Predicting drug response and toxicity in metastatic colorectal cancer: the role of germline markers

ABSTRACT

Introduction

Despite the introduction of targeted agents leading to therapeutic advances, clinical management of patients with metastatic colorectal cancer (mCRC) is still challenged by significant interindividual variability in treatment outcomes, both in terms of toxicity and therapy efficacy. The study of germline genetic variants could help to personalize and optimize therapeutic approaches in mCRC.

Areas covered

A systematic review of pharmacogenetic studies in mCRC patients published on PubMed between 2011 and 2021, evaluating the role of germline variants as predictive markers of toxicity and efficacy of drugs currently approved for treatment of mCRC, was perfomed.

Expert opinion

Despite the large amount of pharmacogenetic data published to date, only a few genetic markers (i.e. DPYD and UGT1A1 variants) reached the clinical practice, mainly to prevent the toxic effects of chemotherapy. The large heterogeneity of available studies represents the major limitation in comparing results and identifying potential markers for clinical use, the role of which remains exploratory in most cases. However, the available published findings are an important starting point for future investigations. They highlighted new promising pharmacogenetic markers within the network of inflammatory and immune response signaling. In addition, the emerging role of previously overlooked rare variants has been pointed out.

KEYWORDS:

• ADME
• biomarkers
• colorectal cancer
• germline variants
• immunogenetics
• immunity
• inflammation
• microenvironment
• pharmacogenetics

Article highlights

• Only few genetic markers, such as specific polymorphisms in DPYD and UGT1A1, are currently recommended for implementation in clinical practice to prevent the toxic effects of chemotherapy.

• TYMS and ERCC1/ERCC2 variants are good candidates for predicting the efficacy of fluoropyrimidine- or oxaliplatin-based treatments, although further confirmatory evidence is required.

• The role of germline variants in predicting efficacy or toxicity of anti-EGFR and anti-angiogenic agents is still under investigation and no validated markers have yet been found.

• Inflammation- and immune-related pathways have emerged in the literature as promising targets for future pharmacogenetic investigation.

• Rare genetic variants will get in the next future a prominent role in the personalization of pharmacological treatment in mCRC.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the Horizon 2020 - the Framework Programme for Research and Innovation (2014-2020) (grant agreement no. 668353; Ubiquitous Pharmacogenomics – UPGx) and by the Italian Ministry of Health (Ricerca Corrente; no grant number provided).