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Most studies have failed to identify any prognostic value of the current T-stage protocol for pancreatic ductal adenocarcinoma (PDAC) by the American Joint Committee on Cancer and the Union for International Cancer Control unless some grouping was performed.To document the parameters included in this T-stage protocol, 223 consecutive pancreatoduodenectomy specimens with PDAC were processed by a uniform grossing protocol.Peripancreatic soft tissue (PST) involvement, the main pT3 parameter, was found to be inapplicable and irreproducible due to lack of a true capsule in the pancreas and variability in the amount and distribution of adipose tissue. Furthermore, 91 % of the cases showed carcinoma in the adipose tissue, presumably representing the PST, and thus were classified as pT3. An additional 4.5 % were qualified as pT3 due to extension into adjacent sites. The T-stage defined as such was not found to have any correlation with survival (p = 0.4). A revised T-stage protocol was devised that defined pT1 as 2 cm or smaller, pT2 as2-4 cm, and pT3 as larger than 4 cm. This revised protocol was tested in 757 consecutive PDACs. The median and 3-year survival rates of this size-based protocol were 26, 18, 13 months, and 40 %, 26 %, 20 %, respectively (p 0.0001). The association between higher T-stage and shorter survival persisted in N0 cases and in multivariate modeling. Analysis of the Surveillance, Epidemiology, and End Results database also confirmed the survival differences (p 0.0001).This study showed that resected PDACs are already spread to various surfaces of the pancreas, leaving only about 4 % of PDACs to truly qualify as pT1/T2, and that the current T-stage protocol does not have any prognostic correlation. In contrast, as shown previously in many studies, size is an important prognosticator, and a size-based T-stage protocol is more applicable and has prognostic value in PDAC.

Intraductal tubulopapillary neoplasm is a well-established entity in the pancreas. A similar, if not identical, tumor occurs also in the biliary tract. We conducted a multicenter study of 20 such lesions, focusing on their clinicopathologic characteristics and molecular profile. Biliary intraductal tubulopapillary neoplasms were seen in patients in their 60s (mean 62 years). The tumors were intrahepatic 70%, extrahepatic 10%, and perihilar 20%; mean tumor size was 6.9 cm. Histologically, all intraductal tubulopapillary neoplasms showed, in addition to their typical tubular pattern, solid areas (70%) or abortive papillae (50%). Necrosis was common (85%), predominantly focal (40%), and with 'comedocarcinoma-like pattern' in 40%. Immunohistochemically, these neoplasms were characterized by the expression of MUC1 (80%) and MUC6 (30%) and by the absence of MUC2 and MUC5AC. Associated invasive carcinomas were present in 16 (80%), mainly conventional tubular adenocarcinoma (50%). The molecular alterations observed included CDKN2A/p16 (intraductal components 44%, invasive 33%) and TP53 (intraductal components 17%, invasive 9%). Mutations in KRAS (intraductal 6%, invasive 0%), PIK3CA (intraductal 6%, invasive 0%), and loss of SMAD4/DPC4 (intraductal 7%, invasive 0%) were rare. No alterations/mutations were identified in IDH1/2, BRAF, GNAS, EGFR, HER2, and β-catenin. Follow-up information was available for 17 patients (85%) with mean follow-up 44 months. Overall combined survival rates showed favorable prognosis: 1 year 100%, 3 years 90%, and 5 years 90%. In conclusion, despite the relatively high incidence of invasive carcinoma (80%), available follow-up suggests that biliary intraductal tubulopapillary neoplasms have an indolent behavior. Molecular analyses highlight the low prevalence of alterations of common oncogenic signaling pathways in intraductal tubulopapillary neoplasm. Further studies using whole-exome sequencing are required to discover yet unknown molecular changes and to understand the carcinogenesis of intraductal tubulopapillary neoplasms.

BackgroundCurrent nodal staging (N-staging) of ampullary carcinoma in the TNM staging system distinguishes between node-negative (N0) and node-positive (N1) disease but does not consider the metastatic lymph node (LN) number.MethodsOverall, 313 patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma were categorized as N0, N1 (1-2 metastatic LNs), or N2 (≥3 metastatic LNs), as proposed by Kang et al. Clinicopathological features and overall survival (OS) of the three groups were compared.ResultsThe median number of LNs examined was 11, and LN metastasis was present in 142 cases (45 %). When LN-positive cases were re-classified according to the proposed staging system, 82 were N1 (26 %) and 60 were N2 (19 %). There was a significant correlation between proposed N-stage and lymphovascular invasion, perineural invasion, increased tumor size (each p < 0.001), and surgical margin positivity (p = 0.001). The median OS in LN-negative cases was significantly longer than that in LN-positive cases (107.5 vs. 32 months; p < 0.001). Patients with N1 and N2 disease had median survivals of 40 and 24.5 months, respectively (p < 0.0001). In addition, 1-, 3-, and 5-year survivals were 88, 76, 62 %, respectively, for N0; 90, 55, 31.5 %, respectively, for N1; and 68, 34, 30 %, respectively for N2 (p < 0.001). Even with multivariate modeling, the association between higher proposed N stage and shorter survival persisted (hazard ratio 1.6 for N1 and 1.9 for N2; p = 0.018).ConclusionsClassification of nodal status in ampullary carcinomas based on the number of metastatic LNs has a significant prognostic value. A revised N-staging classification system should be incorporated into the TNM staging of ampullary cancers.

Background: The current tumor-node-metastasis staging system for the pancreas does not incorporate the number of lymph nodes (LNs) with metastasis. Methods: Among 1649 pancreaticoduodenectomies, 227 stringently defined pancreatic ductal adenocarcinomas (PDACs) that had undergone a specific approach of LN harvesting were analyzed for the prognostic value of LN substaging protocols used for other gastrointestinal (GI) organs. Results: The median number of LNs harvested was 18, and the median number of LNs with metastasis was 3. Lymph node metastasis was detected in 175 cases (77 %). The number of LNs involved correlated significantly with clinical outcome. When cases were substaged with the protocol already in use for the upper GI organs (N0: no metastasis, N1: metastasis to 1–2 LNs; N2: metastasis to ?3 LNs), the median overall survival times were 35, 21, and 18 months, and the respective 3-year survival rates were 46, 34, and 20 % (p = 0.004). Analysis of the Surveillance, Epidemiology and End Results (SEER) database also confirmed the survival differences between these substages (median overall survival times of 23, 15, and 14 months and respective 3-year survival rates of 37, 22, and 18 %; p

To the Editor The article by Renshaw and Gould1 brings up a question that not only is challenging for our field but also is an issue with far-reaching implications on how sampling of specimens will be performed in the cost containment era with upcoming health care changes in the United States and the world. The authors advocate that, in the pathologic sampling of gallbladder (GB) specimens, taking additional sections to rule out a neoplastic process may not be justifiable. We believe that the authors have a valid point, but this approach reflects only one side of this challenging equation. Let us take this approach to the extreme: annually, approximately 1 million cholecystectomies are performed in the United States, with an estimated 9,000 gallbladder cancer (GBC) diagnoses.2 Therefore, even if we stopped examining GBs pathologically altogether, our “miss” rate of a GBC would be only 0.04%, which some may consider negligible and may even regard as a reasonable health care policy considering the upcoming finances. We suspect, however, that those patients with GBC may have another stance on this issue and may question the justification for the hundreds of billions of dollars that continue to be spent on identifying clinically silent prostate cancer with minimal or no impact on survival from the global health care perspective.3,4 Accountable care issues and health care policies aside, in a discussion about sampling of GBs, one thing that needs to be kept in the forefront is the fact that GBC is highly insidious, notorious for being “inapparent” both clinically and at the macroscopic level. In fact, even in experts’ hands that perform careful macroscopic and complete microscopic evaluation of the GBs, more than one-third of the advanced GBCs (pT2 and above) are missed during gross examination,5–7 and …

WOS: 000353774200008 PubMed ID: 25412850 Ki67 index is now an essential part of classification of pancreatic neuroendocrine tumors. However, its adaptation into daily practice has been fraught with challenges related to counting methodology. In this study, three reviewers used four counting methodologies to calculate Ki67 index in 68 well-differentiated pancreatic neuroendocrine tumors: (1) 'eye-ball' estimation, which has been advocated as reliable and is widely used; (2) automated counting by image analyzer; (3) manual eye-counting (eye under a microscope without a grid); and (4) manual count of camera-captured/printed image. Pearson's correlation (R) was used to measure pair-wise correlation among three reviewers using all four methodologies. Average level of agreement was calculated using mean of R values. The results showed that: (1) 'eye-balling' was least expensive and fastest (average time

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor outcomes with current therapies. Gemcitabine is the primary adjuvant drug used clinically, but its effectiveness is limited. In this study, our objective was to use a rationale-driven approach to identify novel biomarkers for outcome in patients with early-stage resected PDAC treated with adjuvant gemcitabine. Using a synthetic lethal screen in human PDAC cells, we identified 93 genes, including 55 genes linked to DNA damage responses (DDR), that demonstrated gemcitabine sensitization when silenced, including CHD7, which functions in chromatin remodeling. CHD7 depletion sensitized PDAC cells to gemcitabine and delayed their growth in tumor xenografts. Moreover, CHD7 silencing impaired ATR-dependent phosphorylation of CHK1 and increased DNA damage induced by gemcitabine. CHD7 was dysregulated, ranking above the 90th percentile in differential expression in a panel of PDAC clinical specimens, highlighting its potential as a biomarker. Immunohistochemical analysis of specimens from 59 patients with resected PDAC receiving adjuvant gemcitabine revealed that low CHD7 expression was associated with increased recurrence-free survival (RFS) and overall survival (OS), in univariate and multivariate analyses. Notably, CHD7 expression was not associated with RFS or OS for patients not receiving gemcitabine. Thus, low CHD7 expression was correlated selectively with gemcitabine sensitivity in this patient population. These results supported our rationale-driven strategy to exploit dysregulated DDR pathways in PDAC to identify genetic determinants of gemcitabine sensitivity, identifying CHD7 as a novel biomarker candidate to evaluate further for individualizing PDAC treatment. Cancer Res; 74(10); 2677–87. ©2014 AACR.

In the pancreas, poorly differentiated neuroendocrine carcinomas include small cell carcinoma and large cell neuroendocrine carcinoma and are rare; data regarding their pathologic and clinical features are very limited.A total of 107 pancreatic resections originally diagnosed as poorly differentiated neuroendocrine carcinomas were reassessed using the classification and grading (mitotic rate/Ki67 index) criteria put forth by the World Health Organization in 2010 for the gastroenteropancreatic system. Immunohistochemical labeling for neuroendocrine and acinar differentiation markers was performed. Sixty-three cases were reclassified, mostly as well-differentiated neuroendocrine tumor (NET) or acinar cell carcinoma, and eliminated. The clinicopathologic features and survival of the remaining 44 poorly differentiated neuroendocrine carcinomas were further assessed.The mean patient age was 59 years (range, 21 to 82 y), and the male/female ratio was 1.4. Twenty-seven tumors were located in the head of the pancreas, 3 in the body, and 11 in the tail. The median tumor size was 4 cm (range, 2 to 18 cm). Twenty-seven tumors were large cell neuroendocrine carcinomas, and 17 were small cell carcinomas (mean mitotic rate, 37/10 and 51/10 HPF; mean Ki67 index, 66% and 75%, respectively). Eight tumors had combined components, mostly adenocarcinomas. In addition, 2 tumors had components of well-differentiated NET. Eighty-eight percent of the patients had nodal or distant metastatic disease at presentation, and an additional 7% developed metastases subsequently. Follow-up information was available for 43 patients; 33 died of disease, with a median survival of 11 months (range, 0 to 104 mo); 8 were alive with disease, with a median follow-up of 19.5 months (range, 0 to 71 mo). The 2- and 5-year survival rates were 22.5% and 16.1%, respectively.Poorly differentiated neuroendocrine carcinoma of the pancreas is a highly aggressive neoplasm, with frequent metastases and poor survival. Most patients die within less than a year. Most (61%) are large cell neuroendocrine carcinomas. Well-differentiated NET and acinar cell carcinoma are often misdiagnosed as poorly differentiated neuroendocrine carcinoma, emphasizing that diagnostic criteria need to be clearly followed to ensure accurate diagnosis.

Purpose: To determine how often loss of ataxia-telangiectasia–mutated (ATM) protein expression occurs in primary pancreatic ductal adenocarcinomas and to determine its prognostic significance. Experimental Design: The expression of ATM and TP53 was determined by immunohistochemistry in 397 surgically resected pancreatic ductal adenocarcinomas (Hopkins; Johns Hopkins Medical Institutions, Baltimore, MD), a second set of 159 cases (Emory; Emory University Hospital, Atlanta, GA), and 21 cancers after neoadjuvant chemoradiotherapy. Expression was correlated with the clinicopathologic parameters, including survival. Results: Tumoral ATM loss was observed in one cancer known to have biallelic inactivation of ATM and 50 of the first 396 (12.8%) cases, significantly more often in patients with a family history of pancreatic cancer (12/49; 24.5%) than in those without (38/347; 11.0%; P = 0.019). In the Hopkins series, ATM loss was associated with a significantly decreased overall survival in patients whose cancers had normal TP53 expression (P = 0.019) and was a significant independent predictor of decreased overall survival (P = 0.014). Seventeen (10.7%) of 159 Emory cases had tumoral ATM loss and tumoral ATM loss/normal TP53 was associated with poorer overall survival (P = 0.1). Multivariate analysis of the combined Hopkins/Emory cases found that tumoral ATM loss/normal TP53 was an independent predictor of decreased overall survival [HR = 2.61; confidence interval (CI), 1.27–5.37; P = 0.009]. Of 21 cancers examined after neoadjuvant chemoradiotherapy, one had tumoral loss of ATM; it had no histologic evidence of tumor response. Conclusions: Tumoral loss of ATM protein was detected more often in patients with a family history of pancreatic cancer than in those without. Patients whose pancreatic cancers had loss of ATM but normal TP53 had worse overall survival after pancreatic resection. Clin Cancer Res; 20(7); 1865–72. ©2014 AACR.

To summarize the most clinically and biologically relevant advances in molecular/genetic characteristics of various pancreatic neoplasms, with morphologic correlation.Whole-exome sequencing of numerous benign and malignant pancreatic tumors, along with the plethora of highly sensitive molecular studies now available for analyzing these tumors, provide mounting evidence to support the long-held belief that cancer is essentially a genetic disease. These genetic discoveries have not only helped to confirm the age-old, morphology-based classifications of pancreatic neoplasia but have shed new light on their mechanisms. Many of these molecular discoveries are currently being used in preoperative diagnosis.Mutations in KRAS, P16/CDKN2A, TP53, and SMAD4/DPC4 are commonly seen in ductal neoplasia but not in nonductal tumors; ductal adenocarcinomas with SMAD4/DPC4 loss are associated with widespread metastasis and poor prognosis. GNAS and RNF43 mutations have been discovered in most intraductal pancreatic mucinous neoplasms, providing critical molecular fingerprints for their diagnosis. Mutation in DAXX/ATRX is only seen in pancreatic neuroendocrine tumors, making it a useful potential marker in distinguishing these tumors from mimics.When combined with morphologic observations, molecular studies will increase our understanding of the pathogenesis and morphomolecular signatures associated with specific neoplasms and provide new horizons for precision medicine and targeted therapies.

The general impression about gallbladder carcinomas is that they are uniformly fatal; however, for the early forms, an entirely different picture indicating a very good prognosis is evolving from the high-incidence regions. We subjected 190 early gallbladder carcinomas (EGBC), defined as carcinomas confined to and above the tunica muscularis (AJCC's Tis, T1a, and T1b), and identified in cholecystectomy specimens sampled entirely according to an established protocol, to detailed analysis. Average patient age was 57.9 years (29–95). In more than half of the cases (114/190; 60 %), the tumor was inapparent by gross examination. In 81 cases (42.6 %), carcinomatous epithelium abutted the muscularis, whereas 57.4 % (n = 109) were qualified as intramucosal with no overt contiguity with muscularis. Intraepithelial extension into Rokitansky–Aschoff sinuses (RAS) was found in 34 cases (17.8 %). At the time of data analysis, 171 patients (99 %) were alive. Overall actuarial survival was 92.3 % at 5 years and 90.4 % at 10 years. The 5- and 10-year actuarial survival rates of the intramucosal group (93.2 and 92.1 %, respectively) were not statistically different from that of the muscle-abutting group (89.7 % and 88.2 % ; p = 0.334). Patients with RAS involvement had a significantly shorter survival than those without (p

Mixed lineage kinase domain-like protein (MLKL) is a necrosome component mediating programmed necrosis that may be an important determinant of cancer cell death. The goal of the current study was to evaluate the prognostic value of MLKL expression in patients with pancreatic adenocarcinoma (PAC).Tissue from 80 patients was collected from a prospectively maintained database of patients with PAC who underwent pancreaticoduodenectomy between January 2000 and October 2008. Immunohistochemistry analysis was performed and scored using an established scoring system. Kaplan-Meier survival curves were generated for recurrence-free survival (RFS) and overall survival (OS) for all patients and for patients receiving adjuvant chemotherapy. MLKL scores were correlated with RFS and OS using univariate and multivariate Cox regression analyses incorporating clinically relevant covariates.The median age of the patients was 63 years and 53% were men. Low MLKL expression was associated with decreased OS (6 months vs 17 months; P = .006). In the subset of 59 patients who received adjuvant chemotherapy, low MLKL expression was associated with decreased RFS (5 months vs 15 months; P = .006) and decreased OS (6 months vs 19 months; P .0001). On multivariate analysis, low MLKL expression was associated with poor OS in all patients (hazards ratio, 4.6 [95% confidence interval, 1.6-13.8]; P = .006) and in patients receiving adjuvant chemotherapy (hazards ratio, 8.1 [95% confidence interval, 2.2-29.2]; P = .002).Low expression of MLKL is associated with decreased OS in patients with resected PAC and decreased RFS and OS in the subset of patients with resected PAC who receive adjuvant chemotherapy. The use of this biomarker in patients with PAC may provide important prognostic information.

Objective: As there is continuing disagreement among the observers on the differential diagnosis between the epithelial changes/lesions and neoplasms of the gallbladder, this multicentre study was planned in order to assess the rate of the epithelial gallbladder lesions in Turkey and to propose microscopy and macroscopy protocols. Material and Method: With the participation of 22 institutions around Turkey that were included in the Hepato-Pancreato-Biliary Study Group, 89,324 cholecystectomy specimens sampled from 2003 to 2016 were retrospectively evaluated. The numbers of adenocarcinomas, dysplasias, intracholecystic neoplasms/adenomas, intestinal metaplasias and reactive atypia were identified with the review of pathology reports and the regional and countrywide incidence rates were presented in percentages. Results: Epithelial changes/lesions were reported in 6% of cholecystectomy materials. Of these epithelial lesions, 7% were reported as adenocarcinoma, 0.9% as high-grade dysplasia, 4% as low-grade dysplasia, 7.8% as reactive/regenerative atypia, 1.7% as neoplastic polyp, and 15.6% as intestinal metaplasia. The remaining lesions (63%) primarily included non-neoplastic polypoids/hyperplastic lesions and antral/pyloric metaplasia. There were also differences between pathology laboratories. Conclusion: The major causes of the difference in reporting these epithelial changes/lesions and neoplasms include the differences related to the institute’s oncological surgery frequency, sampling protocols, geographical dissimilarities, and differences in the diagnoses/interpretations of the pathologists. It seems that the diagnosis may change if new sections are taken from the specimen when any epithelial abnormality is seen during microscopic examination of the cholecystectomy materials. © 2018, Federation of Turkish Pathology Societies. All rights reserved.

The information in the literature on squamous cell and adenosquamous carcinomas of the gallbladder is highly limited. In this study, 606 resected invasive gallbladder carcinoma cases were analyzed. Squamous differentiation was identified in 41 cases (7%). Those without any identifiable glandular-type invasive component were classified as pure squamous cell carcinomas (8 cases) and those with the squamous component constituting 25-99% of the tumors were classified as adenosquamous carcinomas (26 cases) and included into the analysis. The remaining 7 that had

Cancer survivors have a higher risk of new primary cancer, in the same or in another organ, than the general population. We report a 78-year-old women who has metachronous quadruple adenocarcinoma, includes bilateral breast cancer, ovarian cancer and retroperitoneal neuroendocrine carcinoma. The development of second cancer in cancer survivors can be expected but third or higher order malignancies are rare.

Introduction: The majority of pancreatic ductal adenocarcinoma (PDAC) patients present with metastases and nearly all will succumb to disease within 6-12 months of clinical presentation (Hidalgo, 2010). Recently, p120catenin (p120) was identified as a “cancer candidate gene” in sleeping beauty-induced PDAC and p120 loss is associated with poor patient survival (Mann et al, 2012). P120 is critical in stabilizing E-cadherin (E-cad) at the adherens junctions. In this study, we wished to unravel new roles for p120 in the context of PDAC initiation and progression (epithelial-mesenchymal transition or EMT), as well as metastasis. Results: We have introduced a floxed p120 allele into the Pdx1cre;LSL-KrasG12D;R26YFP (KCY) PDAC mouse model. Mice with homozygous p120 deletion in the context of a LSL-KrasG12D allele (KCYp120fl/fl) are not viable. However, mice with heterozygous p120 loss (KCYp120fl/wt) are born according to Mendelian ratios. At 20 weeks of age, KCYp120fl/wt mice show a remarkable acceleration of the Kras-driven phenotype. KCYp120fl/wt mice (n=21) harbor the entire spectrum of precursor lesions, including PanINs (1-3), mucinous cystic neoplasms (MCN) and intraductal papillary mucinous neoplasms (IPMN) and metastatic PDAC. The phenotype in control KCYp120wt/wt mice (n=12) was restricted to early PanINs. We next asked whether the second allele of p120 is lost during metastatic dissemination. We demonstrated that the remaining p120 allele is expressed in liver metastases, indicating that p120 loss-of-heterozygosity did not occur. Of note, in liver metastases, p120 co-localizes with E-cad, thereby indicating that a single p120 allele is sufficient to stabilize E-cad. This raised the question of whether one p120 allele is required to establish epithelial integrity at the metastatic site. In order to address this mechanistically, and since KCYp120fl/fl are not viable, we performed three-dimensional (3D) culture experiments with pancreatic cells isolated from non-recombined LSL-KrasG12D/+;p120wt/wt;R26YFP (KYp120wt/wt), KYp120fl/wt and KYp120fl/fl mice. Cells were Cre-recombined in vitro. In 3D culture, KYp120wt/wt cells form round multicellular cysts. Monoallelic p120 loss only disrupts the symmetry of cysts while biallelic loss completely prevents cells from forming organized, cyctic structures. We next injected these cell lines orthotopically into the pancreata of immunodeficient mice. KYp120wt/wt cells form PanIN-like structures. Interestingly, KYp120fl/wt establish large cysts reminiscent of IPMN/MCN lesions. In the cysts, p120 is localized at the plasma membrane with E-cad. However, the invasive fronts of tumors show significantly less p120 expression. Finally, KYp120fl/fl cells form poorly differentiated tumors invading into the surrounding stroma. Given the fact that p120 stabilizes E-cad and that E-cad is critical in EMT and MET, we injected the KYp120wt/wt, KYp120fl/wt and KYp120fl/fl cell lines directly into the portal veins of these mice. KYp120fl/wt cells colonize the liver and retain the remaining p120 allele and display membranous E-cad localization. By contrast, although KYp120fl/fl cells are able to generate invasive primary pancreatic tumors when being injected orthotopically, these cells fail to colonize the liver. Conclusions: Our findings demonstrate that monoallelic loss of p120 accelerates Kras-driven PDAC formation. However, one allele of p120 is required to establish epithelial integrity and metastases. Taken together, these results for the first time underscore the importance of p120-mediated EMT plasticity in order to complete the metastatic cascade in vivo. Furthermore, therapeutic strategies to prevent EMT alone may not be sufficient in light of our results but rather require novel approaches to target EMT plasticity so as to enhance survival in metastatic PDAC. This abstract is also presented as Poster A63. Citation Format: Maximilian Reichert, Basil S. Bakir, Christopher M. Hahn, Gregory P. Botta, Andrew D. Rhim, Robert H. Vonderheide, Albert B. Reynolds, Yingtao Bi, Ramana Davuluri, Burcu Saka, N. Volkan Adsay, Anil K. Rustgi. p120 catenin mediated epithelial-to-mesenchymal plasticity determines the metastatic potential of pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr PR05.

Background/ Objectives Chromodomain helicase DNA Binding protein 7 (CHD7) modulates chromatin remodeling during genome maintenance. Its role in pancreatic cancer (PAC) is unestablished, but preliminary data for Gemcitabine (GEM) sensitivity in pancreatic cell lines and pilot clinical data is promising. This study will evaluate CHD7 as a prognostic and predictive factor in resected PAC using 1) immunohistochemistry (IHC) of patient samples from RTOG 97-04, 2) prospective evaluation of CHD7 over-expression and treatment response in patients receiving FOLFIRINOX and GEM-based chemoradiotherapy (CRT) for locally advanced PAC at our institution and 3) a Phase II molecular-driven randomized trial of personalized therapy based on CHD7 expression. Methodology A loss of function siRNA screen identified genes, including CHD7, that conferred GEM sensitivity when silenced using GEM-treated Mia PaCa-2 cells. CHD7 expression was assessed by IHC scoring in 80 patients who underwent curative intent resection of PAC between 1/2000 and 10/2008. Kaplan-meier survival analysis was performed for recurrence-free survival (RFS) and overall survival (OS). Univariate (UV) and Multivariate (MV) Cox regression analyses using clinically relevant covariates were used to correlate CHD7 expression levels with RFS and OS in patients receiving GEM therapy (n=42). This analysis will be validated in 200 patient samples from RTOG 97-04. CHD7 expression will be correlated with RFS and OS in GEM and 5-Fluorouracil (5-FU) treatment arms. CHD7 expression will also be measured in pre-chemotherapy core biopsies from locally advanced PAC patients treated at our institution. Patients will receive either two cycles of FOLFIRINOX (FOL) followed by GEM-based CRT at a dose of 1000mg/m2 once weekly or two cycles of FOL followed by Capecitabine (CAP)-based CRT. CHD7 expression will again be correlated with survival. These results will be followed by an ECOG- sponsored multi-institutional Phase II randomized trial of FOL and GEM-based CRT or FOL and CAP-based CRT based on CHD7 gene expression. Preliminary Data/ Anticipated Results In patients receiving GEM (n=42), high CHD7 was associated with poor RFS (7 months vs 15 months; p=.025) and poor OS (10 months vs 18 months; p=.015). On MV analysis, high CHD7 expression remained a predictor of poor RFS (HR 8.2 [95% CI 2.4-28]; p=.001) and poor OS (HR 11.6 [95% CI 3.4-40); p We expect our RTOG 97-04 validation study to demonstrate stronger correlation of low CHD7 expression with improved RFS and OS in GEM-treated patients. Similarly, we expect our institutional trial to demonstrate improved RFS and OS with low CHD7 in the GEM-treated arm. Citation Format: Lauren E. Colbert, William A. Hall, Claire W. Hardy, Sarah B. Fisher, David S. Yu, Shishir K. Maithel, Bassel El-Rayes, Burcu Saka, N Volkan Adsay, Aleksandra Petrova, Brooke Pantazides, Jeanne Kowalski, Khanjan Gandhi, David Kooby, Charles Staley, Jerome C. Landry. A pilot clinical trial of chromodomain-helicase-DNA-binding protein 7 (CHD7) expression as a prognostic and predictive biomarker in patients with early-stage pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-168. doi:10.1158/1538-7445.AM2013-LB-168