseases, ras Proteins, FOLFOX4, business
Abstract: Summary Background Since the 1990s, fluorouracil-based adjuvant chemotherapy has significantly reduced the risk of tumour recurrence in patients with stage III colon cancer. We aimed to assess whether the addition of cetuximab to standard adjuvant oxaliplatin, fluorouracil, and leucovorin chemotherapy (FOLFOX4) in patients with stage III colon cancer improved disease-free survival (DFS). Methods For this open-label, randomised phase 3 study done in nine European countries, we enrolled patients through an interactive voice response system to the central randomisation centre, with a central stratified permuted block randomisation procedure. We randomly assigned patients with resected (R0) stage III disease (1:1) to receive 12 cycles of FOLFOX4 twice a week with or without cetuximab. Patients were stratified by N-status (N1 vs N2), T-status (T1-3 vs T4), and obstruction or perforation status (no obstruction and no perforation vs obstruction or perforation or both). A protocol amendment (applied in June, 2008, after 2096 patients had been randomly assigned to treatment-restricted enrolment to patients with tumours wild-type at codons 12 and 13 in exon 2 of the KRAS gene ( KRAS exon 2 wild-type). The primary endpoint was DFS. Analysis was intention to treat in all patients with KRAS exon 2 wild-type tumours. The study is registered at EudraCT, number 2005-003463-23. Findings Between Dec 22, 2005, and Nov 5, 2009, 2559 patients from 340 sites in Europe were randomly assigned. Of these patients, 1602 had KRAS exon 2 wild-type tumours (intention-to-treat population), 791 in the FOLFOX4 plus cetuximab group and 811 in the FOLFOX4 group. Median follow-up was 3·3 years (IQR 3·2–3·4). In the experimental and control groups, DFS was similar in the intention-to-treat population (hazard ratio [HR] 1·05; 95% CI 0·85–1·29; p=0·66), and in patients with KRAS exon 2/ BRAF wild-type (n=984, HR 0·99; 95% CI 0·76–1·28) or KRAS exon 2-mutated tumours (n=742, HR 1·06; 95% CI 0·82–1·37). We noted heterogeneous responses to the addition of cetuximab in preplanned subgroup analyses. Grade 3 or 4 acne-like rash (in 209 of 785 patients [27%] vs four of 805 [ vs 70 [9%]), mucositis (63 [8%] vs 10 [1%]), and infusion-related reactions (55 [7%] vs 30 [4%]) were more frequent in patients treated with FOLFOX4 plus cetuximab than in those patients who received FOLFOX4 alone. Interpretation The addition of cetuximab to FOLFOX4 did not improve DFS compared with FOLFOX4 alone in patients with KRAS exon 2 wild-type resected stage III colon cancer. This trial cannot conclude on the benefit of cetuximab in the studied population, but the heterogeneity of response suggests that further investigation of the role of FOLFOX4 plus cetuximab in specific patient subgroups is warranted. Funding Federation Francophone de Cancerologie Digestive (FFCD), Merck KGaA, and Sanofi-Aventis.
Published: 2014
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41. Ultra-selection of metastatic colorectal cancer patients using next-generation sequencing to improve clinical efficacy of anti-EGFR therapy.

Author: Vidal, J, Bellosillo, B, Vivas, C Santos, García-Alfonso, P, Carrato, A, Cano, M T, García-Carbonero, R, Élez, E, Losa, F, Massutí, B, Valladares-Ayerbes, M, Viéitez, J M, Manzano, J L, Azuara, D, Gallego, J, Pairet, S, Capellá, G, Salazar, R, Tabernero, J, and Aranda, E
Subjects: *GENETIC mutation, *COLORECTAL cancer, *ENDOTHELIAL growth factors, *METASTASIS, *CANCER patients, *TECHNOLOGY
Abstract: Background Extended RAS analysis is mandatory in metastatic colorectal cancer (mCRC) patients. The optimal threshold of RAS mutated subclones to identify patients most likely to benefit from antiepidermal growth factor receptor (EGFR) therapy is controversial. Our aim was to assess the clinical impact of detecting mutations in RAS, BRAF, PIK3CA and EGFRS492R in basal tissue tumour samples by using a highly sensitive next-generation sequencing (NGS) technology in mCRC patients treated with chemotherapy plus anti-EGFR or anti-vascular endothelial growth factor. Patients and methods Five hundred and eighty-one tumour samples from untreated mCRC patients from 7 clinical studies were collected. Mutational analysis was carried out by standard-of-care (therascreen pyro) with a sensitivity detection of 5% mutant allele fraction (MAF), and compared with NGS technology using 454GS Junior platform (Roche Applied Science, Germany) with a sensitivity of 1%. Molecular results were correlated with clinical outcomes. Results After quality assessment, 380 samples were evaluable for molecular analysis. Standard-of-care mutational analysis detected RAS, BRAFV600E or PIK3CA mutations in 56.05% of samples compared with 69.21% by NGS (P = 0.00018). NGS identified coexistence of multiple low-frequency mutant alleles in 96 of the 263 mutated cases (36.5%; range 2–7). Response rate (RR), progression-free survival (PFS) and overall survival (OS) were increasingly improved in patients with RAS wild-type, RAS/BRAF wild-type or quadruple (KRAS/NRAS/BRAF/PIK3CA) wild-type tumours treated with anti-EGFR, assessed by standard-of-care. No additional benefit in RR, PFS or OS was observed by increasing the detection threshold to 1% by NGS. An inverse correlation between the MAF of the most prevalent mutation detected by NGS and anti-EGFR response was observed (P = 0.039). EGFR S492R mutation was not detected in untreated samples. Conclusions No improvement in the selection of patients for anti-EGFR therapy was obtained by adjusting the mutation detection threshold in tissue samples from 5% to 1% MAF. Response to anti-EGFR was significantly better in patients with quadruple wild-type tumours. [ABSTRACT FROM AUTHOR]
Published: 2019
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42. 626P Mucinous differentiation (MD) as predictor of response in BRAF-V600E mutated metastatic colorectal cancer (mCRC) treated with BRAF inhibitors (BRAFi) combinations.

Author: Ros Montana, F.J., Navarro, V., Comas, R., Landolfi, S., Ramirez, L., Palmer, H.G., Garcia Rodriguez, A., Saoudi Gonzalez, N., Baraibar Argota, I., Rodriguez Castells, M., Salvà Ballabrera, F., Tabernero, J., and Elez Fernandez, M.E.
Subjects: *COLORECTAL cancer, *METASTASIS, *BRAF genes
Published: 2023
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43. Clinical and exploratory biomarker findings from the MODUL trial (Cohorts 1, 3 and 4) of biomarker-driven maintenance therapy for metastatic colorectal cancer

Author: Michel Ducreux, Josep Tabernero, Axel Grothey, Dirk Arnold, Peter J. O'Dwyer, Frank Gilberg, Alexander Abbas, Meghna Das Thakur, Hen Prizant, Natsumi Irahara, Anila Tahiri, Hans-Joachim Schmoll, Eric Van Cutsem, Aimery de Gramont, Institut Català de la Salut, [Ducreux M] Université Paris-Saclay, Gustave Roussy, Villejuif, France. [Tabernero J] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. IOB-Quiron, UVic-UCC, Barcelona, Spain. [Grothey A] West Cancer Center, Germantown, TN, USA. [Arnold D] Asklepios Tumorzentrum Hamburg, AK Altona, Hamburg, Germany. [O'Dwyer PJ] Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. [Gilberg F] F. Hoffmann-La Roche Ltd, Basel, Switzerland, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Cancer Research, INHIBITION, Medicaments antineoplàstics - Ús terapèutic, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Cetuximab, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Biological Factors::Biomarkers [CHEMICALS AND DRUGS], VEMURAFENIB, factores biológicos::biomarcadores [COMPUESTOS QUÍMICOS Y DROGAS], BRAF, Còlon - Càncer - Tractament, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES], HER2, Recte - Càncer - Tractament, PLUS CETUXIMAB, Science & Technology, MUTATIONS, acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS], CHEMOTHERAPY, neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES], Colorectal cancer, Oncology, Marcadors bioquímics, Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS], Maintenance therapy, Life Sciences & Biomedicine, Biomarkers, RESISTANCE
Abstract: Biomarkers; Colorectal cancer; Maintenance therapy Biomarcadors; Càncer colorectal; Teràpia de manteniment Biomarcadores; Cáncer colorrectal; Terapia de mantenimiento Purpose MODUL is an adaptable, signal-seeking trial of biomarker-driven maintenance therapy following first-line induction treatment in patients with metastatic colorectal cancer (mCRC). We report findings from Cohorts 1 (BRAFmut), 3 (human epidermal growth factor 2 [HER2]+) and 4 (HER2‒/high microsatellite instability, HER2‒/microsatellite stable [MSS]/BRAFwt or HER2‒/MSS/BRAFmut/RASmut). Methods Patients with unresectable, previously untreated mCRC without disease progression following standard induction treatment (5-fluorouracil/leucovorin [5-FU/LV] plus oxaliplatin plus bevacizumab) were randomly assigned to control (fluoropyrimidine plus bevacizumab) or cohort-specific experimental maintenance therapy (Cohort 1: vemurafenib plus cetuximab plus 5-FU/LV; Cohort 3: capecitabine plus trastuzumab plus pertuzumab; Cohort 4: cobimetinib plus atezolizumab). The primary efficacy end-point was progression-free survival (PFS). Results Cohorts 1, 3 and 4 did not reach target sample size because of early study closure. In Cohort 1 (n = 60), PFS did not differ between treatment arms (hazard ratio, 0.95; 95% confidence intervals 0.50–1.82; P = 0.872). However, Cohort 1 exploratory biomarker data showed preferential selection for mitogen-activated protein kinase (MAPK) pathway mutations (mainly KRAS, NRAS, MAP2K1 or BRAF) in the experimental arm but not the control arm. In Cohort 3 (n = 5), PFS ranged from 3.6 to 14.7 months versus 4.0 to 5.4 months in the experimental and control arms, respectively. In Cohort 4 (n = 99), PFS was shorter in the experimental arm (hazard ratio, 1.44; 95% confidence intervals 0.90–2.29; P = 0.128). Conclusions Vemurafenib plus cetuximab plus 5-FU/LV warrants further investigation as first-line maintenance treatment for BRAFmut mCRC. MAPK-pathway emergent genomic alterations may offer novel therapeutic opportunities in BRAFmut mCRC. Cobimetinib plus atezolizumab had an unfavourable benefit:risk ratio in HER2‒/MSS/BRAFwt mCRC. New strategies are required to increase the susceptibility of MSS mCRC to immunotherapy. This work was supported by F. Hoffmann-La Roche Ltd.
Published: 2023
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44. 46MO FRESCO-2: A global / multiregional phase III clinical trial (MRCT) evaluating the efficacy and safety of fruquintinib in patients with metastatic colorectal cancer.

Author: Yoshino, T., Dasari, N.A., Lonardi, S., Garcia-Carbonero, R., Elez Fernandez, M.E., Sobrero, A., Yao, J.C., García Alfonso, P., Kocsis, J., Cubillo Gracian, A., Sartore Bianchi, A., Randrian, V., Tomasek, J., Chong, G., Yang, Z., Schelman, W., Kania, M., Tabernero, J., Eng, C., and Satoh, T.
Subjects: *CLINICAL trials, *COLORECTAL cancer, *PATIENT safety, *METASTASIS
Published: 2022
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45. LBA25 FRESCO-2: A global phase III multiregional clinical trial (MRCT) evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer.

Author: Dasari, N.A., Lonardi, S., Garcia-Carbonero, R., Fernandez, M.E. Elez, Yoshino, T., Sobrero, A.F., Yao, J.C., García-Alfonso, P., Kocsis, J., Gracian, A. Cubillo, Bianchi, A. Sartore, Satoh, T., Randrian, V., Tomasek, J., Chong, G., Yang, Z., Schelman, W., Kania, M., Tabernero, J., and Eng, C.
Subjects: *COLORECTAL cancer, *PATIENT safety, *METASTASIS, *CLINICAL trials
Published: 2022
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46. 436TiP COLSTAR: Randomized, open-label, multicentre, phase III study comparing futuximab/modotuximab plus trifluridine/tipiracil to trifluridine/tipiracil in KRAS/NRAS and BRAF wild type (wt) metastatic colorectal cancer (mCRC) previously treated with both standard and anti-EGFR treatment

Author: Ciardiello, F., Yoshino, T., Modest, D.P., Martin Fernandez, L., Roby, L., Fougeray, R., Lockhart, B.P., and Tabernero, J.
Subjects: *COLORECTAL cancer, *BRAF genes, *METASTASIS
Published: 2022
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47. 316O Genomic mechanisms of acquired resistance of patients (pts) with BRAF V600E-mutant (mt) metastatic colorectal cancer (mCRC) treated in the BEACON study.

Author: Kopetz, S., Murphy, D.A., Pu, J., Yaeger, R., Ciardiello, F., Desai, J., Van Cutsem, E., Wasan, H.S., Yoshino, T., Alkuzweny, B., Xie, T., Zhang, X., and Tabernero, J.
Subjects: *COLORECTAL cancer, *METASTASIS, *BRAF genes
Published: 2022
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48. Incorporating BEAMing technology as a liquid biopsy into clinical practice for the management of colorectal cancer patients: an expert taskforce review.

Author: García-Foncillas, J., Alba, E., Aranda, E., Díaz-Rubio, E., López-López, R., Tabernero, J., and Vivancos, A.
Subjects: *BIOPSY, *COLON cancer patients, *GLOMERULAR filtration rate, *NEUROBLASTOMA, *DNA
Abstract: The importance of mutation identification for advanced colorectal cancer treatment with anti-epidermal growth factor receptor agents is well established. However, due to delays in turnaround time, low-quality tissue samples, and/or lack of standardization of testing methods a significant proportion of patients are being treated without the information that Kirsten rat sarcoma and neuroblastoma rat sarcoma (RAS) testing can provide. The detection of mutated circulating tumor DNA by BEAMing technology addresses this gap in care and allows these patients to receive international guideline-recommended expanded RAS testing with rapid turnaround times. Furthermore, the overall concordance between OncoBEAM RAS colorectal cancer testing and standard of care tissue testing is very high (93.3%). This article presents an overview of the clinical utility and potential applications of this minimally invasive method, such as early detection of emergent resistance to anti-epidermal growth factor receptor therapy. If appropriately implemented, BEAMing technology holds considerable promise to enhance the quality of patient care and improve clinical outcomes. [ABSTRACT FROM AUTHOR]
Published: 2017
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49. BRAF mutant colorectal cancer: prognosis, treatment, and new perspectives.

Author: Sanz-Garcia, E., Argiles, G., Elez, E., and Tabernero, J.
Subjects: *TUMORS, *COLON cancer, *COLON cancer treatment, *PROGNOSIS, *CELL proliferation, *EPIDERMAL growth factor receptors, *CLINICAL trials
Abstract: The MAPK cascade plays a crucial role in tumor cell proliferation and survival. Accumulating evidence suggests that mutations in the BRAF oncogene are not only associated with poor prognosis but also linked with less benefit when treated with antiepidermal growth factor receptor antibodies in metastatic colorectal cancer (mCRC). Targeting this molecular aberration has thus become a matter of particular interest in mCRC drug development. In contrast to other malignances such as BRAF mutant melanoma, efficacy observed with BRAF inhibitors in monotherapy in mCRC is poor. Several mechanisms of resistance have been identified leading to the development of different treatment strategies that have shown promising activity in early clinical trials. Hence, rational combination of targeted therapies is expected to further increase the efficacy of selective BRAF inhibitors. Herein, we discuss the main clinical and molecular characteristics of BRAF mutant colorectal cancer and its translation into the clinic, with a focus on developmental therapeutics and combination strategies. In addition, we contextualize the available data with potential future approaches that include the extended access to next-generation sequencing platforms and gene expression strategies for molecular subtyping. These approaches will facilitate the identification of certain patient profiles providing more therapeutic possibilities. [ABSTRACT FROM AUTHOR]
Published: 2017
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50. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials.

Author: Arnold, D., Lueza, B., Douillard, J.-Y., Peeters, M., Lenz, H.-J., Venook, A., Heinemann, V., Van Cutsem, E., Pignon, J.-P., Tabernero, J., Cervantes, A., and Ciardiello, F.
Subjects: *COLON cancer treatment, *METASTASIS, *CANCER chemotherapy, *EPIDERMAL growth factor receptors, *IMMUNOGLOBULINS
Abstract: Background: There is increasing evidence that metastatic colorectal cancer (mCRC) is a genetically heterogeneous disease and that tumours arising from different sides of the colon (left versus right) have different clinical outcomes. Furthermore, previous analyses comparing the activity of different classes of targeted agents in patients with KRAS wild-type (wt) or RAS wt mCRC suggest that primary tumour location (side), might be both prognostic and predictive for clinical outcome. Methods: This retrospective analysis investigated the prognostic and predictive influence of the localization of the primary tumour in patients with unresectable RAS wt mCRC included in six randomized trials (CRYSTAL, FIRE-3, CALGB 80405, PRIME, PEAK and 20050181), comparing chemotherapy plus EGFR antibody therapy (experimental arm) with chemotherapy or chemotherapy and bevacizumab (control arms). Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) for patients with left-sided versus right-sided tumours, and odds ratios (ORs) for objective response rate (ORR) were estimated by pooling individual study HRs/ORs. The predictive value was evaluated by pooling study interaction between treatment effect and tumour side. Results: Primary tumour location and RAS mutation status were available for 2159 of the 5760 patients (37.5%) randomized across the 6 trials, 515 right-sided and 1644 left-sided. A significantly worse prognosis was observed for patients with right-sided tumours compared with those with left-sided tumours in both the pooled control and experimental arms for OS [HRs=2.03 (95% CI: 1.69-2.42) and 1.38 (1.17-1.63), respectively], PFS [HRs=1.59 (1.34-1.88) and 1.25 (1.06-1.47)], and ORR [ORs=0.38 (0.28-0.50) and 0.56 (0.43-0.73)]. In terms of a predictive effect, a significant benefit for chemotherapy plus EGFR antibody therapy was observed in patients with left-sided tumours [HRs=0.75 (0.67-0.84) and 0.78 (0.70-0.87) for OS and PFS, respectively] compared with no significant benefit for those with right-sided tumours [HRs=1.12 (0.87-1.45) and 1.12 (0.87-1.44) for OS and PFS, respectively; P value for interaction<0.001 and 0.002, respectively]. For ORR, there was a trend (P value for interaction =0.07) towards a greater benefit for chemotherapy plus EGFR antibody therapy in the patients with left-sided tumours [OR=2.12 (1.77-2.55)] compared with those with right-sided tumours [OR=1.47 (0.94-2.29)]. Exclusion of the unique phase II trial or the unique second-line trial had no impact on the results. The predictive effect on PFS may depend of the type of EGFR antibody therapy and on the presence or absence of bevacizumab in the control arm. Conclusion: This pooled analysis showed a worse prognosis for OS, PFS and ORR for patients with right-sided tumours compared with those with left-sided tumours in patients with RAS wt mCRC and a predictive effect of tumour side, with a greater effect of chemotherapy plus EGFR antibody therapy compared with chemotherapy or chemotherapy and bevacizumab, the effect being greatest in patients with left-sided tumours. These predictive results should be interpreted with caution due to the retrospective nature of the analysis, which was carried out on subpopulations of patients included in these trials, and because none of these studies contemplated a full treatment sequence strategy. [ABSTRACT FROM AUTHOR]
Published: 2017
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