Faculty Bibliography

Earlier detection is key to reducing cancer deaths. Here, we describe a blood test that can detect eight common cancer types through assessment of the levels of circulating proteins and mutations in cell-free DNA. We applied this test, called CancerSEEK, to 1005 patients with nonmetastatic, clinically detected cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung, or breast. CancerSEEK tests were positive in a median of 70% of the eight cancer types. The sensitivities ranged from 69 to 98% for the detection of five cancer types (ovary, liver, stomach, pancreas, and esophagus) for which there are no screening tests available for average-risk individuals. The specificity of CancerSEEK was greater than 99%: only 7 of 812 healthy controls scored positive. In addition, CancerSEEK localized the cancer to a small number of anatomic sites in a median of 83% of the patients.

Invasive pancreatic ductal adenocarcinoma (PDAC) can infiltrate back into and spread along preexisting pancreatic ducts and ductules in a process known as cancerization of ducts (COD). Histologically COD can mimic high-grade pancreatic intraepithelial neoplasia (HG-PanIN). We reviewed pancreatic resections from 100 patients with PDAC for the presence or absence of ducts with histologic features of COD. Features supporting COD included adjacent histologically similar invasive PDAC and an abrupt transition between markedly atypical intraductal epithelium and normal duct epithelium or circumferential involvement of a duct. As the TP53 and SMAD4 genes are frequently targeted in invasive PDAC but not HG-PanIN, paired PDAC and histologically suspected COD lesions were immunolabeled with antibodies to the p53 and Smad4 proteins. Suspected COD was identified on hematoxylin and eosin sections in 89 (89%) of the cases. Immunolabeling for p53 and Smad4 was performed in 68 (76%) of 89 cases. p53 was interpretable in 55 cases and all 55 (100%) cases showed concordant labeling between COD and invasive PDAC. There was matched aberrant p53 immunolabeling in 37 (67%) cases including overexpression in 30 (55%) cases and lack of expression in 7 (13%) cases. Smad4 immunolabeling was interpretable in 61 cases and 59 (97%) cases showed concordant labeling between COD and invasive PDAC. Matched loss of Smad4 was seen in 28 (46%) cases. The immunolabeling of invasive PDAC and COD for p53 and Smad4 supports the high prevalence of COD observed on hematoxylin and eosin and highlights the utility of p53 and Smad4 immunolabeling in differentiating COD and HG-PanIN.

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: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.

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.

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: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.

Context:McCune-Albright syndrome (MAS) is a rare disorder characterized by fibrous dysplasia of bone, café-au-lait macules, and hyperfunctioning endocrinopathies. It arises from somatic gain-of-function mutations in GNAS, which encodes the cAMP-regulating protein Gαs. Somatic GNAS mutations have been reported in intraductal papillary mucinous neoplasms (IPMNs) and various gastrointestinal (GI) tumors. The clinical spectrum and prevalence of MAS-associated GI disease is not well established. Objective:Define the spectrum and prevalence of MAS-associated GI pathology in a large cohort of patients with MAS. Design:Cross-sectional study. Setting:National Institutes of Health Clinical Center and The Johns Hopkins Hospital. Methods:Fifty-four consecutive subjects with MAS (28 males; age range, 7 to 67 years) were screened with magnetic resonance cholangiopancreatography (MRCP). Results:Thirty of 54 subjects (56%) had radiographic GI abnormalities. Twenty-five (46%) of the screened subjects had IPMNs (mean age of 35.1 years). Fourteen of the 25 had IPMNs alone, and 11 had IPMNs and abnormal hepatobiliary imaging. The 30 patients with MAS-associated GI pathology had a higher prevalence of acute pancreatitis, diabetes mellitus, and skeletal disease burden of fibrous dysplasia than patients without GI disease. Conclusions:A broad spectrum of GI pathology is associated with MAS. IPMNs are common and occur at a younger age than in the general population. Patients with MAS should be considered for screening with a focused GI history and baseline MRCP. Further determination of the natural history and malignant potential of IPMNs in MAS is needed.

BACKGROUND:The incidence of occult metastatic disease (OMD) in pancreatic ductal adenocarcinoma (PDAC) and associated risk factors are largely unknown. METHODS:We identified all patients with PDAC, who had an aborted oncologic operation due to OMD within a 10-year period. The cases were matched to a cohort of resected PDAC patients on a 1:3 ratio, based on age and sex, for comparison of preoperative clinical characteristics and potential risk factors for OMD. RESULTS:In the studied period, 117 patients with OMD were identified in 1423 pancreatectomies performed for PDAC (8%). Liver metastases were the most common finding (79%) followed by peritoneal implants (16%). When compared with non-OMD cases, patients with OMD presented more often with abdominal pain (P < 0.001), and higher preoperative carbohydrate antigen 19-9 (CA 19-9) values ( P = 0.007). Additionally, indeterminate liver lesions on preoperative computed tomography (CT) were identified in 40% of OMD versus 17% of non-OMD patients ( P < 0.001). Multivariable analysis distinguished four independent predictors for OMD: indeterminate lesions on preoperative CT, tumor size > 30 mm, abdominal pain, and preoperative CA 19-9 > 192 U/mL. CONCLUSIONS:Occurrence of OMD in PDAC accounts for 8% of cases. Preoperative CA 19-9 > 192 U/mL, primary tumor size > 30 mm, and identification of indeterminate lesions in preoperative CT may indicate the need for diagnostic laparoscopy.