Preliminary Evaluation of Screening for Pancreatic Cancer in Patients With Inherited Genetic Risk

Description

Endoscopic Ultrasound (EUS) has emerged as a critical component in the imaging, staging, and diagnosis of pancreatic cancer. Not only can EUS delineate a mass utilizing sonography through the wall of the stomach or duodenum, but it also can obtain diagnostic fine needle aspiration of suspicious lesions. Especially in patients with incomplete visualization of a mass on cross-sectional imaging, EUS can provide valuable anatomic information prior to surgical exploration. While several studies have demonstrated that EUS has high sensitivity and specificity in diagnosing pancreatic masses, head-to-head comparisons with established modalities like CT have been often methodologically flawed. In a meta-analysis, it was found that of 4 studies that assessed resectability, 2 showed no difference and 1 favored each modality. As such, estimates of accuracy for assessing preoperative resectability have also ranged in several studies from 63-93%. As such it has been recognized as an accepted modality for the evaluation of potential pancreatic malignany.

While screening in the general population is not feasible given the low incidence of PDAC, screening in high risk cohorts may allow for early detection of resectable, and potentially curable tumors. Clinical outcome of patients with smaller, non-metastasized tumors have a significantly improved 5-year survival. Generally the current recommendation is that patients who are first degree relatives of patients with PDAC from a familial PDAC kindred with at least 2 affected first-degree relatives, patients with Peutz-Jegher's syndrome, and patients with CDKN2A/BRCA1/BRCA2/ATM/PALB2/Lynch mutations with a first or second degree relative with pancreatic cancer would qualify for screening in the context of the CAPS5 trial. However, very recent evidence in a large Canadian study of pancreatic cancer patients demonstrated germline carrier status for BRCA1/2, and ATM in their cohort was associated with first degree relatives with breast and colorectal cancer but not pancreatic cancer, suggesting that we may have to re-evaluate criteria for pancreatic cancer screening in this population. Thus, the risk of pancreatic cancer development in this cohort of patients would not be addressed by the CAPS5 protocol, but would uniquely be addressed in our proposed study. In terms of modality, interval, and age to start/stop, there remains debate but generally annual EUS/MRI has been utilized. Therefore, amongst patients with increased risk of pancreatic cancer, like those with BRCA1/2, ATM, or PALB2 mutations, the successful identification of early neoplastic/preneoplastic lesions of the pancreas would allow for timely intervention and improved survival in this cohort and thus would be of high clinical relevance.

Thus we propose to utilize the unique cohort of increased risk patients followed at the University of Pennsylvania, to identify patients with BRCA1, BRCA2, ATM, or PALB2 mutations, regardless of family history of pancreatic cancer, and enroll them on an annual prospective pancreatic screening program. The hypothesis is that through early screening interventions, morbidity and mortality from this under-recognized malignancy in this high-risk patient population will be reduced.

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