Tabernero, J. (J.)
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- Analysis of mutant allele fractions in driver genes in colorectal cancer – biological and clinical insights(2017) Vilaro, M. (Marta); Tabernero, J. (J.); Nuciforo, P. (Paolo); Verdaguer, H. (Helena); Matos, I. (Ignacio); Alsina, M. (María); Sauri, T. (Tamara); Dienstmann, R. (Rodrigo); Palmer, H.G. (Héctor G.); Ruiz-Pace, F. (Fiorella); Ortiz, C. (Carolina); Sanz-Garcia, E. (Enrique); Garcia, A. (Ariadna); Landolf, S. (Stefania); Viaplana, C. (Cristina); Macarulla, M.T. (M. Teresa); Vivancos, A. (Ana); Argiles, G. (Guillem); Capdevila, J. (Jaume); Rodon, J. (Jordi); Elez, E. (E.)Sequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions (MAFs, or the 'mutation dose') of a driver gene may reveal the genomic structure of tumors and influence response to targeted therapies. We performed a comprehensive analysis of MAFs of driver alterations in unpaired primary and metastatic colorectal cancer (CRC) at our institution from 2010 to 2015 and studied their potential clinical relevance. Of 763 CRC samples, 622 had detailed annotation on overall survival in the metastatic setting (OSmet) and 89 received targeted agents matched to KRAS (MEK inhibitors), BRAF (BRAF inhibitors), or PIK3CA mutations (PI3K pathway inhibitors). MAFs of each variant were normalized for tumor purity in the sample (adjMAFs). We found lower adjMAFs for BRAFV600E and PIK3CA than for KRAS, NRAS, and BRAF non-V600 variants. TP53 and BRAFV600E adjMAFs were higher in metastases as compared to primary tumors, and high KRAS adjMAFs were found in CRC metastases of patients with KRAS wild-type primary tumors previously exposed to EGFR antibodies. Patients with RAS- or BRAFV600E -mutated tumors, irrespective of adjMAFs, had worse OSmet. There was no significant association between adjMAFs and time to progression on targeted therapies matched to KRAS, BRAF, or PIK3CA mutations, potentially related to the limited antitumor activity of the employed drugs (overall response rate of 4.5%). In conclusion, the lower BRAFV600E and PIK3CA adjMAFs in subsets of primary CRC tumors indicate subclonality of these driver genes. Differences in adjMAFs between metastases and primary tumors suggest that approved therapies may result in selection of BRAFV600E - and KRAS-resistant clones and an increase in genomic heterogeneity with acquired TP53 alterations. Despite significant differences in prognosis according to mutations in driver oncogenes, adjMAFs levels did not impact on survival and did not help predict benefit with matched targeted agents in the metastatic setting.
- Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT)(Elsevier, 2018) Tersago, D. (Dominique); Massacesi, C. (C.); Klumper, E. (E.); Robert, C. (C.); Rahimian, S. (S.); Kumar, R. (R.); Hendriks, M. (M.); Tabernero, J. (J.); Douillard, J.Y. (J. Y.); Andtbacka, R. (R.); Leidner, R. (R.); Baurain, J.F. (J. F.); Haanen, J. (J.); Marabelle, A. (Aurelien); Stern, M. (M.); Harrington, K. (K.); Brody, J. (J.); Baere, T. (T.) de; Melero, I. (Ignacio); Tse, A. (A.); Imperiale, M. (M.); Tchakov, I. (I.); Ascierto, P.A. (Paolo Antonio); Öhrling, K. (K.)A European Society for Medical Oncology (ESMO)-sponsored expert meeting was held in Paris on 8 March 2018 which comprised 11 experts from academia, 11 experts from the pharmaceutical industry and 2 clinicians who were representatives of ESMO. The focus of the meeting was exclusively on the intratumoral injection/delivery of immunostimulatory agents with the aim of harmonizing the standard terms and methodologies used in the reporting of human intratumoral immunotherapy (HIT-IT) clinical trials to ensure quality assurance and avoid a blurring of the data reported from different studies. The goal was to provide a reference document, endorsed by the panel members that could provide guidance to clinical investigators, pharmaceutical companies, ethics committees, independent review boards, patient advocates and the regulatory authorities and promote an increase in the number and quality of HIT-IT clinical trials in the future. Particular emphasis was placed not only on the development of precise definitions to facilitate a better understanding between investigators but also on the importance of systematic serial biopsies as a driver for translational research and the need for the recording and reporting of data, to facilitate a better understanding of the key processes involved.
- The management of hepatocellular carcinoma. Current expert opinion and recommendations derived from the 24th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2022(2023) Osterlund, P. (P.); O'Reilly, E.M. (E. M.); Gill, S. (S.); Tabernero, J. (J.); Berlin, J. (J.); Galle, P. (P.); Lordick, F. (F.); Van-Cutsem, E. (E.); Ruiz-Garcia, E. (E.); Cervantes, A. (Andrés); Verslype, C. (Chris); O'Connor, J.M. (J. M.); Wasan, H. (H.); Sangro, B. (Bruno); Bekaii-Saab, T. (T.); Llovet, J.M. (J. M.); Philip, P. (P.); Laurent-Puig, P. (P.); Baere, T. (T.) de; Mukherji, D. (D.); Prager, G. (G.); Haustermans, K. (K.); Ducreux, M. (M.); Macarulla, T. (T.); Eng, C. (C.); Obermannova, R. (R.); Lamarca, A. (Angela); Muro, K. (K.); Seufferlein, T. (T.); Gruenberger, T. (T.); Abou-Alfa, G.K. (Ghassan K.)This article summarises expert discussion on the management of patients with hepatocellular carcinoma (HCC), which took place during the 24th World Gastrointestinal Cancer Congress (WGICC) in Barcelona, July 2022. A multidisciplinary approach is mandatory to ensure an optimal diagnosis and staging of HCC, planning of curative and therapeutic options, including surgical, embolisation, ablative strategies, or systemic therapy. Furthermore, in many patients with HCC, underlying liver cirrhosis represents a challenge and influences the therapeutic options.
- Early evolutionary divergence between papillary and anaplastic thyroid cancers(Elsevier, 2018) Zafón, C. (Carles); Iglesias, C. (C.); Petit, A. (A.); Tabernero, J. (J.); Nuciforo, P. (Paolo); Matías‑Guiu, X. (X.); Matos, I. (Ignacio); Álvarez, C. (C.); Mancuso, F.M. (F.M.); Mayor, R. (R.); Recio, J.A. (Juan A.); Caratú, G. (G.); Vivancos, A. (Ana); Hernando, J. (Jorge); Capdevila, J. (Jaume); Seoane, J. (J.); Cameselle-Teijeiro, J.M. (J.M.)Background: Papillary thyroid cancer (PTC) is the most common thyroid carcinoma and exhibits an almost uniformly good prognosis, while anaplastic thyroid cancer (ATC) is less frequent and is one of the most aggressive cancers usually resistant to conventional treatment. Current hypothesis posits that ATC derives from PTC through the progressive acquisition of a discrete number of genomic alterations and implies that the mutational landscape of ATC resembles that of PTC. However, the clinical behaviour of ATC and PTC is radically different. We decided to address the disconnection between the clinical behaviour of ATC and PTC and the proposed model of the progressive development of ATC from PTC. Patients and methods: We carried out exome sequencing of DNA from 14 ATC specimens including three cases of concomitant ATC and PTC as well as their corresponding normal DNA from 14 patients. The sequencing results were validated using droplet digital PCR. We carried out immunohistochemistry and immunofluorescence studies of the concomitant ATC and PTC cases. In addition, we integrated our sequencing results with the existing TCGA data. Results: Most of the somatic mutations identified in the ATC component differed from the ones in PTC in the cases of concomitant ATC and PTC. The trunks of the phylogenetic trees representing the somatic mutations were short with long branches. In one case of concomitant PTC and ATC specimens, we observed an infiltration of PTC cells within the ATC component. Moreover, we integrated our results with data obtained from TCGA and observed that the most frequent mutations found in ATC presented high cancer cell fraction values and were significantly different from the PTC ones. Conclusion: ATC diverge from PTC early in tumour development and both tumour types evolve independently. Our work allows the understanding of the relationship between ATC and PTC facilitating the clinical management of these malignancies.