Pancreatic ductal adenocarcinoma in the era of precision medicine

Abstract

The paradigm for treatment of PDAC is shifting from a "one size fits all" of cytotoxic therapy to a precision medicine approach based on specific predictive biomarkers for a subset of patients. As the genomic landscape of pancreatic carcinogenesis has become increasingly defined, several oncogenic alterations have emerged as actionable targets and their use has been validated in novel approaches such as targeting mutated germline DNA damage response genes (BRCA) and mismatch deficiency (dMMR/MSI-H) or blockade of rare somatic oncogenic fusions. Chemotherapy selection based on transcriptomic subtypes and developing stroma- and immune-modulating strategies have yielded encouraging results and may open therapeutic refinement to a broader PDAC population. Notwithstanding, a series of negative late-stage trials over the last year continue to underscore the inherent challenges in the treatment of PDAC. Multifactorial therapy resistance warrants further exploration in PDAC "omics" and tumor-stroma-immune cells crosstalk. Herein, we discuss precision medicine approaches applied to the treatment of PDAC, its current state and future perspective.

Keywords: BRCA; KRAS; germline; pancreatic ductal adenocarcinoma; precision medicine; somatic; targeted therapy.

Figure 1.

Molecular Classifications of Pancreas Cancer. Outer ring represents transcriptional subtypes from selective pancreatic cancer sequencing cohorts. Inner ring compiles main similarities in gene expressions amongst the subtypes. Abbrev. ADEX, aberrantly differentiated endocrine exocrine.

Figure 2a.

Selective Targeted Approaches in Development for the treatment of Pancreas Cancer. Inner circle represents key potentially actionable pathways implicated in pancreatic tumorigenesis. Outer color-coded squares contain specifically targeted mutations, followed by key therapeutic agents in development. 2b. Key Genomic Alterations, Prevalence and Overview of Detection Methods. *Approximate detection rate based on published cohorts. Abbreviations. CTGF, connective tissue growth factor. dMMR, mismatch repair-deficiency. HCQ, hydroxychloroquine. IHC, immunohistochemistry. mAb, monoclonal antibody. MSI-H, microsatellite instability-high. NGS, next generation sequencing. PBL, peripheral blood lymphocyte. PCR, polymerase chain reaction.

Figure 2a.

Selective Targeted Approaches in Development for the treatment of Pancreas Cancer. Inner circle represents key potentially actionable pathways implicated in pancreatic tumorigenesis. Outer color-coded squares contain specifically targeted mutations, followed by key therapeutic agents in development. 2b. Key Genomic Alterations, Prevalence and Overview of Detection Methods. *Approximate detection rate based on published cohorts. Abbreviations. CTGF, connective tissue growth factor. dMMR, mismatch repair-deficiency. HCQ, hydroxychloroquine. IHC, immunohistochemistry. mAb, monoclonal antibody. MSI-H, microsatellite instability-high. NGS, next generation sequencing. PBL, peripheral blood lymphocyte. PCR, polymerase chain reaction.