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2017 has been full of new discoveries that will influence the treatment of colorectal cancer. In the adjuvant setting, 3 months of chemotherapy might now be considered a new standard of care. Various other new treatments and promising biomarkers have also become available that will improve survival outcomes and the quality of life of many patients with metastatic disease.

The role of aberrant hepatocyte growth factor receptor (c-MET, also known as tyrosine-protein kinase MET)/hepatocyte growth factor (HGF) signaling in cancer progression and invasion has been extensively studied. c-MET inhibitors have shown promising pre-clinical and early phase clinical trial anti-tumor activity in several tumor types, although results of most phase III trials with these agents have been negative. To date, two small molecule c-MET inhibitors, cabozantinib and crizotinib, have been approved by regulatory authorities for the treatment of selected cancer types, but several novel c-MET inhibitors (either monoclonal antibodies or small molecule c-MET tyrosine kinase inhibitors) and treatment combinations are currently under study in different settings. Here we provide an overview of the mechanism of action and rationale of c-MET inhibition in cancer, the efficacy of approved agents, and novel promising c-MET-inhibitors and novel targeted combination strategies under development in different cancer types, with a focus on the safety profile and tolerability of these compounds.

Gastro-esophageal adenocarcinomas (GEA) represent a severe global health burden and despite improvements in the multimodality treatment of these malignancies the prognosis of patients remains poor. HER2 overexpression/amplification has been the first predictive biomarker approved in clinical practice to guide patient selection for targeted treatment with trastuzumab in advanced gastric and gastro-esophageal junction cancers. More recently, immunotherapy has been approved for the treatment of GEA and PD-L1 expression is now a biomarker required for the administration of pembrolizumab in these diseases. Significant progress has been made in recent years in dissecting the genomic makeup of GEA in order to identify distinct molecular subtypes linked to distinct patterns of molecular alterations. GEA have been found to be highly heterogeneous malignances, representing a challenge for biomarkers discovery and targeted treatment development. The current review focuses on an overview of established and novel promising biomarkers in GEA, covering recent molecular classifications from TCGA and ACRG. Main elements of molecular heterogeneity are discussed, as well as emerging mechanisms of primary and secondary resistance to HER2 targeted treatment and recent biomarker-driven trials. Future perspectives on the role of epigenetics, miRNA/lncRNA and liquid biopsy, and patient-derived xenograft models as a new platform for molecular-targeted drug discovery in GEA are presented. Our knowledge on the genomic landscape of GEA continues to evolve, uncovering the high heterogeneity and deep complexity of these tumors. The availability of new technologies and the identification of promising novel biomarker will be critical to optimize targeted treatment development in a setting where therapeutic options are currently lacking. Nevertheless, clinical validation of novel biomarkers and treatment strategies still represents an issue.

In the last few years, the unprecedented results of immune checkpoint inhibitors have led to a paradigm shift in clinical practice for the treatment of several cancer types. However, the vast majority of patients with gastrointestinal cancer do not benefit from immunotherapy. To date, microsatellite instability high and DNA mismatch repair deficiency are the only robust predictive biomarkers of response to immune checkpoint inhibitors. Unfortunately, these patients comprise only 5%–10% of all gastrointestinal cancers. Several mechanisms of both innate and adaptive resistance to immunotherapy have been recognized that may be at least in part responsible for the failure of immune checkpoint inhibitors in this population of patients. In the first part of this review article, we provide an overview of the main clinical trials with immune checkpoint inhibitors in patients with gastrointestinal cancer and the role of predictive biomarkers. In the second part, we discuss the actual body of knowledge in terms of mechanisms of resistance to immunotherapy and the most promising approach that are currently under investigation in order to expand the population of patients with gastrointestinal cancer who could benefit from immune checkpoint inhibitors.

Background The standard treatment for localized/locally advanced gastroesophageal adenocarcinoma (GEA) is radical surgery and peri-operative FLOT treatment (5-fluorouracil plus leucovorin, oxaliplatin, and docetaxel), but around half patients still experience disease relapse. In gastrointestinal cancers, the presence of circulating tumor DNA (ctDNA) after surgery is associated with a high risk of relapse, and the lack of ctDNA clearance after post-operative treatment is strongly associated with early relapse. Therefore, liquid biopsy may guide the selection of patients with micrometastatic disease after preoperative chemotherapy and surgery for non-cross resistant regimens in the post-operative setting. Trastuzumab deruxtecan (T-DXd) is approved in patients with HER2-positive advanced gastric or gastroesophageal adenocarcinoma after failure of at least one prior trastuzumab-based regimen. The DESTINY-Gastric01 and 02 trials showed remarkable activity and efficacy of T-DXd, thus supporting the investigation of this agent in early-stage disease to increase the chance of achieving disease eradication. Finally, the DESTINY-Gastric03 trial showed the safety profile and feasibility, with preliminary promising activity results of the combination of T-DXd with a fluoropyrimidine. Trial design TRINITY is an ongoing multicentre, randomized, open-label, interventional phase II study which will enroll approximately 46 patients with HER2-positive GEA, treated with pre-operative FLOT and radical surgery, and with the persistence of minimal residual disease detected by the Signatera™ assay in a liquid biopsy collected between 2 and 6 weeks after surgery. The trial is designed with an observational phase enrolling patients with HER2-positive GEA eligible for standard treatment with peri-operative FLOT and surgery. Eligible patients will be randomized on a 1:1 basis to the experimental treatment arm consisting of adjuvant T-DXd (6.4 mg/kg IV on day 1) plus either capecitabine (1000 mg/sqm BID orally on days 1–14) or 5-fluorouracil (600 mg/sqm continuous IV infusion on days 1–5) Q3 W for 6 cycles, or to the control arm with standard post-operative FLOT (at the same dose used during the last pre-operative cycle) for 4 cycles. Patients non-eligible for the interventional trial will continue the standard therapy and follow-up in the frame of the observational phase with collection of exploratory longitudinal liquid biopsies. The primary objective is ctDNA clearance at 1 year after randomization. Considering alpha- and beta-errors of 0.10 and 0.20 and hypothesizing a ctDNA clearance of 10% and 35% in the control and experimental arm, respectively, 23 patients per arm are required to prove the superiority of the experimental strategy. Secondary endpoints include disease-free survival, overall survival, metastases-free survival, patient-reported outcomes and safety. The trial also represents a translational platform, including extensive analysis of circulating, tissue, and immune biomarkers as exploratory endpoints. Enrollment is active and ongoing. Trial registration TRINITY is registered at ClinicalTrials.gov (NCT06253650).

Approximately 3% of colorectal cancers (CRCs) are due to Lynch syndrome (LS), a hereditary cancer syndrome caused by pathogenic variants (PVs) in the mismatch repair (MMR) genes. Patients with CRC and LS have elevated lifetime risks for a range of cancers and require personalized treatment and targeted surveillance. Relatives of people affected by LS who share the same PV also have elevated cancer risks and can benefit from preventive measures and/or risk-reducing surgeries. Despite this, LS remains vastly underdiagnosed. Universal tumor screening (UTS) for deficient MMR is recommended in diagnosing LS in patients with CRC. This process, when combined with genetic testing (GT) offered within routine cancer care (termed \"mainstream GT\"), aims to identify individuals at risk efficiently, but integrating UTS and mainstream GT for LS in CRC is a complex endeavor. The aim of the proposed scoping review will be to comprehensively explore the literature on diagnostic pathways comprising UTS and mainstream GT for LS among patients with CRC and barriers and facilitators in their implementation. The scoping review will follow Arksey and O'Malley's expanded framework. Results will be reported following the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines and summarized quantitatively. A narrative synthesis will also be performed using the Theoretical Domains Framework. The results will be presented in a forthcoming scoping review, which we expect to publish in a peer-reviewed journal by early 2026. Aligning UTS with mainstream GT for LS in CRC may boost early diagnosis and prevention while reducing waiting times and other patient burdens. By addressing barriers to and facilitators in diagnostic pathways, health care systems can improve the identification and management of LS, ultimately leading to better outcomes for patients and their families. The insights gained from this scoping review will inform the development of a mixed methods study about implementing diagnostic pathways for LS in CRC that integrate UTS and mainstream GT in Italy. PRR1-10.2196/70831.

Panitumumab is a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR). It is currently approved for the treatment of wild-type (WT) metastatic colorectal cancer (mCRC) in combination with chemotherapy in first- and second-line and as monotherapy in chemorefractory patients. This review will provide an overview of main efficacy data on panitumumab from its early development up to latest evidences, including novel perspectives on predictive biomarkers of anti-EGFRs efficacy and mechanisms of secondary resistance. Quality of life (QoL) related issues and panitumumab safety profile will be addressed as well.

KRAS status serves as a predictive biomarker of response to treatment in metastatic colorectal cancer (mCRC). We hypothesize that complex interactions between multiple pathways contribute to prognostic differences between KRAS wild-type and KRAS mutant patients with mCRC, and aim to identify polymorphisms predictive of clinical outcomes in this subpopulation. Most pathway association studies are limited in assessing gene–gene interactions and are restricted to an individual pathway. In this study, we use a random survival forests (RSF) method for identifying predictive markers of overall survival (OS) and progression-free survival (PFS) in mCRC patients treated with FOLFIRI/bevacizumab. A total of 486 mCRC patients treated with FOLFIRI/bevacizumab from two randomized phase III trials, TRIBE and FIRE-3, were included in the current study. Two RSF approaches were used, namely variable importance and minimal depth. We discovered that Wnt/β-catenin and tumor associated macrophage pathway SNPs are strong predictors of OS and PFS in mCRC patients treated with FOLFIRI/bevacizumab independent of KRAS status, whereas a SNP in the sex-differentiation pathway gene, DMRT1, is strongly predictive of OS and PFS in KRAS mutant mCRC patients. Our results highlight RSF as a useful method for identifying predictive SNPs in multiple pathways.

ObjectivePatient-reported outcomes (PROs) are considered the gold standard for the assessment of subjective symptoms, quality of life (QoL) and patient well-being in both clinical trials and clinical practice. Here, we report key discussions and findings from the 21st National Conference of the Italian Association of Medical Oncology, held in Bologna on 21–22 June 2024, with a focus on the integration and impact of PROs in oncology research and clinical practice.Methods and analysisLeading national and international experts presented and analysed data regarding the use of PROs in clinical trials and routine oncology care. Topics included the role of electronic PROs (ePROs), digital therapeutics, financial toxicity as a PRO and methodologies for standardising QoL assessment. Insights were drawn from expert presentations, consensus discussions and practical experiences shared during the conference sessions.ResultsExperts emphasised that PROs should be included as key endpoints in clinical trials, with timely publication of results and standardised methodologies for analysis and interpretation. The conference highlighted the critical importance of incorporating PROs and QoL measures throughout the cancer care continuum—from screening to survivorship. In clinical practice, PROs improve patient-centred care and communication, particularly when oncologists are trained to interpret QoL data. The use of ePROs was noted as a valuable tool to support digital health interventions. Financial toxicity emerged as a significant PRO, with screening tools recommended to identify and support at-risk patients. Key organisational challenges were identified, including technological barriers, resource constraints and the need for responsive infrastructure to support real-time PRO integration.ConclusionThe implementation of PROs, including ePROs and financial toxicity assessments, is essential for advancing quality cancer care. Standardisation, digital innovation and targeted clinician education are critical to integrating PROs effectively in both research and clinical settings. Addressing infrastructural and technological challenges will be vital for optimising patient outcomes and ensuring optimal care across the cancer journey.

Polybromo-1 ( PBRM1 ) loss of function mutations are present in a fraction of biliary tract cancers (BTCs). PBRM1 , a subunit of the PBAF chromatin-remodeling complex, is involved in DNA damage repair. Herein, we aimed to decipher the molecular landscape of PBRM1 mutated (mut) BTCs and to define potential translational aspects. Totally, 1848 BTC samples were analyzed using next-generation DNA-sequencing and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). siRNA-mediated knockdown of PBRM1 was performed in the BTC cell line EGI1 to assess the therapeutic vulnerabilities of ATR and PARP inhibitors in vitro. PBRM1 mutations were identified in 8.1% ( n  = 150) of BTCs and were more prevalent in intrahepatic BTCs (9.9%) compared to gallbladder cancers (6.0%) or extrahepatic BTCs (4.5%). Higher rates of co-mutations in chromatin-remodeling genes (e.g., ARID1A 31% vs. 16%) and DNA damage repair genes (e.g., ATRX 4.4% vs. 0.3%) were detected in PBRM1 -mutated (mut) vs. PBRM1 -wildtype (wt) BTCs. No difference in real-world overall survival was observed between PBRM1 -mut and PBRM1 -wt patients (HR 1.043, 95% CI 0.821–1.325, p  = 0.731). In vitro, experiments suggested that PARP ± ATR inhibitors induce synthetic lethality in the PBRM1 knockdown BTC model. Our findings served as the scientific rationale for PARP inhibition in a heavily pretreated PBRM1- mut BTC patient, which induced disease control. This study represents the largest and most extensive molecular profiling study of PBRM1- mut BTCs, which in vitro sensitizes to DNA damage repair inhibiting compounds. Our findings might serve as a rationale for future testing of PARP/ATR inhibitors in PBRM1- mut BTCs.