Pharmacogenetics of treatments for pancreatic cancer

ABSTRACT

Introduction: Despite clinical efforts, pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The scarcity of effective therapies can be reflected by the lack of reliable biomarkers to adapt anticancer drugs prescription to tumors’ and patients’ features.

Areas covered: Pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best matches individual and tumor genetic profile, but it has not yet led to gains in outcome. This review describes PDAC pharmacogenetics findings, critically reappraising studies on polymorphisms and -omics profiles correlated to response to gemcitabine, FOLFIRINOX, and nab-paclitaxel combinations, as well as limitations of targeted therapies. Further, we question whether personalized approaches will benefit patients to any significant degree, supporting the need of new strategies within well-designed trials and validated genomic tests for treatment decision-making.

Expert opinion: A major challenge in PDAC is the identification of subgroups of patients who will benefit from treatments. Minimally-invasive tests to analyze biomarkers of drug sensitivity/toxicity should be developed alongside anticancer treatments. However, progress might fall below expectations because of tumor heterogeneity and clonal evolution. Whole-genome sequencing and liquid biopsies, as well as prospective validation in selected cohorts, should overcome the limitations of traditional pharmacogenetic approaches.

KEYWORDS:

• Pancreatic cancer
• pharmacogenetic studies
• gemcitabine
• FOLFIRINOX
• nab-paclitaxel
• promises and pitfalls of pharmacogenetic approaches
• validated tests and clinical trials

Article highlights

• Improving survival in pancreatic ductal adenocarcinoma (PDAC) is a critical unmet need.

• Over the last years, patients have slightly benefitted from new combinations of conventional chemotherapy agents, improved surgical outcomes, and advancements in diagnostics, such as refinement of endoscopy.

• However, late-stage diagnosis and resistance to chemotherapy remain the biggest hurdles for PDAC treatment.

• Immunotherapy and targeted therapies lack effectiveness in treatment of PDAC due to its complex tumor microenvironment.

• Pharmacogenetics of standard treatments modalities has suggested several candidate biomarkers, but most studies showed conflicting results that are difficult to translate in the clinical setting.

• New technologies should improve pharmacogenetic approaches by moving from candidate gene methods toward genome-wide studies.

• In the future, oncologists should strive for biomarker-driven clinical trials, improving selection of clinical trial participants and more standardized protocols in biomedical research data processing.

• Liquid biopsies have the potential to pair with genomic tests and new trials, establishing more effective clinical management strategies for PDAC patients.

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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 work was partially supported in the collection and analysis of data by the following grants to Elisa Giovannetti: AIRC/Start-Up grant, CCA Foundation 2015 and 2016 grants, Fondazione Pisana per la Scienza grant, and KWF Dutch Cancer Society grants (KWF project #10401 and #11957).