Pharmacogenomics in colorectal cancer: current role in clinical practice and future perspectives

Battaglin, Francesca; Puccini, Alberto; Naseem, Madiha; Schirripa, Marta; Berger, Martin D.; Tokunaga, Ryuma; McSkane, Michelle; Khoukaz, Taline; Soni, Shivani; Zhang, Wu; Lenz, Heinz‐Josef

doi:10.20517/2394-4722.2018.04

Cited by 54 publications

(70 citation statements)

References 170 publications

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“…14,29 These results raise the hypothesis that PD-1 therapy in earlier-stage dMMR cancers may have greater clinical activity than in stage IV disease, before the development of additional mechanisms of immune evasion that enable metastatic dissemination. 3 Clinical benefit was seen across a variety of subgroups; however, one subgroup that appeared to demonstrate less activity was dMMR pancreatic cancer, in which both patients demonstrated adaptive progression and failed to demonstrate a pCR. This is similar to other trials in which activity in pancreatic patients appears less than other patients.…”

Section: Discussionmentioning

confidence: 99%

Neoadjuvant Pembrolizumab in Localized Microsatellite Instability High/Deficient Mismatch Repair Solid Tumors

Ludford

Thomas

et al. 2023

JCO

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PURPOSE Pembrolizumab significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors but is not well studied in the neoadjuvant space. METHODS This is a phase II open-label, single-center trial of localized unresectable or high-risk resectable MSI-H/dMMR tumors. Treatment is pembrolizumab 200 mg once every 3 weeks for 6 months followed by surgical resection with an option to continue therapy for 1 year followed by observation. To continue on study, patients are required to have radiographic or clinical benefit. The coprimary end points are safety and pathologic complete response. Key secondary end points are response rate and organ-sparing at one year for patients who declined surgery. Exploratory analyses include interrogation of the tumor immune microenvironment using imaging mass cytometry. RESULTS A total of 35 patients were enrolled, including 27 patients with colorectal cancer and eight patients with noncolorectal cancer. Among 33 evaluable patients, best overall response rate was 82%. Among 17 (49%) patients who underwent surgery, the pathologic complete response rate was 65%. Ten patients elected to receive one year of pembrolizumab followed by surveillance without surgical resection (median follow-up of 23 weeks [range, 0-54 weeks]). An additional eight did not undergo surgical resection and received less than 1 year of pembrolizumab. During the study course of the trial and subsequent follow-up, progression events were seen in six patients (four of whom underwent salvage surgery). There were no new safety signals. Spatial immune profiling with imaging mass cytometry noted a significantly closer proximity between granulocytic cells and cytotoxic T cells in patients with progressive events compared with those without progression. CONCLUSION Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of pathologic, radiographic, and endoscopic response, which has implications for organ-sparing strategies.

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Section: Discussionmentioning

confidence: 99%

Neoadjuvant Pembrolizumab in Localized Microsatellite Instability High/Deficient Mismatch Repair Solid Tumors

Ludford

Thomas

et al. 2023

JCO

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“…An example of integration of somatic and germline variations in the therapeutic decision is the use of cetuximab, in elderly patients with metastatic colorectal cancer, in combination with FOLFIRI (irinotecan plus 5‐fuorouracil/leucovorin) or FOLFOX (oxaliplatin plus 5‐fuorouracil/leucovorin). This schedule requires the assessment of RAS mutations as well as DPYD and UGT polymorphisms before treatment 9 …”

Section: Genetic Variations In Pgxmentioning

confidence: 99%

Pharmacogenomics Biomarker Discovery and Validation for Translation in Clinical Practice

Arbitrio

Scionti

Martino

et al. 2020

Clinical Translational Sci

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Interindividual variability in drug efficacy and toxicity is a major challenge in clinical practice. Variations in drug pharmacokinetics (PKs) and pharmacodynamics (PDs) can be, in part, explained by polymorphic variants in genes encoding drug metabolizing enzymes and transporters (absorption, distribution, metabolism, and excretion) or in genes encoding drug receptors. Pharmacogenomics (PGx) has allowed the identification of predictive biomarkers of drug PKs and PDs and the current knowledge of genome‐disease and genome‐drug interactions offers the opportunity to optimize tailored drug therapy. High‐throughput PGx genotyping, from targeted to more comprehensive strategies, allows the identification of PK/PD genotypes to be developed as clinical predictive biomarkers. However, a biomarker needs a robust process of validation followed by clinical‐grade assay development and must comply to stringent regulatory guidelines. We here discuss the methodological challenges and the emerging technological tools in PGx biomarker discovery and validation, at the crossroad among molecular genetics, bioinformatics, and clinical medicine.

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“…The contribution of MSI to the tumor mutational burden (TMB) due to a defective mismatch repair system is considered important in about 15% of CRC patients. According to the phenotype, MSI tumors can be divided into two distinct MSI phenotypes: MSI-high and MSI-low[ 83 ]. Recently, considering that the defective mismatch repair phenotype is crucial to define the efficacy of immune checkpoint inhibitor treatment, Xiao et al [ 84 ] used WES to evaluate the immune microenvironment and 2539 microsatellite loci in a group of 98 CRC patients.…”

Section: Methods Based On Ngs Technologiesmentioning

confidence: 99%

Molecular methods for colorectal cancer screening: Progress with next-generation sequencing evolution

Abbes¹,

Baldi²,

Sellami³

et al. 2023

World J Gastrointest Oncol

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Currently, colorectal cancer (CRC) represents the third most common malignancy and the second most deadly cancer worldwide, with a higher incidence in developed countries. Like other solid tumors, CRC is a heterogeneous genomic disease in which various alterations, such as point mutations, genomic rearrangements, gene fusions or chromosomal copy number alterations, can contribute to the disease development. However, because of its orderly natural history, easily accessible onset location and high lifetime incidence, CRC is ideally suited for preventive intervention, but the many screening efforts of the last decades have been compromised by performance limitations and low penetrance of the standard screening tools. The advent of next-generation sequencing (NGS) has both facilitated the identification of previously unrecognized CRC features such as its relationship with gut microbial pathogens and revolutionized the speed and throughput of cataloguing CRC-related genomic alterations. Hence, in this review, we summarized the several diagnostic tools used for CRC screening in the past and the present, focusing on recent NGS approaches and their revolutionary role in the identification of novel genomic CRC characteristics, the advancement of understanding the CRC carcinogenesis and the screening of clinically actionable targets for personalized medicine.

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Pharmacogenomics in colorectal cancer: current role in clinical practice and future perspectives

Cited by 54 publications

References 170 publications

Neoadjuvant Pembrolizumab in Localized Microsatellite Instability High/Deficient Mismatch Repair Solid Tumors

Neoadjuvant Pembrolizumab in Localized Microsatellite Instability High/Deficient Mismatch Repair Solid Tumors

Pharmacogenomics Biomarker Discovery and Validation for Translation in Clinical Practice

Molecular methods for colorectal cancer screening: Progress with next-generation sequencing evolution

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