The Sol Goldman Pancreatic Cancer Research Center

Advances and Discoveries Made at Johns Hopkins

Advances Made in a Blood Test for Pancreatic Cancer
In the February 19, 2014 issue of Science Translational Medicine (Sci Transl Med. 2014 Feb 19;6(224):224ra24), Bettegowda and colleagues in the Sol Goldman Pancreatic Cancer Research center at Johns Hopkins report on an exciting approach to the detection of pancreatic cancer. Bettegowda and colleagues applied cutting edge DNA sequencing to blood samples from a large number of patients with a number of different cancers. They found that many cancers, even some small curable cancers, shed mutant DNA into the blood. This mutant DNA circulating in the blood is called "circulating tumor DNA," or ctDNA for short. The team at Hopkins was able to show that ctDNA is detectable in >80% of patients with advanced pancreatic cancer, and close to half of the patients they studied with early, surgically resectable pancreatic cancers. There is more work to be done, but this study, we believe, represents a significant advance towards the development of a blood test for pancreatic cancer.

Multidiciplinary Cyst Clinic
As the complexity of diseases grows, more and more patients are seeking treatment at specialized centers of excellence such as Johns Hopkins. At these centers patients are often offered "multidisciplinary" care. This means that rather than just being evaluated by a physician from one specialty, patients' cases are evaluated by a team of doctors from multiple specialties. The team at Johns Hopkins established one of the first multidisciplinary clinics for the management of patients with pancreatic cysts. In the Annals of Surgical Oncology, Dr. Lennon and colleagues from Hopkins report on the impact that this cyst clinic has had.on improving patient care. Remarkably, the recommended management was changed for ~30% of the patients who were seen in the clinic. What does this mean for patients with a pancreatic cyst? The results suggest that patients may want to be evaluated at a major pancreatic center that has a multidisciplinary clinic dedicated to treating patients with pancreatic cysts.

Lennon AM, Manos LL, Hruban RH, Ali SZ, Fishman EK, Kamel IR, Raman SP, Zaheer A, Hutfless S, Salamone A, Kiswani V, Ahuja N, Makary MA, Weiss MJ, Hirose K, Goggins M, Wolfgang CL. Role of a multidisciplinary clinic in the management of patients with pancreatic cysts: a single-center cohort study. Ann Surg Oncol. 21:3668-74, 2014.

Genetic Changes in Precancers
In a wonderful collaboration between US and Italian scientists, Dr. E. Amato and colleagues reported the results of extensive sequencing of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. The collaborative team sequenced 48 IPMNs and in so doing, they were able to confirm the genes that are frequently targeted in IPMNs (such as KRAS and GNAS), and they provided additional evidence that non-invasive IPMNs can give rise to invasive pancreatic cancer by showing that matched IPMNs and invasive cancers from the same patients had the same mutations. What does this mean for patients with an IPMN? It adds to the growing body of evidence that non-invasive curable precancerous lesions of the pancreas (IPMNs) should be detectable using DNA sequencing techniques before they progress to invasive cancer.

Amato E, dal Molin M, Mafficini A, Yu J, Malleo G, Rusev B, Fassan M, Antonello D, Sadakari Y, Castelli, Zamboni G, Maitra A, Salvia R, Hruban RH, Bassi C, Capelli P, Lawlor RT, Goggins M, Scarpa A. Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas. J Pathol. 2014. (Awarded the Jeremy Jass Prize for Research Excellence in Pathology).

Blood test for Pancreatic Cancer
Early detection offers one of the best hopes for curing cancer. Dr. C. Bettegowda and colleagues from the Sol Goldman Pancreatic Cancer Research Center reported in the journal Science Translational Medicine that pancreatic cancers release abnormal (mutant) DNA into the blood stream (so called "circulating tumor DNA") and that this abnormal DNA can be detected. This is a significance advance in early detection because it suggested that a blood test could have the sensitivity and specificity needed for an early detection test. Further studies are needed to validate this approach. In the meanwhile the investigators are hard at work improving on their approach to early detection.

Bettegowda C, Sausen M, Leary RJ, Kinde I,…Hruban RH, Wu J, Allen PJ, Schmidt CM, Choti MA, Velculescu VE, Kinzler KW, Vogelstein B, Papadopoulos N, Diaz LA. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 6:224ra24, 2014.

Sequencing Acinar Cancers
Not all tumors of the pancreas are "ductal adenocarcinomas," the type of tumor we usually mean when we refer to "pancreatic cancer." There are a number of variant tumors that can arise in the pancreas. One of the more aggressive of these is the acinar carcinoma. Acinar carcinomas only account for 1% of all cancers of the pancreas, but they can be very aggressive and are important to recognize. Jiao and colleagues from Johns Hopkins sequenced all known genes (the exomes) of a series of acinar carcinomas of the pancreas. They found that some of the genes targeted (mutated) in acinar carcinomas have been previously associated with familial pancreatic cancer. These genes include ATM, BRCA2 and PALB2. They also found that more than one-third of acinar carcinomas have potentially targetable genetic alterations, including mutations in the genes BRCA2, PALB2, ATM, BAP1, BRAF and JAK1.

Jiao Y, Yonescu R, Offerhaus GJ, Klimstra DS, Maitra A, Eshleman JR, Herman JG, Poh W, Pelosof L, Wolfgang CL, Vogelstein B, Kinzler KW, Hruban RH, Papadopoulos N, Wood LD. Whole exome sequencing of pancreatic neoplasms with acinar differentiation. J Pathol. 232:428-35, 2014.

Outcome After Surgery
Surgical resection remains the best hope for curing patients with pancreatic cancer. In the journal HPB, Dr. He and colleagues report their results with over 2,500 surgical resections (Whipple resections). Whipple resections are typically done for one of four tumor types that can arise near the head of the pancreas- pancreas cancer, duodenqal cancer, bile duct cancer, or "ampullary" cancer. He and colleagues report operative mortality rates of only 1% (it seems high, but in the 1970s the operative mortality rate at some centers was 25%). Pancreatic cancer was associated with the worst survival (average 19 months) compared with cancers that arose in the ampulla (survival: 47 months), bile duct (survival: 23 months) and duodenum (survival: 54 months). What does it mean for a patient with a mass in the area of the pancreas? This paper highlights that surgery can be safe at specialized centers such as Johns Hopkins, and it shows that it is important to have resected tumors correctly classified.

He J, Ahuja N, Makary MA, Cameron JL, Eckhauser FE, Choti MA, Hruban RH, Pawlik TM, Wolfgang CL. 2564 resected periampullary adenocarcinomas at a single institution: trends over three decades. HPB. 16:83-90, 2014.