Mechanisms Contributing to Tyrosin Kinase Inhibitor Resistance in GISTs: Toward a Personalized Therapy

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal tract. This work considers the pharmacological response in GIST patients treated with imatinib by two different angles: the genetic and somatic point of view. We analyzed polymorphisms influence on treatment outcome, keeping in consideration SNPs in genes involved in drug transport and folate pathway. Naturally, all these intriguing results cannot be considered as the only main mechanism in imatinib response. GIST mainly depends by oncogenic gain of function mutations in tyrosin kinase receptor genes, KIT or PDGFRA, and the mutational status of these two genes or acquisition of secondary mutation is considered the main player in GIST development and progression. To this purpose we analyzed the secondary mutations to better understand how these are involved in imatinib resistance. In our analysis we considered both imatinib and the second line treatment, sunitinib, in a subset of progressive patients. KIT/PDGFRA mutation analysis is an important tool for physicians, as specific mutations may guide therapeutic choices. Currently, the only adaptations in treatment strategy include imatinib starting dose of 800 mg/daily in KIT exon-9-mutated GISTs. In the attempt to individualize treatment, genetic polymorphisms represent a novelty in the definition of biomarkers of imatinib response in addition to the use of tumor genotype. Accumulating data indicate a contributing role of pharmacokinetics in imatinib efficacy, as well as initial response, time to progression and acquired resistance. At the same time it is becoming evident that genetic host factors may contribute to the observed pharmacokinetic inter-patient variability. Genetic polymorphisms in transporters and metabolism may affect the activity or stability of the encoded enzymes. Thus, integrating pharmacogenetic data of imatinib transporters and metabolizing genes, whose interplay has yet to be fully unraveled, has the potential to provide further insight into imatinib response/resistance mechanisms

Recommendations for the use of next-generation sequencing (NGS) for patients with advanced cancer in 2024: a report from the ESMO Precision Medicine Working Group

Advanced cancer; Next-generation sequencing; Precision medicineCàncer avançat; Seqüenciació de nova generació; Medicina de precisióCáncer avanzado; Secuenciación de nueva generación; Medicina de precisiónBackground Advancements in the field of precision medicine have prompted the European Society for Medical Oncology (ESMO) Precision Medicine Working Group to update the recommendations for the use of tumour next-generation sequencing (NGS) for patients with advanced cancers in routine practice. Methods The group discussed the clinical impact of tumour NGS in guiding treatment decision using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) considering cost-effectiveness and accessibility. Results As for 2020 recommendations, ESMO recommends running tumour NGS in advanced non-squamous non-small-cell lung cancer, prostate cancer, colorectal cancer, cholangiocarcinoma, and ovarian cancer. Moreover, it is recommended to carry out tumour NGS in clinical research centres and under specific circumstances discussed with patients. In this updated report, the consensus within the group has led to an expansion of the recommendations to encompass patients with advanced breast cancer and rare tumours such as gastrointestinal stromal tumours, sarcoma, thyroid cancer, and cancer of unknown primary. Finally, ESMO recommends carrying out tumour NGS to detect tumour-agnostic alterations in patients with metastatic cancers where access to matched therapies is available. Conclusion Tumour NGS is increasingly expanding its scope and application within oncology with the aim of enhancing the efficacy of precision medicine for patients with cancer.This project was funded by the European Society for Medical Oncology (no grant numbers are applicable)

Personalized Medicine in Cancer of the Gastro-Intestinal Tract: a pharmacokinetic and pharmacogenetic approach

This thesis describes research on the personalization of treatment of gastro-intestinal cancers by use of pharmacokinetic and pharmacogenetic principles

Soft tissue and visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up

open63siNo abstractopenCasali, P.G.; Abecassis, N.; Bauer, S.; Biagini, R.; Bielack, S.; Bonvalot, S.; Boukovinas, I.; Bovee, J.V.M.G.; Brodowicz, T.; Broto, J.M.; Buonadonna, A.; De Álava, E.; Dei Tos, A.P.; Del Muro, X.G.; Dileo, P.; Eriksson, M.; Fedenko, A.; Ferraresi, V.; Ferrari, A.; Ferrari, S.; Frezza, A.M.; Gasperoni, S.; Gelderblom, H.; Gil, T.; Grignani, G.; Gronchi, A.; Haas, R.L.; Hannu, A.; Hassan, B.; Hohenberger, P.; Issels, R.; Joensuu, H.; Jones, R.L.; Judson, I.; Jutte, P.; Kaal, S.; Kasper, B.; Kopeckova, K.; Krákorová, D.A.; Le Cesne, A.; Lugowska, I.; Merimsky, O.; Montemurro, M.; Pantaleo, M.A.; Piana, R.; Picci, P.; Piperno-Neumann, S.; Pousa, A.L.; Reichardt, P.; Robinson, M.H.; Rutkowski, P.; Safwat, A.A.; Schöffski, P.; Sleijfer, S.; Stacchiotti, S.; Sundby Hall, K.; Unk, M.; Van Coevorden, F.; Van Der Graaf, W.; Whelan, J.; Wardelmann, E.; Zaikova, O.; Blay, J.Y.Casali, P.G.; Abecassis, N.; Bauer, S.; Biagini, R.; Bielack, S.; Bonvalot, S.; Boukovinas, I.; Bovee, J.V.M.G.; Brodowicz, T.; Broto, J.M.; Buonadonna, A.; De Álava, E.; Dei Tos, A.P.; Del Muro, X.G.; Dileo, P.; Eriksson, M.; Fedenko, A.; Ferraresi, V.; Ferrari, A.; Ferrari, S.; Frezza, A.M.; Gasperoni, S.; Gelderblom, H.; Gil, T.; Grignani, G.; Gronchi, A.; Haas, R.L.; Hannu, A.; Hassan, B.; Hohenberger, P.; Issels, R.; Joensuu, H.; Jones, R.L.; Judson, I.; Jutte, P.; Kaal, S.; Kasper, B.; Kopeckova, K.; Krákorová, D.A.; Le Cesne, A.; Lugowska, I.; Merimsky, O.; Montemurro, M.; Pantaleo, M.A.; Piana, R.; Picci, P.; Piperno-Neumann, S.; Pousa, A.L.; Reichardt, P.; Robinson, M.H.; Rutkowski, P.; Safwat, A.A.; Schöffski, P.; Sleijfer, S.; Stacchiotti, S.; Sundby Hall, K.; Unk, M.; Van Coevorden, F.; Van Der Graaf, W.; Whelan, J.; Wardelmann, E.; Zaikova, O.; Blay, J.Y

Soft tissue and visceral sarcomas: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up

Soft tissue sarcomas (STSs) comprise ∼80 entities defined by the World Health Organization (WHO) classification based on a combination of distinctive morphological, immunohistochemical and molecular features.1 These ESMO–EURACAN–GENTURIS (European Society for Medical Oncology; European Reference Network for Rare Adult Solid Cancers; European Reference Network for Genetic Tumour Risk Syndromes) Clinical Practice Guidelines (CPGs) will cover STSs, with the exception of gastrointestinal stromal tumours (GISTs) that are covered in the ESMO–EURACAN–GENTURIS GIST CPGs.2 EURACAN and GENTURIS are the European Reference Networks connecting European institutions, appointed by their governments, to cover rare adult solid cancers and genetic cancer risk syndromes, respectively. Extraskeletal Ewing sarcoma, round cell sarcoma with EWSR1-non-ETS fusion and sarcomas with CIC rearrangements and BCOR genetic alterations are covered by the ESMO–EURACAN–GENTURIS–ERN PaedCan (European Reference Network for Paediatric Oncology) bone sarcomas CPG.3 Kaposi's sarcoma, embryonal and alveolar rhabdomyosarcoma are not discussed in this manuscript, while pleomorphic rhabdomyosarcoma is viewed as a high-grade, adult-type STS. Finally, extraskeletal osteosarcoma is also a considered a high-grade STS, whose clinical resemblance with osteosarcoma of bone is doubtful. The methodology followed during the consensus meeting is specified at the end of the manuscript in a dedicated paragraph