Faculty Bibliography

OBJECTIVES:Previous retrospective studies demonstrated that circulating tumor cells (CTCs) subtypes correlate with overall survival in patients with pancreatic ductal adenocarcinoma (PDAC). Herein, we report results of a prospective observational study on CTCs dynamics to assess their clinical significance. METHODS:The CLUSTER study is a prospective longitudinal study on PDAC CTCs dynamics (NCT02974764). Multiple peripheral blood samples were collected from 200 consecutively enrolled patients with presumed PDAC diagnosis. CTCs were isolated and characterized by immunofluorescence. RESULTS:Two major CTCs subtypes were identified in PDAC patients: epithelial CTCs (eCTCs) and epithelial/mesenchymal CTCs (mCTCs). Patients who received neoadjuvant chemotherapy had significantly lower total CTCs (tCTCs, P = 0.007), eCTCs (P = 0.007), and mCTCs (P = 0.034), compared with untreated patients eligible for upfront resection. Surgical resection of the primary tumor resulted in significant reduction, but not disappearance, of CTCs burden across all cell subtypes (P < 0.001). In multivariable logistic regression analysis, preoperative numbers of all CTCs subpopulations were the only predictors of early recurrence within 12 months from surgery in both chemo-naive and post-neoadjuvant patients (odds ratio 5.9 to 11.0). Alterations in CTCs were also observed longitudinally, before disease recurrence. A risk assessment score based on the difference of tCTCs increase accurately identified disease recurrence within the next 2 months, with an accuracy of 75% and 84% for chemo-naive and post-neoadjuvant patients, respectively. CONCLUSION:We report novel findings regarding CTCs from a large prospective cohort of PDAC patients. CTCs dynamics reflect progression of disease and response to treatment, providing important information on clinical outcomes, not available by current tumor markers and imaging.

Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.Significance: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. Cancer Discov; 8(9); 1112-29. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047.

BACKGROUND & AIMS:Screening of individuals who have a high risk of pancreatic ductal adenocarcinoma (PDAC), because of genetic factors, frequently leads to identification of pancreatic lesions. We investigated the incidence of PDAC and risk factors for neoplastic progression in individuals at high risk for PDAC enrolled in a long-term screening study. METHODS:We analyzed data from 354 individuals at high risk for PDAC (based on genetic factors of family history), enrolled in Cancer of the Pancreas Screening cohort studies at tertiary care academic centers from 1998 through 2014 (median follow-up time, 5.6 years). All subjects were evaluated at study entry (baseline) by endoscopic ultrasonography and underwent surveillance with endoscopic ultrasonography, magnetic resonance imaging, and/or computed tomography. The primary endpoint was the cumulative incidence of PDAC, pancreatic intraepithelial neoplasia grade 3, or intraductal papillary mucinous neoplasm with high-grade dysplasia (HGD) after baseline. We performed multivariate Cox regression and Kaplan-Meier analyses. RESULTS:During the follow-up period, pancreatic lesions with worrisome features (solid mass, multiple cysts, cyst size > 3 cm, thickened/enhancing walls, mural nodule, dilated main pancreatic duct > 5 mm, or abrupt change in duct caliber) or rapid cyst growth (>4 mm/year) were detected in 68 patients (19%). Overall, 24 of 354 patients (7%) had neoplastic progression (14 PDACs and 10 HGDs) over a 16-year period; the rate of progression was 1.6%/year, and 93% had detectable lesions with worrisome features before diagnosis of the PDAC or HGD. Nine of the 10 PDACs detected during routine surveillance were resectable; a significantly higher proportion of patients with resectable PDACs survived 3 years (85%) compared with the 4 subjects with symptomatic, unresectable PDACs (25%), which developed outside surveillance (log rank P < .0001). Neoplastic progression occurred at a median age of 67 years; the median time from baseline screening until PDAC diagnosis was 4.8 years (interquartile range, 1.6-6.9 years). CONCLUSIONS:In a long-term (16-year) follow-up study of individuals at high-risk for PDAC, we found most PDACs detected during surveillance (9/10) to be resectable, and 85% of these patients survived for 3 years. We identified radiologic features associated with neoplastic progression.

BACKGROUND:Despite strong evidence demonstrating the clinical and economic benefits of minimally invasive surgery (MIS), utilization of MIS in the Medicare population is highly variable and tends to be lower than in the general population. We sought to compare the post-operative and economic outcomes of MIS versus open surgery for seven common surgical procedures in the Medicare population. METHODS:Using the 2014 Medicare Provider Analysis and Review Inpatient Limited Data Set, patients undergoing bariatric, cholecystectomy, colectomy, hysterectomy, inguinal hernia, thoracic, and ventral hernia procedures were identified using DRG and ICD-9 codes. Adjusting for patient demographics and comorbidities, the odds of complication and all-cause 30-day re-admission were compared among patients undergoing MIS versus open surgery stratified by operation type. A generalized linear model was used to calculate the estimated difference in length of stay (LOS), Medicare claim cost, and Medicare reimbursement. RESULTS:Among 233,984 patients, 102,729 patients underwent an open procedure versus 131,255 who underwent an MIS procedure. The incidence of complication after MIS was lower for 5 out of the 7 procedures examined (OR 0.36-0.69). Re-admission was lower for MIS for 6 out of 7 procedures (OR 0.43-0.87). MIS was associated with shorter LOS for 6 procedures (point estimate range 0.35-2.47 days shorter). Medicare claim costs for MIS were lower for 4 (range $3010.23-$4832.74 less per procedure) and Medicare reimbursements were lower for 3 (range $841.10-$939.69 less per procedure). CONCLUSIONS:MIS benefited Medicare patients undergoing a range of surgical procedures. MIS was associated with fewer complications and re-admissions as well as shorter LOS and lower Medicare costs and reimbursements versus open surgery. MIS may represent a better quality and cost proposition in the Medicare population.

BACKGROUND:The aim of the present study was to compare the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging system for pancreas head cancer and to validate the 8th edition using three multinational tertiary center data. METHODS:Data of 2,864 patients with pancreas head cancer were collected from Korea (571), Japan (824), and the USA (1,469). Survival analysis was performed to compare the 7th and 8th editions. Validation was performed by log-rank tests and test for trend repeated 1,000 times with random sets. RESULTS:In the 7th edition, 4.1%, 3.1%, 18.6%, 67.5%, 3.6%, and 3.1% were stage IA, IB, IIA, IIB, III, and IV. In the 8th edition, 8.8%, 13.9%, 3.1%, 38.2%, 32.9%, and 3.1% were stage IA, IB, IIA, IIB, III, and IV, respectively. The change in T category downstaged 459 patients from IIA to the new IA and IB. The new N2 category upstaged 856 patients from the former IIB to III. The 7th edition reversely stratified IA and IB. The 8th edition corrected this mis-stratification of the 7th edition, but lacked discriminatory power between IB and IIA (P = 0.271). Validation using the log-rank showed that the 8th edition provided better discrimination in 6.387 test sets among 10 tests. The test for trend validated the 8th edition to stratify stages in correct order more often (7.815/10). CONCLUSION/CONCLUSIONS:The 8th edition provides more even distribution with more powerful discrimination compared to the 7th edition.

OBJECTIVE:Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions that can give rise to invasive pancreatic carcinoma. Although approximately 8% of patients with resected pancreatic ductal adenocarcinoma have a co-occurring IPMN, the precise genetic relationship between these two lesions has not been systematically investigated. DESIGN:We analysed all available patients with co-occurring IPMN and invasive intrapancreatic carcinoma over a 10-year period at a single institution. For each patient, we separately isolated DNA from the carcinoma, adjacent IPMN and distant IPMN and performed targeted next generation sequencing of a panel of pancreatic cancer driver genes. We then used the identified mutations to infer the relatedness of the IPMN and co-occurring invasive carcinoma in each patient. RESULTS:We analysed co-occurring IPMN and invasive carcinoma from 61 patients with IPMN/ductal adenocarcinoma as well as 13 patients with IPMN/colloid carcinoma and 7 patients with IPMN/carcinoma of the ampullary region. Of the patients with co-occurring IPMN and ductal adenocarcinoma, 51% were likely related. Surprisingly, 18% of co-occurring IPMN and ductal adenocarcinomas were likely independent, suggesting that the carcinoma arose from an independent precursor. By contrast, all colloid carcinomas were likely related to their associated IPMNs. In addition, these analyses showed striking genetic heterogeneity in IPMNs, even with respect to well-characterised driver genes. CONCLUSION:This study demonstrates a higher prevalence of likely independent co-occurring IPMN and ductal adenocarcinoma than previously appreciated. These findings have important implications for molecular risk stratification of patients with IPMN.

Biomarkers refer to a plethora of biological characteristics that can be quantified to facilitate cancer diagnosis, forecast the prognosis of disease, and predict a response to treatment. The identification of objective biomarkers is among the most crucial steps in the realization of individualized cancer care. Several tumor biomarkers for gastrointestinal malignancies have been applied in the clinical setting to help differentiate between cancer and other conditions, facilitate patient selection for targeted therapies, and to monitor treatment response and recurrence. With the coming of the immunotherapy age, the need for a new development of biomarkers that are indicative of the immune response to tumors are unprecedentedly urgent. Biomarkers from the tumor microenvironment, tumor genome, and signatures from liquid biopsies have been explored, but the majority have shown a limited prognostic or predictive value as single biomarkers. Nevertheless, use of multiplex biomarkers has the potential to provide a significantly increased diagnostic accuracy compared to traditional single biomarker. A comprehensive analysis of immune-biomarkers is needed to reveal the dynamic and multifaceted anti-tumor immunity and thus imply for the rational design of assays and combinational strategies.

BACKGROUND:After radical resection of pancreatic ductal adenocarcinoma (PDAC), approximately 80% of patients will develop disease recurrence. It remains unclear to what extent the location of recurrence carries prognostic significance. Additionally, stratifying the pattern of recurrence may lead to a deeper understanding of the heterogeneous biological behavior of PDAC. OBJECTIVE:The aim of this study was to characterize the relationship of recurrence patterns with survival in patients with resected PDAC. METHODS:This single-center cohort study included patients undergoing pancreatectomy at the Johns Hopkins Hospital between 2000 and 2013. Exclusion criteria were neoadjuvant therapy and incomplete follow-up. Sites of first recurrence were stratified into five groups and survival outcomes were estimated using Kaplan-Meier curves. The association of specific recurrence locations with overall survival (OS) was analyzed using Cox proportional-hazards models with and without landmark analysis. RESULTS:Accurate follow-up data were available for 877 patients, 662 (75.5%) of whom had documented recurrence at last follow-up. Patients with multiple-site (n = 227, 4.7 months) or liver-only recurrence (n = 166, 7.2 months) had significantly worse median survival after recurrence when compared with lung- (n = 93) or local-only (n = 158) recurrence (15.4 and 9.7 months, respectively). On multivariable analysis, the unique recurrence patterns had variable predictive values for OS. Landmark analyses, with landmarks set at 12, 18, and 24 months, confirmed these findings. CONCLUSIONS:This study demonstrates that specific patterns of PDAC recurrence result in different survival outcomes. Furthermore, distinct first recurrence locations have unique independent predictive values for OS, which could help with prognostic stratification and decisions regarding treatment after the diagnosis of recurrence.

BACKGROUND:Varying definitions of resection margin clearance are currently employed among patients with colorectal cancer liver metastases (CRLM). Specifically, a microscopically positive margin (R1) has alternatively been equated with an involved margin (margin width = 0 mm) or a margin width < 1 mm. Consequently, patients with a margin width of 0-1 mm (sub-mm) are inconsistently classified in either the R0 or R1 categories, thus obscuring the prognostic implications of sub-mm margins. METHODS:Six hundred thirty-three patients who underwent resection of CRLM were identified. Both R1 definitions were alternatively employed and multivariable analysis was used to determine the predictive power of each definition, as well as the prognostic implications of a sub-mm margin. RESULTS:Five hundred thirty-nine (85.2%) patients had a margin width ≥ 1 mm, 42 had a sub-mm margin width, and 52 had an involved margin (0 mm). A margin width ≥ 1 mm was associated with improved survival vs. a sub-mm margin (65 vs. 36 months; P = 0.03) or an involved margin (65 vs. 33 months; P < 0.001). No significant difference in survival was detected between patients with involved vs. sub-mm margins (P = 0.31). A sub-mm margin and an involved margin were both independent predictors of worse OS (HR 1.66, 1.04-2.67; P = 0.04, and HR 2.14, 1.46-3.16; P < 0.001, respectively) in multivariable analysis. Importantly, after combining the two definitions, patients with either an involved margin or a sub-mm margin were associated with worse OS in multivariable analysis (HR 1.94, 1.41-2.65; P < 0.001). CONCLUSIONS:Patients with involved or sub-mm margins demonstrated a similar inferior OS vs. patients with a margin width > 1 mm. Consequently, a uniform definition of R1 as a margin width < 1 mm should perhaps be employed by future studies.