Pharmacogenetics of pancreatic cancer: from standard chemotherapy to personalized strategies

Dear Colleagues,

In this address from the Editor-in-Chief, as I welcome you to the new issue of our journal, I feel compelled to highlight one of the most dynamically evolving and clinically significant fields in our science—pharmacogenetics in oncology—an area to which we frequently devote particular attention. As a prime illustration of the current trajectory of this field, I would like to draw your attention to a recent comprehensive review by Langer A. et al., which focuses on therapeutic biomarkers and pharmacogenetics in pancreatic ductal adenocarcinoma (PDAC). This work exemplifies both the contemporary advancements and the challenges that lie ahead.

Pancreatic cancer, notorious for its aggressive course and limited therapeutic options, is increasingly becoming a testing ground for personalized medicine strategies. For a long time, the standard of care has involved regimens such as FOLFIRINOX or gemcitabine/paclitaxel, yet their efficacy remains limited, with a median overall survival rarely exceeding one year. The key to a breakthrough lies in a personalized approach, and this is where pharmacogenetics takes center stage.

The review clearly demonstrates the evolution of our approach: from attempting to predict the response to standard chemotherapy to actively seeking targets for precision therapeutics. Research indicates that variability in genes encoding biotransformation enzymes (e.g., CYP2C8, CYP3A4) and transporters (e.g., ABCB1, SLCO1B3) for drugs such as paclitaxel can influence their efficacy and toxicity. Although these associations have not yet been integrated into routine clinical practice due to study heterogeneity, they point in the right direction. Similarly, for platinum-based chemotherapy, the status of DNA repair genes (e.g., BRCA1, BRCA2, PALB2, ATM) has emerged as a key predictor of treatment response. A deficiency in the homologous recombination repair (HRD) pathway renders tumors vulnerable to the damage inflicted by platinum agents, directly impacting patient survival.

Furthermore, we are currently witnessing a genuine revolution. With the advent of PARP inhibitors (e.g., olaparib) for patients with germline *BRCA1/2* mutations, we have obtained the first targeted therapy for PDAC to demonstrate efficacy in a phase III clinical trial (POLO). Moreover, next-generation sequencing (NGS) enables the identification of other, rarer yet clinically significant alterations: KRAS G12C mutations (targeted by sotorasib, adagrasib), NTRK fusions (targeted by larotrectinib, etc.), NRG1 fusions (targeted by zenocutuzumab), among others. This is transforming PDAC from a universally "untreatable" disease into one where, for specific patient subgroups, the selection of highly effective and safe therapy is becoming a reality.

Despite evident progress, the work by Langer A. et al. also underscores serious challenges that we must collectively address. The vast majority of pharmacogenetic associations, particularly those identified in genome-wide association studies (GWAS) and candidate-gene studies, require independent validation in large cohorts. It is crucial to acknowledge that PDAC is not a single disease but a spectrum of molecular subtypes with distinct responses to treatment. And, of course, the future lies in the integration of data on somatic mutations, germline variants, gene expression, and tumor microenvironment characteristics to build a comprehensive predictive profile.

One of the most promising avenues is the analysis of circulating tumor DNA (ctDNA). This liquid biopsy approach allows for the non-invasive, real-time assessment of a tumor's molecular profile, enabling the monitoring of resistance development (e.g., the emergence of reversion mutations in the BRCA2 gene) and the detection of minimal residual disease post-surgery. It is a cornerstone for a personalized approach that adapts therapy to the evolving biology of the tumor.

It is already becoming clear that monotherapy, whether chemotherapy or a targeted agent, often succumbs to resistance. The future lies in rational combination strategies: PARP inhibitors plus immunotherapy, KRAS inhibitors plus chemotherapy, targeted agents plus anti-angiogenic therapy. Thus, we are moving from a uniform approach towards a complex, multi-component system of patient stratification.

The task of the scientific community, clinicians, and us, as publishers, is to facilitate the translation of this knowledge into clinical practice. It is imperative to continue large-scale collaborative projects, advance NGS and liquid biopsy technologies, and, most importantly, cultivate a new generation of oncologists who think in terms of personalized medicine.

I am confident that the articles in this issue of the journal will constitute another step forward on this path.

Dmitry Sychev
Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Sciences,
Editor-in-Chief of the Journal "Pharmacogenetics and Pharmacogenomics"

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[1] Langer A, Soucek P, Vymetalkova V, et al. Therapeutic pancreatic cancer biomarkers and pharmacogenetics. Semin Cancer Biol. 2025 Sep 6;116:31-44. doi: 10.1016/j.semcancer.2025.08.002.