Actionable NSCLC Mutation Identification by Comprehensive Genomic Profiling for Clinical Trial Enrollment: The European Program for the Routine Testing of Patients With Advanced Lung Cancer (EPROPA).

Introduction: The advocacy Women Against Lung Cancer in Europe (WALCE) promoted the European Program for the Routine Testing of Patients With Advanced Lung Cancer (EPROPA) and provided a free-of-charge molecular profiling platform for NSCLC sample characterization with the aim of increasing the detection of targetable drivers and improving patients' access to clinical trials in Europe.

Methods: From January 2021 to December 2023, 20 centers located at five different European countries (Greece, Slovenia, Romania, Albania, and Italy) joined EPROPA, with 555 patients with advanced NSCLC registered to the program. Anonymized patients' clinical-pathological data were shared through the EPROPA web platform and tissue samples were collected at the Molecular Pathology Unit of the Reference Center (University of Turin) for molecular analyses.

Implementation of a MSRE ddPCR method for the detection of methylated and genes in colorectal cancer patients.

Background: Colorectal cancer is a worldwide leading cause of death accounting for high-rate mortality. Mutations in the epidermal growth factor receptor and RAS/MAPK pathways, as well as altered methylation genes profiles, have been described as molecular mechanisms promoting and sustaining tumour development and progression. Aberrant methylation is a well-known epigenetic mechanism involved in gene regulation; particularly several genes were reported as hypermethylated in CRC.

Molecular screening with liquid biopsy for anti-EGFR retreatment in metastatic colorectal cancer: preliminary data from the randomized phase 2 PARERE trial.

Background: Retreatment with anti-EGFR monoclonal antibodies is a promising strategy in patients with wild-type (wt) metastatic colorectal cancer (mCRC) who achieved benefit from previous anti-EGFR exposure upon exclusion of mutations in genes according to circulating tumor DNA (ctDNA) analysis by means of liquid biopsy (LB). This treatment approach is now being investigated in the randomized phase II trial PARERE (NCT04787341). We here present preliminary findings of molecular screening.

Clinical Outcomes After Progression on First-Line Therapies in IDH1 Mutated Versus Wild-Type Intrahepatic Cholangiocarcinoma Patients.

Background: Isocitrate dehydrogenase-1 (IDH1) mutations occur in a significant proportion of intrahepatic cholangiocarcinomas (iCCAs). No data are available regarding the prognostic impact of IDH1 mutations in advanced iCCA patients after progression on first-line therapies.

Objective: We investigated the role of IDH1 mutation in advanced iCCA after progression on first-line therapies.

Pralsetinib in RET fusion-positive non-small-cell lung cancer: A real-world data (RWD) analysis from the Italian expanded access program (EAP).

Objectives: The selective RET-inhibitor pralsetinib has shown therapeutic activity in early clinical trials in patients with non-small cell lung cancer (NSCLC) harboring rearranged during transfection (RET) gene fusions. To date, the real-world efficacy of pralsetinib in this population is unknown.

Materials And Methods: A retrospective efficacy and safety analysis was performed on data from patients with RET-fusion positive NSCLC enrolled in the pralsetinib Italian expanded access program between July 2019 and October 2021.

Molecular profile and its clinical impact of IDH1 mutated versus IDH1 wild type intrahepatic cholangiocarcinoma.

IDH1-mutated cholangiocarcinomas (CCAs) are an interesting group of neoplasia with particular behavior and therapeutic implications. The aim of the present work is to highlight the differences characterizing IDH1m and IDH1wt CCAs in terms of genomic landscape. 284 patients with iCCA treated for resectable, locally advanced or metastatic disease were selected and studied with the FOUNDATION Cdx technology.

Interleukin-8 in Colorectal Cancer: A Systematic Review and Meta-Analysis of Its Potential Role as a Prognostic Biomarker.

Among soluble actors that have emerged as druggable factors, the chemokine interleukin-8 (IL-8) has emerged as a possible determinant of response to immunotherapy and targeted treatment in several cancer types; however, its prognostic/predictive role in colorectal cancer (CRC) remains to be established. We: (i) conducted a systematic review of published literature on IL-8 expression in CRC; (ii) searched public transcriptomics databases; (iii) investigated IL-8 expression, by tumor and infiltrating cells, in a series of CRC samples; and (iv) carried out a meta-analysis of published literature correlating IL-8 expression and CRC prognosis. IL-8 possesses an important role as a mediator of the bidirectional crosstalk between tumor/stromal cells.

Next-generation sequencing analysis of cholangiocarcinoma identifies distinct IDH1-mutated clusters.

Background: IDH1-mutated intrahepatic cholangiocarcinomas (IDH1m iCCAs) could be treated with anti-IDH1 drugs, although the high heterogeneity in this class of tumours could limit treatment efficacy.

Methods: We selected 125 IDH1m iCCAs that were treated as resectable, locally advanced, or metastatic and were screened by the NGS-based FoundationOne gene panel. We conducted a mutation-based clustering of tumours and survival analysis.

Gene mutational profile of BRCAness and clinical implication in predicting response to platinum-based chemotherapy in patients with intrahepatic cholangiocarcinoma.

Background And Aims: Biliary tract cancers are rare malignancies with a poor prognosis and scarce therapeutic strategies. The significance of BRCAness in this setting is already unknown.

Method: Tissue specimens of BTC patients treated with platinum-based chemotherapy have been analyzed through the FOUNDATIONPne assay.

State-of-the-Art of Monoclonal Antibodies for the Treatment of Gastric Cancer.

Gastric cancer (GC) is a complex and heterogeneous disease with poor prognosis and limited available treatment options. During recent years, several molecular stratifications have been proposed to optimize the overall treatment strategy for GC patients. Breakthroughs in cancer biology and in molecular profiling through DNA and RNA sequencing are now opening novel landscapes, leading to the personalization of molecular matched therapy.

Cholangiocarcinoma: new perspectives for new horizons.

Introduction: Biliary tract cancer represents a heterogeneous group of malignancies characterized by dismal prognosis and scarce therapeutic options.

Area Covered: In the last years, a growing interest in BTC pathology has emerged, thus highlighting a significant heterogeneity of the pathways underlying the carcinogenesis process, from both a molecular and genomic point of view. A better understanding of these differences is mandatory to deepen the behavior of this complex disease, as well as to identify new targetable target mutations, with the aim to improve the survival outcomes.

Clinical outcomes of NSCLC patients experiencing early immune-related adverse events to PD-1/PD-L1 checkpoint inhibitors leading to treatment discontinuation.

Background: The prognostic relevance of early immune-related adverse events (irAEs) in patients affected by non-small cell lung cancer (NSCLC) upon immunotherapy is not fully understood.

Methods: The Leading to Treatment Discontinuation cohort included 24 patients experiencing severe irAEs after one of two administrations of single anti-PD-1/PD-L1 in any line setting for metastatic NSCLC between November 2015 and June 2019. The control cohort was composed of 526 patients treated with single anti-PD-1/PD-L1 in any line setting with no severe irAE reported.

Rationale and Study Design of the PARERE Trial: Randomized phase II Study of Panitumumab Re-Treatment Followed by Regorafenib Versus the Reverse Sequence in RAS and BRAF Wild-Type Chemo-Refractory Metastatic Colorectal Cancer Patients.

Background: A recent phase II randomized Japanese study reported better survival with regorafenib followed at progression by cetuximab ± irinotecan compared with the reverse standard sequence in chemo-refractory and anti-EGFR-naïve, RAS wild-type (wt) mCRC patients. Nowadays the use of anti-EGFR antibodies is more frequently anticipated to the first-line of therapy especially in patients with left-sided RAS/BRAF wt tumours. However, retrospective analyses and phase II single-arm trials showed promising activity of re-using anti-EGFRs in metastatic colorectal cancer (mCRC) patients who previously achieved benefit from a first-line anti-EGFR-based treatment.

Comparing immunotherapies to other frequently used treatments of gastric cancer.

: Although standard doublet chemotherapy represents the upfront gold standard to increase survival and improve quality of life of gastric cancer patients, overall improvements in long-term outcomes are modest and novel treatments are urgently needed. Among these, immunotherapy is an increasingly attractive option.: A number of clinical trials have shown that checkpoint inhibitors may be of value, but many unclear issues remain controversial and should be promptly untangled.

Role of next-generation genomic sequencing in targeted agents repositioning for pancreaticoduodenal cancer patients.

Background: Pancreaticoduodenal cancer (PDC) is a group of malignant tumors arising in the ampullary region, which lack approved targeted therapies for their treatment.

Methods: This retrospective, observational study is based on Secondary Data Use (SDU) previously collected during a multicenter collaboration, which were subsequently entered into a predefined database and analyzed. FoundationOne CDx or Liquid, a next-generation DNA sequencing (NGS) service, was used to identify genomic alterations of patients who failed standard treatments.

A phase II study of liposomal irinotecan with 5-fluorouracil, leucovorin and oxaliplatin in patients with resectable pancreatic cancer: the nITRO trial.

Background: Up-front surgery followed by postoperative chemotherapy remains the standard paradigm for the treatment of patients with resectable pancreatic cancer. However, the risk for positive surgical margins, the poor recovery after surgery that often impairs postoperative treatment, and the common metastatic relapse limit the overall clinical outcomes achieved with this strategy. Polychemotherapeutic combinations are valid options for postoperative treatment in patients with good performance status.

Case Report: A Metabolic Complete Response to Upfront Osimertinib in a Smoker Non-Small Cell Lung Cancer Patient Harbouring G719A/V769M Complex Mutation.

Complex mutations are rare in non-small cell lung cancer (NSCLC). Limited clinical evidence is available on the efficacy of tyrosine kinase inhibitors (TKIs) in patients with NSCLC harbouring these uncommon mutations. Here, we reported the case of a complete metabolic response in a patient with advanced NSCLC carrying the uncommon G719A/V769M complex mutation treated with the first-line osimertinib.

A phase II trial of the FGFR inhibitor pemigatinib in patients with metastatic esophageal-gastric junction/gastric cancer trastuzumab resistant: the FiGhTeR trial.

Background: Prognosis of patients affected by metastatic esophageal-gastric junction (EGJ) or gastric cancer (GC) remains dismal. Trastuzumab, an anti-HER2 monoclonal antibody, is the only targeted agent approved for the first-line treatment of patients with HER2-overexpressing advanced EGJ or GC in combination with chemotherapy. However, patients invariably become resistant during this treatment.

Plasma IL8 Is a Biomarker for TAK1 Activation and Predicts Resistance to Nanoliposomal Irinotecan in Patients with Gemcitabine-Refractory Pancreatic Cancer.

Purpose: Pancreatic cancer is one of the most lethal solid tumors, mainly because of its intrinsic chemoresistance. We identified TAK1 as a central hub sustaining this resistance. Nanoliposomal irinotecan (nal-IRI) is a novel treatment for metastatic gemcitabine-refractory pancreatic cancer.

From Genetic Alterations to Tumor Microenvironment: The Ariadne's String in Pancreatic Cancer.

The threatening notoriety of pancreatic cancer mainly arises from its negligible early diagnosis, highly aggressive progression, failure of conventional therapeutic options and consequent very poor prognosis. The most important driver genes of pancreatic cancer are the oncogene and the tumor suppressors , and . Although the presence of few drivers, several signaling pathways are involved in the oncogenesis of this cancer type, some of them with promising targets for precision oncology.

Novel Biomarkers for Prediction of Response to Preoperative Systemic Therapies in Gastric Cancer.

Preoperative chemo- and radiotherapeutic strategies followed by surgery are currently a standard approach for treating locally advanced gastric and esophagogastric junction cancer in Western countries. However, in a large number of cases, the tumor is extremely resistant to these treatments and the patients are exposed to unnecessary toxicity and delayed surgical therapy. The current clinical trials evaluating the combination of preoperative systemic therapies with modern targeted and immunotherapeutic agents represent a unique opportunity for identifying predictive biomarkers of response to select patients that would benefit the most from these treatments.

Modulating TAK1 Expression Inhibits YAP and TAZ Oncogenic Functions in Pancreatic Cancer.

YAP and TAZ are central determinants of malignancy; however, their functions remain still undruggable. We identified TGFβ-activated kinase 1 (TAK1) as a central hub integrating the most relevant signals sustaining pancreatic cancer aggressiveness and chemoresistance. Glycogen synthase kinase (GSK)3 is known to stabilize TAK1, and its inhibition causes a reduction in TAK1 levels.

Outcomes of Primary Chemotherapy for Borderline Resectable and Locally Advanced Pancreatic Ductal Adenocarcinoma.

Importance: Chemotherapy is the recommended induction strategy in borderline resectable and locally advanced pancreatic ductal adenocarcinoma. However, the associated results on an intention-to-treat basis are poorly understood.

Objective: To investigate pragmatically the treatment compliance, conversion to surgery, and survival outcomes of patients with borderline resectable and locally advanced pancreatic ductal adenocarcinoma undergoing primary chemotherapy.