Clinical Benefits and Utility of Pretherapeutic DPYD and UGT1A1 Testing in Gastrointestinal Cancer: A Secondary Analysis of the PREPARE Randomized Clinical Trial.

Importance: To date, the clinical benefit and utility of implementing a DPYD/UGT1A1 pharmacogenetic-informed therapy with fluoropyrimidines and/or irinotecan have not been prospectively investigated.

Objective: To examine clinically relevant toxic effects, hospitalizations, and related costs while preserving treatment intensity and efficacy outcomes in patients with gastrointestinal cancer.

Design, Setting, And Participants: This nonprespecified secondary analysis stems from Pre-Emptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions (PREPARE), a multicenter, controlled, open, block-randomized, crossover implementation trial conducted from March 7, 2017, to June 30, 2020, and includes data from Italy according to a sequential study design.

Combination of the PARPi and ARSi in advanced castration resistant prostate cancer: a review of the recent phase III trials.

Tumors with an impaired ability to repair DNA double-strand breaks by homologous recombination, including those with alterations in breast cancer 1 and 2 ( and ) genes, are very sensitive to blocking DNA single-strand repair by inhibition of the poly (ADP-ribose) polymerase (PARP) enzyme. This provides the basis for a synthetic deadly strategy in the treatment of different types of cancer, such as prostate cancer (PCa). The phase 3 PROfound study was the first to lead to olaparib approval in patients with metastatic castration resistant PCa (mCRPC) and genes mutations.

Combi-TED: a new trial testing Tedopi with docetaxel or nivolumab in metastatic non-small-cell lung cancer progressing after first line.

Despite the positive results obtained by first-line chemoimmunotherapy in patients with metastatic non-small-cell lung cancer (NSCLC), only a few second-line options are available after disease progression. Combi-TED is a phase II international study that will assess the efficacy of Tedopi, a cancer vaccine, combined with either docetaxel or nivolumab and compared with docetaxel monotherapy in patients with metastatic NSCLC after chemoimmunotherapy. The study, currently in the recruitment phase, will assess 1-year overall survival (primary end point), patient's progression-free survival and overall response rate, as well as the correlation of efficacy with several tumor or blood biomarkers.

Association of 3'UTR Polymorphisms with Response to First-Line FOLFIRI Treatment in Metastatic Colorectal Cancer.

Microenvironmental factors such as non-classical human leukocyte antigen-G (HLA-G) have been associated with cancer invasiveness and metastatic progression. HLA-G expression has been associated with specific single-nucleotide polymorphisms (SNP) in 3'untranslated region (UTR) in several diseases. The primary aim was to investigate the predictive role of polymorphisms on treatment efficacy in metastatic colorectal cancer (mCRC) patients homogeneously treated with first-line FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) and their association with soluble HLA-G (sHLA-G) plasma concentration.

Lymphocyte antigen 6G6D-mediated modulation through p38α MAPK and DNA methylation in colorectal cancer.

In addition to being novel biomarkers for poor cancer prognosis, members of Lymphocyte antigen-6 (Ly6) gene family also play a crucial role in avoiding immune responses to tumors. However, it has not been possible to identify the underlying mechanism of how Ly6 gene regulation operates in human cancers. Transcriptome, epigenome and proteomic data from independent cancer databases were analyzed in silico and validated independently in 334 colorectal cancer tissues (CRC).

Propensity for Early Metastatic Spread in Breast Cancer: Role of Tumor Vascularization Features and Tumor Immune Infiltrate.

Breast cancer is a complex and highly heterogeneous disease consisting of various subtypes. It is classified into human epidermal growth receptor 2 (HER-2)-enriched, luminal A, luminal B and basal-like/triple negative (TNBC) breast cancer, based on histological and molecular features. At present, clinical decision-making in breast cancer is focused only on the assessment of tumor cells; nevertheless, it has been recognized that the tumor microenvironment (TME) plays a critical biologic role in breast cancer.

Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era.

Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices.

IL15RA and SMAD3 Genetic Variants Predict Overall Survival in Metastatic Colorectal Cancer Patients Treated with FOLFIRI Therapy: A New Paradigm.

A new paradigm in cancer chemotherapy derives from the interaction between chemotherapeutics, including irinotecan and 5-fluorouracil (5-FU), and the immune system. The patient's immune response can modulate chemotherapy effectiveness, and, on the other hand, chemotherapeutic agents can foster tumor cell immunogenicity. On these grounds, the analysis of the cancer patients' immunogenetic characteristics and their effect on survival after chemotherapy represent a new frontier.

Molecular and Clinical Insights in Malignant Brenner Tumor of the Testis With Liver Metastases:A Case Report.

Malignant Brenner Tumor (mBT) is extremely rare. Although BT are almost exclusive ovarian neoplasms, they may constitute a highly unusual tumor of the testis; in fact, only seven fully documented cases have been reported to date. Because of their rarity, the pathogenesis of these tumors has not been clarified and there is no standard therapeutic approach.

[Target therapies in translocated ALK lung cancer: treatment management in oncology center of Lazio.].

Lung cancer is a disease extremely heterogeneous in the molecular aspect and knowing the mutational profile of patients is essential in order to initiate the most appropriate treatment. In 2018, alectinib was approved in Italy for the first-line treatment of patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC), becoming a new therapeutic option for this patient group which constitutes approximately 3-7% of patients with NSCLC. On October 26th a virtual meeting was held in which 10 clinicians from various oncology centers in Lazio took part on the management of therapy of patients with Alk translocation, directed by Dr.

Germline Polymorphisms in the Nuclear Receptors PXR and VDR as Novel Prognostic Markers in Metastatic Colorectal Cancer Patients Treated With FOLFIRI.

Nuclear receptors act as mediators of cancer-related inflammation and gene expression. They have a regulatory effect on genes encoding proteins related to drug adsorption, distribution, metabolism, and excretion. The aim of the present study was to highlight novel prognostic markers among polymorphisms in genes encoding for nuclear receptor proteins and inflammation-related cytokines in patients treated with a FOLFIRI regimen.

Combination of germline variations associated with survival of folinic acid, fluorouracil and irinotecan-treated metastatic colorectal cancer patients.

Germline variants could modify survival of metastatic colorectal cancer patients (mCRC). The association of 285 haplotype-tagging SNPs in 11 candidate genes and overall survival (OS) was tested in two cohorts totalizing 417 FOLFIRI-treated mCRC. Gene expression was investigated and in public datasets.

Germline variability and tumor expression level of ribosomal protein gene RPL28 are associated with survival of metastatic colorectal cancer patients.

This study investigated the potential of single nucleotide polymorphisms as predictors of survival in two cohorts comprising 417 metastatic colorectal cancer (mCRC) patients treated with the FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) regimen. The rs4806668G > T of the ribosomal protein gene RPL28 was associated with shorter progression-free survival and overall survival by 5 and 9 months (P = 0.002), with hazard ratios of 3.

Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (., resection, liver transplantation, percutaneous ablation).

Urothelial bladder carcinoma metastasizing to the eye: A systematic review and case report.

The eye is a rare site for disseminated malignancies; nevertheless, several tumors may metastasize to ocular structures. Few cases of urothelial and bladder cancer with eye involvement have been described in the literature thus far. The rarity of metastatic ocular localization implies an accurate differential diagnosis among the possible primary tumor sites.

A New Genetic Risk Score to Predict the Outcome of Locally Advanced or Metastatic Breast Cancer Patients Treated With First-Line Exemestane: Results From a Prospective Study.

Introduction: Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival.

Colonic Ewing Sarcoma/PNET associated with liver metastases: A systematic review and case report.

Ewing Sarcoma is a highly lethal undifferentiated tumor of bone. ES is a small round cell tumor with etiological and characteristic chromosomal translocations between TET/FET (TLS/FUS, EWSR1, and TAF15) and ETS (E26 transformation-specific) family genes. Generally, therapeutic approach for metastatic Ewing Sarcoma includes both local (surgery and radiotherapy) and systemic (chemotherapy) disease control with an overall cure rate of 20%.

The Genotype for DPYD Risk Variants in Patients With Colorectal Cancer and the Related Toxicity Management Costs in Clinical Practice.

Lack of information on the clinical utility of preemptive DPYD screening before fluoropyrimidine treatment is a major barrier preventing its use in clinical practice. This study aimed to define the association between DPYD variants and fluoropyrimidine-related toxicity management costs. A cost analysis was conducted on the toxicities experienced by 550 patients with colorectal cancer treated with fluoropyrimidine-based chemotherapy.

A Clinical-Genetic Score to Identify Surgically Resected Colorectal Cancer Patients Benefiting From an Adjuvant Fluoropyrimidine-Based Therapy.

There are clinical challenges related to adjuvant treatment in colorectal cancer (CRC) and novel molecular markers are needed for better risk stratification of patients. Our aim was to integrate our previously reported clinical-genetic prognostic score with new immunogenetic markers of 5-year disease-free survival (DFS) to evaluate the recurrence risk stratification before fluoropyrimidine (FL)-based adjuvant therapy. The study population included a total of 270 stage II-III CRC patients treated with adjuvant FL with (FL + OXA, = 119) or without oxaliplatin (FL, = 151).

Association of -3 rs1053004 and rs11574077 With FOLFIRI-Related Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients.

Pharmacogenomics has largely been applied to the personalization of irinotecan-based treatment, focusing mainly on the study of genetic variants in adsorption, distribution, metabolism, and excretion (ADME) genes. The transcriptional control of ADME gene expression is mediated by a set of nuclear factors responding to cancer-related inflammation, which could have pharmacological implications. The aim of the present study was to uncover novel genetic predictors of neutropenia and gastrointestinal toxicity risk among 246 haplotype-tagging polymorphisms in 22 genes encoding inflammation-related cytokines and transcriptional regulators of ADME genes.

Improved Progression-Free Survival in Irinotecan-Treated Metastatic Colorectal Cancer Patients Carrying the HNF1A Coding Variant p.I27L.

Hepatocyte nuclear factor 1-alpha (HNF1A) is a liver-enriched transcription factor that plays a key role in many aspects of hepatic functions including detoxification processes. We examined whether polymorphisms are associated with clinical outcomes in two independent cohorts combining 417 European ancestry patients with metastatic colorectal cancer (mCRC) treated with irinotecan-based chemotherapy. The intronic rs2244608A>G marker was predictive of an improved progression-free survival with a trend in the Canadian cohort and reaching significance in the Italian cohort, with hazard ratios (HR) of 0.

Nano albumin bound-paclitaxel in pancreatic cancer: Current evidences and future directions.

Pancreatic cancer (PDAC) is an aggressive and chemoresistant disease, representing the fourth cause of cancer related deaths in western countries. Majority of patients have unresectable, locally advanced or metastatic disease at time of diagnosis and the 5-year survival rate in these conditions is extremely low. For more than a decade gemcitabine has been the cornerstone of metastatic PDAC treatment, although survival benefit was very poor.

HLA-G 3'UTR Polymorphisms Predict Drug-Induced G3-4 Toxicity Related to Folinic Acid/5-Fluorouracil/Oxaliplatin (FOLFOX4) Chemotherapy in Non-Metastatic Colorectal Cancer.

Polymorphisms in drug-metabolizing enzymes might not completely explain inter-individual differences in toxicity profiles of patients with colorectal cancer (CRC) that receive folinic acid/5-fluorouracil/oxaliplatin (FOLFOX4). Recent data indicate that the immune system could contribute to FOLFOX4 outcomes. In light of the immune inhibitory nature of human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, we aimed to identify novel genomic markers of grades 3 and 4 (G3-4) toxicity related to FOLFOX4 therapy in patients with CRC.