Identifying Actionable Alterations in KRAS Wild-Type Pancreatic Cancer.

The 5-year relative survival rate for pancreatic cancer is currently the lowest among all cancer types with a dismal 13%. A Kirsten rat sarcoma virus (KRAS) gene mutation is present in approximately 90% of patients with pancreatic cancer; however, KRAS-specific drugs are not yet widely used in clinical practice for pancreatic cancer, specifically the KRASG12D variant. Advances in genomic testing revealed an opportunity to detect genetic alterations in a subset of patients with no KRAS mutation termed KRAS wild-type. Patients with KRAS wild-type tumors have a propensity to express driver alterations, hence paving the way for utilizing a targeted therapy approach either via clinical trials or standard-of-care drugs. These alterations include fusions, amplifications, translocations, rearrangements and microsatellite instability-high tumors and can be as high as 11% in some studies. Here, we discuss some of the most notable alterations in KRAS wild-type and highlight promising clinical trials.

Targeting KRAS in pancreatic adenocarcinoma: Progress in demystifying the holy grail.

Pancreatic cancer (PC) remains one of the most challenging diseases, with a very poor 5-year overall survival of around 11.5%. Kirsten rat sarcoma virus (KRAS) mutation is seen in 90%-95% of PC patients and plays an important role in cancer cell proliferation, differentiation, metabolism, and survival, making it an essential mutation for targeted therapy. Despite extensive efforts in studying this oncogene, there has been little success in finding a drug to target this pathway, labelling it for decades as "undruggable". In this article we summarize some of the efforts made to target the KRAS pathway in PC, discuss the challenges, and shed light on promising clinical trials.

A Unicorn Disease: The Large Duct Variant of Invasive Ductal Adenocarcinoma of the Pancreas.

Large duct adenocarcinoma (LDA) is a rare histopathological variant of pancreatic ductal adenocarcinoma (PDAC) that closely mimics intraductal papillary mucinous neoplasm (IPMN). We present a 74-year-old female diagnosed with LDA in 2017. She was initially managed with chemotherapy and laparoscopic distal pancreatectomy. After five years of stable disease on systemic chemotherapy, she was referred to us to explore further definitive treatments. We used a multidisciplinary approach with curative-intent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC), followed by oral maintenance chemotherapy. Subsequent scans showed stable disease; she eventually underwent neoadjuvant radiation and surgery with intraoperative radiation therapy (IORT) and achieved remission.