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The development of innovative technologies and the advances in the genetics and genomics, have offered new opportunities for personalized treatment in oncology. Although the selection of the patient based on the molecular characteristics of the neoplasm has the potential to revolutionize the therapeutic scenario of oncology, this approach is extremely challenging. The access, homogeneity, and economic sustainability of the required genomic tests should be warranted in the clinical practice, as well as the specific scientific and clinical expertise for the choice of medical therapies. All these elements make essential the collaboration of different specialists within the Molecular Tumor Boards (MTBs). In this position paper, based on experts' opinion, the AIOM-SIAPEC/IAP-SIBioC-SIC-SIF-SIGU-SIRM Italian Scientific Societies critically discuss the available molecular profiling technologies, the proposed criteria for the selection of patients candidate for evaluation by the MTB, the criteria for the selection and analysis of biological samples, and the regulatory and pharmaco-economic issues., (Copyright © 2021. Published by Elsevier B.V.)

The personalized medicine is in a rapidly evolving scenario. The identification of actionable mutations is revolutionizing the therapeutic landscape of tumors. The morphological and histological tumor features are enriched by the extensive genomic profiling, and the first tumor-agnostic drugs have been approved regardless of tumor histology, guided by predictive and druggable genetic alterations. This new paradigm of "mutational oncology", presents a great potential to change the oncologic therapeutic scenario, but also some critical aspects need to be underlined. A process governance is mandatory to ensure the genomic testing accuracy and homogeneity, the economic sustainability, and the regulatory issues, ultimately granting the possibility of translating this model in the "real world". In this position paper, based on experts' opinion, the AIOM-SIAPEC-IAP-SIBIOC-SIF Italian Scientific Societies revised the new agnostic biomarkers, the diagnostic technologies available, the current availability of agnostic drugs and their present indication., (Copyright © 2021. Published by Elsevier B.V.)

Importance: Based on a small retrospective study, rechallenge with cetuximab-based therapy for patients with KRAS wild-type metastatic colorectal cancer (mCRC) who were previously treated with the same anti-epidermal growth factor receptor-based regimen might be efficacious. Recent data suggest the role of liquid biopsy as a tool to track molecular events in circulating tumor DNA (ctDNA)., Objective: To prospectively assess the activity of cetuximab plus irinotecan as third-line treatment for patients with RAS and BRAF wild-type mCRC who were initially sensitive to and then resistant to first-line irinotecan- and cetuximab-based therapy., Design, Setting, and Participants: Multicenter phase 2 single-arm trial conducted from January 7, 2015, to June 19, 2017. Liquid biopsies for analysis of ctDNA were collected at baseline. Main eligibility criteria included RAS and BRAF wild-type status on tissue samples; prior first-line irinotecan- and cetuximab-based regimen with at least partial response, progression-free survival of at least 6 months with first-line therapy, and progression within 4 weeks after last dose of cetuximab; and prior second-line oxaliplatin- and bevacizumab-based treatment., Interventions: Biweekly cetuximab, 500 mg/m2, plus irinotecan, 180 mg/m2., Main Outcomes and Measures: Overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival and overall survival and, as an exploratory analysis, RAS mutations in ctDNA., Results: Twenty-eight patients (9 women and 19 men; median age, 69 years [range, 45-79 years]) were enrolled. Six partial responses (4 confirmed) and 9 disease stabilizations were reported (response rate, 21%; 95% CI, 10%-40%; disease control rate, 54%; 95% CI, 36%-70%). Primary end point was met because lower limit of 95% CI of response rate was higher than 5%. RAS mutations were found in ctDNA collected at rechallenge baseline in 12 of 25 evaluable patients (48%). No RAS mutations were detected in samples from patients who achieved confirmed partial response. Patients with RAS wild-type ctDNA had significantly longer progression-free survival than those with RAS mutated ctDNA (median progression-free survival, 4.0 vs 1.9 months; hazard ratio, 0.44; 95% CI, 0.18-0.98; P = .03)., Conclusions and Relevance: This is the first prospective demonstration that a rechallenge strategy with cetuximab and irinotecan may be active in patients with RAS and BRAF wild-type mCRC with acquired resistance to first-line irinotecan- and cetuximab-based therapy. The evaluation of RAS mutational status on ctDNA might be helpful in selecting candidate patients., Trial Registration: ClinicalTrials.gov Identifier: NCT02296203.