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.

Quantification of Letrozole, Palbociclib, Ribociclib, Abemaciclib, and Metabolites in Volumetric Dried Blood Spots: Development and Validation of an LC-MS/MS Method for Therapeutic Drug Monitoring.

Therapeutic drug monitoring (TDM) may be beneficial for cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), such as palbociclib, ribociclib, and abemaciclib, due to established exposure-toxicity relationships and the potential for monitoring treatment adherence. Developing a method for quantifying CDK4/6is, abemaciclib metabolites (M2, M20), and letrozole in dried blood spots (DBS) could be useful to enhance the feasibility of TDM. Thus, an optimized LC-MS/MS method was developed using the HemaXis DB10 device for volumetric (10 µL) DBS collection.

Exploring pharmacokinetic variability of palbociclib in HR+/HER2- metastatic breast cancer: a focus on age, renal function, and drug-gene interactions.

Palbociclib, an oral inhibitor of cyclin-dependent kinase 4 and 6, is approved for the treatment of metastatic breast cancer. This study investigated the influence of diverse clinical and biological factors-age, renal function, genetic variations, and concomitant medications ()-on palbociclib pharmacokinetics. Employing a validated LC-MS/MS method, we analyzed the minimum plasma concentrations (C) of palbociclib in 68 women and determined the percentage deviations from the median C for each dosage group.

The challenge of molecular selection in liver-limited metastatic colorectal cancer for surgical resection: a systematic review and meta-analysis in the context of current and future approaches.

Objectives: Treatment of metastatic colorectal cancer (mCRC) includes resection of liver metastases (LM), however, no validated biomarker identifies patients most likely to benefit from this procedure. This meta-analysis aimed to assess the impact of the most relevant molecular alterations in cancer-related genes of CRC (i.e.

Is ctDNA ready to outpace imaging in monitoring early and advanced breast cancer?

Introduction: Circulating tumor DNA (ctDNA) and radiological imaging are increasingly recognized as crucial elements in breast cancer management. While radiology remains the cornerstone for screening and monitoring, ctDNA holds distinctive advantages in anticipating diagnosis, recurrence, or progression, providing concurrent biological insights complementary to imaging results.

Areas Covered: This review delves into the current evidence on the synergistic relationship between ctDNA and imaging in breast cancer.

Therapeutic Monitoring of Palbociclib, Ribociclib, Abemaciclib, M2, M20, and Letrozole in Human Plasma: A Novel LC-MS/MS Method.

Background: Therapeutic drug monitoring (TDM) using cyclin-dependent kinase inhibitors (CDK4/6is) is a novel approach for optimizing treatment outcomes. Currently, palbociclib, ribociclib, and abemaciclib are the available CDK4/6is and are primarily coadministered with letrozole. This study aimed to develop and validate an LC-MS/MS method for the simultaneous analysis of CDK4/6is, 2 active metabolites of abemaciclib (M2 and M20), and letrozole in human plasma for use in TDM studies.

The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity.

Background: Despite a growing number of publications highlighting the potential impact on the therapy outcome, rare genetic variants (minor allele frequency < 1%) in genes associated to drug adsorption, distribution, metabolism, and elimination are poorly studied. Previously, rare germline DPYD missense variants were shown to identify a subset of fluoropyrimidine-treated patients at high risk for severe toxicity. Here, we investigate the impact of rare genetic variants in a panel of 54 other fluoropyrimidine-related genes on the risk of severe toxicity.

Implementation of pre-emptive testing of a pharmacogenomic panel in clinical practice: Where do we stand?

Adverse drug reactions (ADRs) account for a large proportion of hospitalizations among adults and are more common in multimorbid patients, worsening clinical outcomes and burdening healthcare resources. Over the past decade, pharmacogenomics has been developed as a practical tool for optimizing treatment outcomes by mitigating the risk of ADRs. Some single-gene reactive tests are already used in clinical practice, including the DPYD test for fluoropyrimidines, which demonstrates how integrating pharmacogenomic data into routine care can improve patient safety in a cost-effective manner.

Cost-utility analysis and cross-country comparison of pharmacogenomics-guided treatment in colorectal cancer patients participating in the U-PGx PREPARE study.

Objectives: A cost-utility analysis was conducted to evaluate pharmacogenomic (PGx)-guided treatment compared to the standard-of-care intervention among patients diagnosed with colorectal cancer (CRC) in Italy.

Methods: Data derived from a prospective, open-label, block randomized clinical trial, as a part of the largest PGx study worldwide (355 patients in both arms) were used. Mortality was used as the primary health outcome to estimate life years (LYs) gained in treatment arms within a survival analysis context.

Association of ADME gene polymorphisms on toxicity to CDK4/6 inhibitors in patients with HR+ HER2- metastatic breast cancer.

A wide interindividual variability in therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) palbociclib, ribociclib and abemaciclib, among patients with HR+/HER2- metastatic breast cancer has been reported. This study explored the impact of genetic polymorphisms in ADME genes (responsible for drug absorption, distribution, metabolism, and elimination) on CDKis safety profiles in 230 patients. Selected endpoints include grade 3/4 neutropenia at day 14 of the first treatment cycle, early dose-limiting toxicities (DLTs), and dose reductions within the initial three cycles.

The use of therapeutic drug monitoring to highlight an over-looked drug-drug interaction leading to imatinib treatment failure.

Background: Chronic oral anticancer therapies, are increasingly prescribed and present new challenges including the enhanced risk of overlooked drug-drug interactions (DDIs). Lengthy treatments and patients' management by different professionals can lead to serious prescribing errors that therapeutic drug monitoring (TDM) can help identifying thus allowing a more effective and safer treatment of patients with polypharmacy.

Objectives: This report aims to exemplify how an intensified pharmacological approach could help in the clinical monitoring of patients on chronic treatments.

Ten-year experience with pharmacogenetic testing for in a national cancer center in Italy: Lessons learned on the path to implementation.

Awareness about the importance of implementing pharmacogenetics in clinical practice to prevent severe side effects related to the use of fluoropyrimidines has been raised over the years. Since 2012 at the National Cancer Institute, CRO-Aviano (Italy), a diagnostic genotyping service was set up. This study aims to describe the evolution of diagnostic activity at our center over the last 10 years as a case example of a successful introduction of pharmacogenetic testing in clinical practice.

LC-MS/MS Method for the Quantification of PARP Inhibitors Olaparib, Rucaparib and Niraparib in Human Plasma and Dried Blood Spot: Development, Validation and Clinical Validation for Therapeutic Drug Monitoring.

Poly (ADP-ribose) polymerase inhibitors (PARPis) are becoming increasingly meaningful in oncology, and their therapeutic drug monitoring (TDM) might be beneficial for patients. Several bioanalytical methods have been reported for PARPis quantification in human plasma, but advantages might be obtained using dried blood spot (DBS) as a sampling technique. Our aim was to develop and validate a liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for olaparib, rucaparib, and niraparib quantification in both human plasma and DBS matrices.

Impact of and Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis.

Adequate imatinib plasma levels are necessary to guarantee an efficacious and safe treatment in gastrointestinal stromal tumor (GIST) and chronic myeloid leukemia (CML) patients. Imatinib is a substrate of the drug transporters ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) that can affect its plasma concentration. In the present study, the association between three genetic polymorphisms in (rs1045642, rs2032582, rs1128503) and one in (rs2231142) and the imatinib plasma trough concentration (C) was investigated in 33 GIST patients enrolled in a prospective clinical trial.

A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study.

Background: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed.

Methods: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK).

CYP2D6 and CYP2C8 pharmacogenetics and pharmacological interactions to predict imatinib plasmatic exposure in GIST patients.

Aims: Patients on treatment with oral fixed dose imatinib are frequently under- or overexposed to the drug. We investigated the association between the gene activity score (GAS) of imatinib-metabolizing cytochromes (CYP3A4, CYP3A5, CYP2D6, CYP2C9, CYP2C19, CYP2C8) and imatinib and nor-imatinib exposure. We also investigated the impact of concurrent drug-drug-interactions (DDIs) on the association between GAS and imatinib exposure.

Rare genetic variant burden in DPYD predicts severe fluoropyrimidine-related toxicity risk.

Preemptive targeted pharmacogenetic testing of candidate variations in DPYD is currently being used to limit toxicity associated with fluoropyrimidines. The use of innovative next generation sequencing (NGS) approaches could unveil additional rare (minor allele frequency <1%) genetic risk variants. However, their predictive value and management in clinical practice are still controversial, at least partly due to the challenges associated with functional analyses of rare variants.

An Integrated Pharmacological Counselling Approach to Guide Decision-Making in the Treatment with CDK4/6 Inhibitors for Metastatic Breast Cancer.

A wide inter-individual variability in the therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) has been reported. We herein present a case series of five patients treated with either palbociclib or ribociclib referred to our clinical pharmacological counselling, including therapeutic drug monitoring (TDM), pharmacogenetics, and drug-drug interaction analysis to support clinicians in the management of CDKis treatment for metastatic breast cancer. Patients' plasma samples for TDM analysis were collected at steady state and analyzed by an LC-MS/MS method for minimum plasma concentration (C) evaluation.