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Introduction
Pancreatic cancer (PC) is highly lethal malignancy and consider the fourth most common cause of cancer-related deaths worldwide. The majority of patients, approximately 80%, are diagnosed at an advanced and incurable stage, advanced local (III) or metastatic (IV), of disease, and only around 20% of cancers are suitable for surgical resection. The prognosis for PC is extremely poor, with only 7% five-year survival rate. Few chemotherapy treatments have been shown to slightly improve survival for advanced pancreatic cancer patients, but even with the best treatments currently available, the median survival for these patients is less than one year. For over 40 years, survival rates in pancreatic cancer have not shown any improvement, and there is a clear need for further research of this disease to improve patient outcomes.
Palliative indiscriminate chemotherapy still is the standard of care for patients with advanced PC with no biomarkers currently available to guide the likelihood of an individuals response to treatment. In recent decades, the treatment of many cancers has been evolved, in which screening for specific molecular changes is applied to patients first, and then targeted therapy is applied accordingly. Examples of this approach include the use of EGFR and ALK inhibitors in non-small cell lung cancers harbouring EGFR mutations or ALK gene rearrangements; BRAF and MEK inhibitors in melanoma; and trastuzumab and pertuzumab in HER2 amplified breast cancer, all of which have led to clinically meaningful improvements in patient outcomes. Given the limitations of current treatment regimens, the prospect of applying precision medicine to the treatment of PDAC holds great appeal.
Pancreatic ductal adenocarcinoma (PDAC) accounts for about 90-95% of all pancreatic cancer cases
Genomic landscape of PDAC
Recent advances in next-generation sequencing technologies have allowed for significant progress in the characterization of the genomic landscape of pancreatic cancer, leading to better understanding of the pathogenesis of this disease and identification of a number of potential therapeutic targets.
An activating somatic mutation of the KRAS gene has long been implicated as a critical event occurring early in the development of the overwhelming majority of human PDAC. Mutation of this gene has been implicated in the progression of pre-malignant pancreatic intra-epithelial neoplasia (Pan-IN) into invasive malignancy, and has also been demonstrated to play a vital role in tumour maintenance. Early mutation in KRAS is typically followed by the loss of multiple tumour suppressor genes, most notably CDKN2A, TP53 and SMAD4. However, beyond these common mutations, recent studies have revealed significant tumour heterogeneity among PDAC patients, highlighting a major challenge to the application of precision medicine to this disease.
In 2014, a large genome wide association study of more than 7000 PDAC patients identified numerous susceptibility loci for PDAC lying in close proximity to a variety of genes, some of which have previously been implicated in oncogenesis (e.g. BCAR1, KLF14, PDX1, CHEK2, TERT). More recently, whole exome sequencing on a smaller cohort of 109 patients identified that 5% of tumours contained 24 significantly mutated genes with potential prognostic significance (e.g. KRAS) as well as potential for therapeutic targeting (e.g. BRAF, PIK3CA). Further, comprehensive analysis of 24 PDAC tumours identified an average of 63 genetic mutations in each tumour and described alterations in 12 core signaling pathways, some of which (e.g. DNA damage repair, alterations in cell cycle regulation) may also be amenable to targeted therapy. Indeed, a number of gene mutations with potential for targeted therapy can be identified using resources such as the COSMIC database (Catalogue of Somatic Mutations in Cancer), but most occur at a low overall frequency in PDAC. Despite this, a recent comprehensive analysis integrating genomic, transcriptomic and proteomic profiling of 150 PDAC specimens identified that 42% of patients harboured at least one alteration which could potentially inform enrolment in a genotype directed clinical trial.
EUS FNA as a source of tissue and genetic material
Overwhelmingly, genomic profiling of PDAC has relied on surgical resection specimens to obtain tumour material. EUS FNA is a well-established, minimally invasive biopsy technique which can be utilized in patients at any stage of disease. It is generally considered a safe procedure, as evidenced by a large systematic review of over 10,000 patients undergoing EUS FNA across multiple institutions which reported reassuringly low morbidity (0.98%) and mortality (0.02%) rates associated with the procedure.
EUS FNA biopsy specimens can be used as a source of tissue for genetic analysis of PDAC, although widespread clinical use has been limited due to concerns regarding small tissue quantities, suboptimal yield of genetic material, and potential contamination of samples with non-malignant cells such as blood, inflammatory cells and stomach or intestinal wall cells. However, despite some inherent challenges, the potential to use this technique to obtain tissue from patients at all disease stages with relative ease is a clear advantage.
There are several approaches which have been demonstrated to improve the sensitivity and yield of EUS FNA-derived tissue for diagnosis and genetic analysis, including using larger needles and increased number of passes, utilizing on-site cytology services, and optimizing sample processing including using techniques such as snap freezing biopsies in liquid nitrogen and using RNA-preserving agents such as RNAlater. Multiple studies have reported improved diagnostic sensitivity of the procedure using EUS FNA-derived genomic DNA to detect KRAS mutations
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