Jane Preuss Hasselby

First-line treatment of patients with disseminated poorly differentiated neuroendocrine carcinomas with carboplatin, etoposide, and vincristine: A single institution experience

Abstract Poorly differentiated neuroendocrine carcinomas (PDECs) represent highly malignant tumors with an immense tendency to metastasize and with a poor prognosis. The treatment consists of palliative chemotherapy and corresponds to the treatment of extensive stage small cell lung cancer. Material and methods. We present the patient characteristics and treatment results of 31 consecutive, chemonaïve patients with PDECs treated with carboplatin, etoposide, and vincristine. Results. The response rate was 52%, the disease control rate 77%, and the median overall survival 15.3 months. The one-year survival rate was 55%, and the two-year survival rate was 19%. The median progression free survival (PFS) time was 6.6 months. Survival rates did not correlate with the Ki-67 proliferation index. The treatment was well tolerated. Conclusion. Treatment results with carboplatin, etoposide, and vincristine in chemonaïve patients with PDECs are comparable to those in patients with SCLC. The prognosis is however poor.

Personalized oncology: genomic screening in phase 1

Improvements in cancer genomics and tumor biology have reinforced the evidence of cancer development driven by numerous genomic alterations. Advanced genomics technology can be used to characterize genomic alterations that potentially drive tumor growth. With the possibility of screening thousands of genes simultaneously, personalized molecular medicine has become an option. New treatments are being investigated in phase 1 trials around the world. Traditionally, the goal of phase 1 studies was to determine the optimal dose and assess dose‐limiting toxicity of a potential new experimental drug. Only a limited number of patients will benefit from the treatment. However, introducing genomic mapping to select patients for early clinical trials with targeted molecular therapy according to the genomic findings, may lead to a better outcome for the patient, an enrichment of phase 1 trials, and thereby accelerated drug development. The overall advantage is to determine which mutation profiles correlate with sensitivity or lack of resistance to specific targeted therapies. The utility and current limitations of genomic screening to guide selection to Phase 1 clinical trial will be discussed.

Goblet Cell Carcinoids: Characteristics of a Danish Cohort of 83 Patients

Background Appendiceal goblet cell carcinoids (GCCs) exhibit neuroendocrine and adenocarcinoma features. Patients and Methods Analysis of demography, pathology, prognostic markers, treatment and survival in 83 GCC patients (f/m: 56/27) diagnosed 1992-2013. Results Median age for f/m was 59/58 years, respectively, and similar for localized and disseminated disease. At diagnosis 54 patients had localized appendiceal disease (f/m: 29/25). According to TNM 24% had Stage I, 70% had Stage II and 6% had Stage III. Twenty-nine patients had disseminated disease (f/m: 27/2). Chromogranin A, synaptophysin and p53 were positive in >90%. Serotonin was positive in 70%. Median Ki67 index was 32% (6-75%) and higher in Tang group C (50%) compared to group A (30%; p<0.0001), and group B (30%; p<0.004). All patients had surgery. Sixty-three (76%) had radical resections including all patients with localized disease. Median OS was 83 months. The 1-, 5- and 10-year survival rates were 90%, 58%, and 38%, respectively. For localized disease OS was 164 months and 1-, 5- and 10-year survival rates were 100%, 80%, and 55%, respectively. For disseminated disease OS was 19 months and 1-, 5- and 10-year survival rates were 73%, 18% and 6%, respectively. The 1-, 5- and 10 year-survival rates for f/m were 87%/96%, 49%/76% and 31%/57%, respectively (p = 0.02). According to the Tang classification group A, B, and C OS was 118, 83 and 20 months, respectively (p = 0.0002). Conclusion The Tang classification was found to be a significant prognostic factor, while the Ki67 index was not. Localized GCCs occurred equally in males and females, while disseminated GCCs were mostly seen in females. Median age of patients with localized disease and disseminated disease was identical. Cox regression analysis found Stage IV, focally positive synaptophysin and non-radical surgery as strongest negative prognostic factors.

Gene Expression of Glucose Transporter 1 (GLUT1), Hexokinase 1 and Hexokinase 2 in Gastroenteropancreatic Neuroendocrine Tumors: Correlation with F-18-fluorodeoxyglucose Positron Emission Tomography and Cellular Proliferation.

Neoplastic tissue exhibits high glucose utilization and over-expression of glucose transporters (GLUTs) and hexokinases (HKs), which can be imaged by 18F-Fluorodeoxyglucose-positron emission tomography (FDG-PET). The aim of the present study was to investigate the expression of glycolysis-associated genes and to compare this with FDG-PET imaging as well as with the cellular proliferation index in two cancer entities with different malignant potential. Using real-time PCR, gene expression of GLUT1, HK1 and HK2 were studied in 34 neuroendocrine tumors (NETs) in comparison with 14 colorectal adenocarcinomas (CRAs). The Ki67 proliferation index and, when available, FDG-PET imaging was compared with gene expression. Overexpression of GLUT1 gene expression was less frequent in NETs (38%) compared to CRAs (86%), P = 0.004. HK1 was overexpressed in 41% and 71% of NETs and CRAs, respectively (P = 0.111) and HK2 was overexpressed in 50% and 64% of NETs and CRAs, respectively (P = 0.53). There was a significant correlation between the Ki67 proliferation index and GLUT1 gene expression for the NETs (R = 0.34, P = 0.047), but no correlation with the hexokinases. FDG-PET identified foci in significantly fewer NETs (36%) than CRAs (86%), (P = 0.04). The gene expression results, with less frequent GLUT1 and HK1 upregulation in NETs, confirmed the lower metabolic activity of NETs compared to the more aggressive CRAs. In accordance with this, fewer NETs were FDG-PET positive compared to CRA tumors and FDG uptake correlated with GLUT1 gene expression.

Primary peritoneal carcinoma: a rare neoplasm with pleomorphic trophoblastic morphology.

We report a case of primary peritoneal carcinoma with trophoblastic morphology in a 78‐year‐old woman, diagnosed by histological and immunohistochemical analysis of surgically resected specimens, including the omentum and part of the small bowel. Microscopically, the resected specimens showed diffuse infiltration of a poorly differentiated tumor. Numerous large, often multinucleated cells were seen, and mitotic figures were frequent. Immunohistochemical staining showed a positive reaction for most cytokeratins, EP4, EMA, CA‐125, Glut1, WT1, β‐hCG and PLAP. We reached a diagnosis of primary peritoneal carcinoma with trophoblastic morphology. To our knowledge this morphology of a primary peritoneal carcinoma has not been described previously.

Diagnosis of intraductal papillary mucinous neoplasm using endoscopic ultrasound guided microbiopsies: A case report

Pancreatic cysts are increasingly diagnosed due to expanding use of cross-sectional imaging, but current diagnostic modalities have limited diagnostic accuracy. Recently, a novel through-the-needle microbiopsy forceps has become available, offering the possibility of obtaining cyst-wall biopsies. We present a case of 41-year-old male with chronic pancreatitis and a 2-cm pancreatic cyst, initially considered a pseudocyst. Subsequently, endoscopic ultrasound guided microbiopsies were successfully obtained, which surprisingly revealed an intraductal papillary mucinous neoplasm of mixed subtype with low grade dysplasia. In conclusion, obtaining biopsies from the wall of the pancreatic cystic lesions with this novel instrument is feasible and, as demonstrated in this case, can possibly alter the clinical outcome. Microbiopsies offered enough cellular material, allowing supplemental gene mutation analysis, which combined with other modalities could lead to a more individual approach when treating pancreatic cysts. However, prospective studies are warranted before routine clinical implementation.

Actionable targets in recurrent bile duct and pancreatic cancer in a prospective cohort of patients evaluated by whole exome sequencing and SNP array analysis.

e23256Background: No standard therapy exists for recurrent bile duct cancer. In this study, we characterized actionable targets in patients with recurrent bile duct- and pancreatic cancer included ...

Dynamics of mutant BRAF V600E in free circulating DNA (fcDNA) of non-melanoma cancer patients (pts) in response to treatment with BRAF and MEK/EGFR inhibitors.

11531Background: Therapies targeting mutant BRAF V600E have changed practice in the treatment of metastatic melanoma and are currently tested in other malignancies. Treatment response can be monito...

Abstract 5240: Comparative levels of KRAS mutations circulating tumor DNA for association with overall survival in patients with non-resectable pancreatic cancer

Background: The median overall survival (OS) time of patients with non-resectable pancreatic cancer varies widely. Diagnostic tools are presently lacking to predict patient outcome at diagnosis. The vast majority of pancreatic tumors harbor KRAS mutations. In this study, we evaluated whether quantitative baseline and longitudinal monitoring of KRAS mutations in plasma circulating tumor DNA (ctDNA) may be used to stratify patients for predicting outcome. Methods: The Danish BIOPAC study prospectively collected plasma from patients with non-resectable pancreatic cancer undergoing treatment with gemcitabine or FOLFIRINOX. Archival (3-5 years) plasma specimens were collected from 113 patients pre-treatment (baseline),on chemotherapy, as well as at multiple additional time intervals for up to 977 days from baseline. Interim analysis of ctDNA KRAS was conducted (after 105 deaths). Levels of ctDNA KRAS mutations were assessed in 35 patients with long OS (median 473 days; range 360-1134), 33 patients with medium OS (median 227 days; range 155-349) and 37 patients with short OS (median 94 days; range 21-146). PCR enrichment of KRAS G12A/C/D/R/S/V, and G13D mutations was performed, followed by massively parallel deep sequencing and quantification with standardization of reporting number of copies detected per 105 genome equivalents (GE). Results: In a prospective-retrospective biomarker study of 113 patients, interim analysis of ctDNA KRAS was conducted (after 105 deaths). 92 of 105 patients had evaluable baseline plasma samples. Number of mutant KRAS copies was higher in patients with short OS (median 661; range 0-190,490 copies/105 GE) versus with median OS (median 103; range 0 to 275,918 copies/105 GE) versus with long OS (median, 15; range, 0-1,369 copies/105 GE). Longitudinally, KRAS mutation levels remained mostly low with long OS (last time point median 9; range 0-70,451 copies/105 GE) vs. medium OS (median 155; range 0-314,103 copies/105 GE) or short OS where levels increased or remained high (median 803; range 0-138,508 copies/105 GE). As this dramatic difference in systemic KRAS levels may reflect distinct tumor phenotypes, the underlying tumor biology was further investigated by interrogating additional cancer mutational hotspots (using massively parallel deep sequencing) in plasma ctDNA of patients stratified by systemic KRAS and the OS. Conclusion: Shorter OS in patients with non-resectable pancreatic cancer tended to associate with high levels of ctDNA KRAS mutations at diagnosis and with post-treatment elevation of KRAS mutations. ctDNA KRAS mutation levels in patients with non-resectable pancreatic cancer observed at diagnosis or on treatment may predict patient outcome and could reflect distinct underlying tumor biology. Citation Format: Julia S. Johansen, Cecile Rose T. Vibat, Saege Hancock, Latifa Hassaine, Errin Samuelsz, Inna Chen, Eric A. Collisson, Dan Calatayud, Benny V. Jensen, Jane Preuss Hasselby, Timothy T. Lu, Jason C. Poole, Vlada Melnikova, Mark G. Erlander. Comparative levels of KRAS mutations circulating tumor DNA for association with overall survival in patients with non-resectable pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5240. doi:10.1158/1538-7445.AM2015-5240