Ultrasensitive sequencing to detect local and circulating tumor burden as a driver of recurrence in patients with resectable pancreas cancer

Abstract public domain (NIH RePORTER)

Abstract Pancreas Ductal AdenoCarcinoma (PDAC) is a highly lethal cancer and progress towards improving patient outcomes over the past decade has been limited. Early detection and surgery to remove early-stage PDAC before it has spread beyond the pancreas is the only treatment with the potential to yield long-term patient survival. However, resecting PDAC tumors requires a highly morbid surgery that can limit or delay other forms of treatment if the disease recurs, thus identifying the patients most appropriate for surgery is critical. The current clinical approach of using imaging features and the CA19-9 blood test is insufficient, as evidenced by the fact that the majority of patients eligible for curative resection experience disease recurrence and will succumb to their disease within five years. We propose that occult residual disease, either present at the surgical margin or circulating in patient blood, could predict a patient’s risk of PDAC recurrence after surgery. Nearly all PDAC tumors have an oncogenic point mutation in the gene KRAS, which demarks a cell in PDAC patients as being derived from their tumor. However, screening for such mutations has been thwarted by the high error-rate of next generation sequencing. I therefore adopted ultrasensitive Maximum Depth Sequencing (MDS) to screen the diagnostic exon in KRAS for oncogenic mutations and now propose to develop this approach to screen patients eligible for curative resection for occult residual disease in three aims. In AIM 1 I will prospectively profile PDAC resection margins for occult tumor DNA via MDS and then monitor how this predicts patient recurrence risk at the surgical margin. In AIM 2 I will simultaneously profile blood at the time surgery of the same patients for the presence of circulating tumor DNA (ctDNA) by MDS and then evaluate the relationship between ctDNA and risk of metastatic recurrence. In AIM 3, I will multiplex MDS to simultaneously screen for the second most common mutations in PDAC, namely mutations in the tumor suppressor gene TP53, and evaluate the ability of the assay to increase specificity and clinical utility. Completion of these three aims will inform future approaches to identify those PDAC patients most likely to benefit from surgical resection and direct perioperative use of chemotherapy and radiation. The methodology developed by this proposal will provide the foundation for future research in early PDAC detection and use of targeted therapy for early-stage patients. Additionally, this project and associated mentorship team will provide an invaluable resource to help launch my future translational research program focused on improving the use of molecular profiling for PDAC patients.

Public health relevance public domain (NIH RePORTER)

Project Narrative In the majority of pancreatic cancer patients undergoing tumor resection with the intent to cure, their cancer returns, which is usually lethal. This study will develop and test the ability of ultrasensitive sequencing to detect residual tumor DNA in the surgical margins and blood of these patients. Completion of this study will then inform future approaches to limiting patient risk of recurrence and diagnosis patients at an early disease stage.