Molecular markers associated with response to chemotherapy in gastro-entero-pancreatic neuroendocrine tumors

Dermot O'Toole, Anne Couvelard, Vinciane Rebours, Magali Zappa, Olivia Hentic, Pascal Hamme, Philippe Levy, Pierre Bedossa, Eric Raymond and Philippe Ruszniewski

Response rates to cytotoxics in gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) vary; recent trials demonstrated lack of objective response rates in up to 70% of patients. Identification of predictive therapeutic biomarkers would be beneficial in the treatment of GEP. Selected markers with known or suspected capability of predicting response to cytotoxics or prognosis (Ki-67, p53, multidrug resistance protein-1 (MDR1), Akt, thymidylate synthase (TS), phosphatase and tensin homolog (PTEN), CA9, cluster of differentiation 34 (CD34), vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1, mismatch repair gene – human mutL homolog 1 (hLMH1), and Bcl-2) were analyzed using immunohistochemisrtry in 60 treatment-naive patients receiving chemotherapy (n=46) or chemoembolization (n=14) for inoperable advanced and/or metastatic GEP and correlated with prognosis (survival and response rates). Therapy included systemic chemotherapy with streptozotocin (n=28), doxorubicin (n=14), 5-fluorouracil (n=18), and etoposide/cisplatinum (n=16), or chemoembolization (streptozotocin, 9; doxorubicin, 5). Factors associated with overall survival in the entire cohort were Ki-67, P<0.001; tumor grade, P<0.001; tumor differentiation, P<0.001; CA9, P=0.004; Akt, P=0.01; HIF-1, P<0.001; p53, P<0.0001; and hMLH1, P=0.005. Markers associated with treatment response included overall group: Akt and PTEN (P=0.05 and 0.05 respectively); streptozotocin: Akt (P=0.07), TS (P=0.02), and PTEN (P=0.017); doxorubicin: Ki-67 (P=0.05), Akt (P=0.06), and CA9 (P=0.02). At multivariate analysis, Akt was significantly associated with a nonresponse to therapy (objective response (OR): 0.2 (0.05–0.8)). For patients receiving only systemic chemotherapy (n=46), PTEN (0.04) and hLMH1 (0.03) were correlated with treatment response and for individual molecules were streptozotocin: PTEN (P=0.008) and hLMH1 (0.07); doxorubicin: Akt (P=0.09), CA9 (P=0.09), and hLMH1 (P=0.09). These results demonstrate a number of new prognostic biomarkers in GEP-NET, and in addition, response to chemotherapy was correlated with a simple panel of selected markers (such as CA9, Akt, PTEN, TS, and hLMH1).

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Systematic comparison of sporadic and syndromic pancreatic islet cell tumors

Zoran Erlic, Ursula Ploeckinge1, Alberto Cascon, Michael M Hoffmann, Laura von Duecker, Aurelia Winter, Gerit Kammel, Janina Bacher, Maren Sullivan, Berend Isermann, Lars Fischer, Andreas Raffel, Wolfram Trudo Knoefel, Matthias Schott, Tobias Baumann, Oliver Schaefer, Tobias Keck, Richard P Baum, Ioana Milos, Mihaela Muresan, Mariola Peczkowsk, Andrzej Januszewicz, Kenko Cupisti, Anke Tönjes, Mathias Fasshauer, Jan Langrehr, Peter von Wussow, Abbas Agaimy, Günter Schlimok, Regina Lamberts, Thorsten Wiech, Kurt Werner Schmid, Alexander Weber, Mercedes Nunez, Mercedes Robledo, Charis Eng, Hartmut P H Neumann and for the VHL-ICT Consortium and the German NET Registry

Pancreatic islet cell tumors (ICTs) occur as sporadic neoplasias or as a manifestation of multiple endocrine neoplasia type 1 (MEN1) and von Hippel–Lindau disease (VHL). Molecular classification of ICTs is mandatory for timely diagnosis and surveillance. Systematic comparison of VHL-ICTs and sporadic ICTs has been lacking. Our registry-based approaches used the German NET-Registry with 259 patients with neuroendocrine tumors (NETs), who were primarily diagnosed with NETs, and the German VHL-Registry with 485 molecular genetically confirmed patients who had undergone magnetic resonance imaging or computed tomography of the abdomen. All patients provided blood DNA for testing of the MEN1 and VHL genes for intragenic mutations and large deletions. In the NET-Registry, 9/101 patients (8.9%) with ICTs had germline mutations, 8 in MEN1 and 1 in VHL. In the VHL-Registry, prevalence of NETs was 52/487 (10.6%), and all were ICTs. Interestingly, of those with VHL p.R167W, 47% developed ICTs, compared to 2% of those with p.Y98H. In total, there were 92 truly sporadic, i.e. mutation-negative ICT patients. Comparing these with the 53 VHL-ICT patients, the statistically significant differences were predominance of female gender (P=0.01), multifocal ICTs (P=0.0029), and lower malignancy rate (P<0.001) in VHL-ICTs compared to sporadic cases. VHL was prevalent in <0.5% of NETs, while NETs occur in ~10% of VHL, virtually exclusively as ICTs, which are rarely the first presentation. Patients with NETs should not be subjected to genetic testing of the VHL gene, unless they have multifocal ICTs, other VHL-associated tumors, and/or a family history for VHL.

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Gastroenteropancreatic neuroendocrine tumours: the current incidence and staging based on the WHO and European Neuroendocrine Tumour Society classification: an analysis based on prospectively collected parameters

Martin B Niederle, Monika Hackl, Klaus Kaserer and Bruno Niederle

As incidence data on gastroenteropancreatic neuroendocrine tumours (GEP-NETs) have so far only been retrospectively obtained and based on inhomogeneous material, we conducted a prospective study in Austria collecting all newly diagnosed GEP-NETs during 1 year. Using the current WHO classification, the tumor, nodes, metastases (TNM) staging and Ki67 grading and the standard diagnostic procedure proposed by the European Neuroendocrine Tumor Society (ENETS), GEP-NETs from 285 patients (male: 148; female: 137) were recorded. The annual incidence rates were 2.51 per 100 000 inhabitants for men, 2.36 per 100 000 for women. The stomach (23%) was the main site, followed by appendix (21%), small intestine (15%) and rectum (14%). Patients with appendiceal tumours were significantly younger than patients with tumours in any other site. About 46.0% were classified as benign, 15.4% as uncertain, 31.9% as well differentiated malignant and 6.7% as poorly differentiated malignant. Patients with benign or uncertain tumours were significantly younger than patients with malignant tumours. Among the malignant tumours of the digestive tract, 1.49% arose from neuroendocrine cells. For malignant gastrointestinal NETs, the incidence was 0.80 per 100 000: 40.9% were ENETS stage I, 23.8% stage II, 11.6% stage III and 23.8% stage IV. The majority (59.7%) were grade 1, 31.2% grade 2 and 9.1% grade 3. NETs of the digestive tract are more common than previously reported; the majority show benign behaviour, are located in the stomach and are well differentiated. G3 tumours are very rare.

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SDHB loss predicts malignancy in pheochromocytomas/sympathethic paragangliomas, but not through hypoxia signalling

Annika Blank, Anja M Schmitt, Esther Korpershoek, Francien van Nederveen, Thomas Rudolph, Nicole Weber, Räto Thomas Strebe, Ronald de Krijger, Paul Komminoth and Aurel Perren

Prediction of malignant behaviour of pheochromocytomas/sympathetic paragangliomas (PCCs/PGLs) is very difficult if not impossible on a histopathological basis. In a familial setting, it is well known that succinate dehydrogenase subunit B (SDHB)-associated PCC/PGL very often metastasise. Recently, absence of SDHB expression as measured through immunohistochemistry was shown to be an excellent indicator of the presence of an SDH germline mutation in PCC/PGL. SDHB loss is believed to lead to tumour formation by activation of hypoxia signals. To clarify the potential use of SDHB immunohistochemistry as a marker of malignancy in PCC/PGL and its association with classic hypoxia signalling we examined SDHB, hypoxia inducible factor-1{alpha} (Hif-1{alpha}) and its targets CA-9 and GLUT-1 expression on protein level using immunohistochemistry on a tissue micro array on a series of familial and sporadic tumours of 115 patients. Survival data was available for 66 patients. SDHB protein expression was lost in the tumour tissue of 12 of 99 patients. Of those 12 patients, 5 had an SDHB germline mutation, in 4 patients no germline mutation was detected and mutational status remained unknown in parts in 3 patients. Loss of SDHB expression was not associated with increased classic hypoxia signalling as detected by Hif-1{alpha}, CA-9 or GLUT-1 staining. Loss of SDHB expression was associated with an adverse outcome. The lack of correlation of SDHB loss with classic hypoxia signals argues against the current hypoxia hypothesis in malignant PCC/PGL. We suggest SDHB protein loss as a marker of adverse outcome both in sporadic and in familial PCC/PGL.

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The RET polymorphic allele S836S is associated with early metastatic disease in patients with hereditary or sporadic medullary thyroid carcinoma

Débora R Siqueira, Mírian Romitti, Andreia P da Rocha, Lucieli Ceolin, Camila Meotti, Aline Estivalet, Marcia K Puñales and Ana Luiza Maia

The possible role of RET variants in modifying the natural course of medullary thyroid carcinoma (MTC) is still a matter of debate. Here, we investigate whether the RET variants L769L, S836S, and G691S/S904S influence disease presentation in hereditary or sporadic MTC patients. One hundred and two patients with hereditary MTC and 81 patients with sporadic MTC attending our institution were evaluated. The frequencies of RET polymorphisms in hereditary MTC were as follows: L769L, 17.3%; S836S, 7.95%; and S904S/G691S, 18.2%. No associations were observed between these polymorphisms and pheochromocytoma, hyperparathyroidism, lymph node, or distant metastasis. However, patients harboring the S836S variant were younger than those without this allele (17±8.2 vs 28.6±14.4 years, P=0.01), suggesting that these patients had metastases at a young age. Accordingly, the cumulative frequency of local and/or distant metastases as estimated by Kaplan–Meier curves showed that lymph node and distant metastases occurred earlier in patients harboring the S836S variant (P=0.003 and P=0.026 respectively). The S836S allele frequency was higher in sporadic MTC patients than in controls (10.5 vs 3.1%, P=0.01). Individuals harboring the S836S variant were younger (38.6±13.3 vs 48.5±16.7 years, P=0.02) and showed a higher percentage of lymph node and distant metastases (P=0.02 and P=0.04 respectively). Kaplan–Meier estimates of lymph node and distant metastases yielded distinct curves for patients with or without the S836S allele (P=0.002 and P=0.001 respectively). Additional analyses using a COX regression model showed that the S836S variant was independently associated with metastatic disease (hazard ratio 2.82 (95% confidence interval 1.51–5.26), P=0.001). In conclusion, the RET S836S variant is associated with early onset and increased risk for metastatic disease in patients with hereditary or sporadic MTC.

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Hormonal contraception and risk of endometrial cancer: a systematic review

Alfred O Mueck, Harald Seeger and Thomas Rabe

More than 15 case–control studies and at least four large cohort studies demonstrated a decrease in the risk of endometrial cancer of about 50% for ever use of combined oral contraceptives (COCs). In most of these studies, this protective effect persisted for more than 10–15–20 years after cessation of the COC. An increasing protective effect with longer duration of COC use has been found in most studies. The beneficial effect was independent of the composition of COC, i.e. dosage and type of progestogen, combined with ethinyl estradiol 30–50 µg/day. COCs with higher progestogen potency seem to be somewhat more effective. Nonhormonal uterine devices have also been found to be strongly protective; however, data on oral or injectable progestogen-only preparations (POPs) including the levonorgestrel-releasing intrauterine system (LNG-IUS) are still rare, but also suggest similar protective action. COCs, POPs, as well as LNG-IUS can effectively reduce endometrial hyperplasia but should only be used in exceptional cases in patients with or after endometrial cancer. In contrast to nonhormonal IUS, systemic side effects cannot be excluded with LNG-IUS, but they are certainly rare, as the main effect has decreased the endometrial estrogen response because of the high endometrial tissue levels of LNG.

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Balancing biosynthesis and bioenergetics: metabolic programs in oncogenesis

Jennifer F Barger and David R Plas

Cancer biologists' search for new chemotherapy targets is reinvigorating the study of how cancer cell metabolism determines both oncogenic potential and chemotherapeutic responses. Oncogenic metabolic programs support the bioenergetics associated with resistance to programed cell death and provide biosynthetic building blocks for cell growth and mitogenesis. Both signal transduction pathway activation and direct mutations in key metabolic enzymes can activate the metabolic programs that support cancer cell growth. Cancer-associated metabolic programs include glycolysis, glutamine oxidation, and fatty acid metabolism. Recent observations are revealing the regulatory mechanisms that activate cancer-associated metabolism, and the competitive advantages provided to transformed cells by their metabolic programs. In this study, we review recent results illustrating the mechanisms and functional impact of each of these oncogenic metabolic programs in cancer cell growth and survival.

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Molecular markers associated with response to chemotherapy in gastro-entero-pancreatic neuroendocrine tumors

Dermot O' Toole, Anne Couvelard, Vinciane Rebours, Magali Zappa, Olivia Hentic, Pascal Hammel, Philippe Levy, Pierre Bedossa, Eric Raymond and Philippe Ruszniewski

Response rates to cytotoxics in gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) vary; recent trials demonstrated lack of objective response rates in up to 70% of patients. Identification of predictive therapeutic biomarkers would be beneficial in the treatment of GEP. Selected markers with known or suspected capability of predicting response to cytotoxics or prognosis (Ki-67, p53, multidrug resistance protein-1 (MDR1), Akt, thymidylate synthase (TS), phosphatase and tensin homolog (PTEN), CA9, cluster of differentiation 34 (CD34), vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1, mismatch repair gene – human mutL homolog 1 (hLMH1), and Bcl-2) were analyzed using immunohistochemisrtry in 60 treatment-naive patients receiving chemotherapy (n=46) or chemoembolization (n=14) for inoperable advanced and/or metastatic GEP and correlated with prognosis (survival and response rates). Therapy included systemic chemotherapy with streptozotocin (n=28), doxorubicin (n=14), 5-fluorouracil (n=18), and etoposide/cisplatinum (n=16), or chemoembolization (streptozotocin, 9; doxorubicin, 5). Factors associated with overall survival in the entire cohort were Ki-67, P<0.001; tumor grade, P<0.001; tumor differentiation, P<0.001; CA9, P=0.004; Akt, P=0.01; HIF-1, P<0.001; p53, P<0.0001; and hMLH1, P=0.005. Markers associated with treatment response included overall group: Akt and PTEN (P=0.05 and 0.05 respectively); streptozotocin: Akt (P=0.07), TS (P=0.02), and PTEN (P=0.017); doxorubicin: Ki-67 (P=0.05), Akt (P=0.06), and CA9 (P=0.02). At multivariate analysis, Akt was significantly associated with a nonresponse to therapy (objective response (OR): 0.2 (0.05–0.8)). For patients receiving only systemic chemotherapy (n=46), PTEN (0.04) and hLMH1 (0.03) were correlated with treatment response and for individual molecules were streptozotocin: PTEN (P=0.008) and hLMH1 (0.07); doxorubicin: Akt (P=0.09), CA9 (P=0.09), and hLMH1 (P=0.09). These results demonstrate a number of new prognostic biomarkers in GEP-NET, and in addition, response to chemotherapy was correlated with a simple panel of selected markers (such as CA9, Akt, PTEN, TS, and hLMH1).

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Systematic comparison of sporadic and syndromic pancreatic islet cell tumors

Zoran Erlic, Ursula Ploeckinger, Alberto Cascon, Michael M Hoffmann, Laura von Duecker, Aurelia Winter, Gerit Kammel, Janina Bacher, Maren Sullivan, Berend Isermann, Lars Fischer, Andreas Raffel, Wolfram Trudo Knoefel, Matthias Schott, Tobias Baumann, Oliver Schaefer, Tobias Keck, Richard P Baum, Ioana Milos, Mihaela Muresan, Mariola Peczkowska, Andrzej Januszewicz, Kenko Cupisti, Anke Tönjes, Mathias Fasshauer, Jan Langrehr, Peter von Wussow, Abbas Agaimy, Günter Schlimok, Regina Lamberts, Thorsten Wiech, Kurt Werner Schmid, Alexander Weber, Mercedes Nunez, Mercedes Robledo , Charis Eng , Hartmut P H Neumann and for the VHL-ICT Consortium and the German NET Registry

Pancreatic islet cell tumors (ICTs) occur as sporadic neoplasias or as a manifestation of multiple endocrine neoplasia type 1 (MEN1) and von Hippel–Lindau disease (VHL). Molecular classification of ICTs is mandatory for timely diagnosis and surveillance. Systematic comparison of VHL-ICTs and sporadic ICTs has been lacking. Our registry-based approaches used the German NET-Registry with 259 patients with neuroendocrine tumors (NETs), who were primarily diagnosed with NETs, and the German VHL-Registry with 485 molecular genetically confirmed patients who had undergone magnetic resonance imaging or computed tomography of the abdomen. All patients provided blood DNA for testing of the MEN1 and VHL genes for intragenic mutations and large deletions. In the NET-Registry, 9/101 patients (8.9%) with ICTs had germline mutations, 8 in MEN1 and 1 in VHL. In the VHL-Registry, prevalence of NETs was 52/487 (10.6%), and all were ICTs. Interestingly, of those with VHL p.R167W, 47% developed ICTs, compared to 2% of those with p.Y98H. In total, there were 92 truly sporadic, i.e. mutation-negative ICT patients. Comparing these with the 53 VHL-ICT patients, the statistically significant differences were predominance of female gender (P=0.01), multifocal ICTs (P=0.0029), and lower malignancy rate (P<0.001) in VHL-ICTs compared to sporadic cases. VHL was prevalent in <0.5% of NETs, while NETs occur in 10% of VHL, virtually exclusively as ICTs, which are rarely the first presentation. Patients with NETs should not be subjected to genetic testing of the VHL gene, unless they have multifocal ICTs, other VHL-associated tumors, and/or a family history for VHL.

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Obesity, inflammatory markers, and endometrial cancer risk: a prospective case–control studys

Laure Dossus, Sabina Rinaldi, Susen Becker, Annekatrin Lukanova, Anne Tjonneland, Anja Olsen, Jakob Stegger, Kim Overvad, Nathalie Chabbert-Buffet, Aida Jimenez-Corona, Francoise Clavel-Chapelon, Sabine Rohrmann, Birgit Teucher, Heiner Boeing, Madlen Schütze, Antonia Trichopoulou, Vassiliki Benetou, Pagona Lagiou, Domenico Palli, Franco Berrino, Salvatore Panico, Rosario Tumino, Carlotta Sacerdote, Maria-Luisa Redondo, Noémie Travier, Maria-Jose Sanchez, Jone M Altzibar, Maria-Dolores Chirlaque, Eva Ardanaz, H Bas Bueno-de-Mesquita, Fränzel J B van Duijnhoven, N Charlotte Onland-Moret, Petra H M Peeters, Goran Hallmans, Eva Lundin, Kay-Tee Khaw, Nicholas Wareham, Naomi Allen, Tim J Key, Nadia Slimani, Pierre Hainaut, Dora Romaguera, Teresa Norat, Elio Riboli and Rudolf Kaaks

Obesity, a major risk factor for endometrial cancer, is a low-grade inflammatory state characterized by elevated concentrations of cytokines and acute phase reactants. The current study had two aims: first to investigate the associations of C-reactive protein (CRP), interleukin 6 (IL6), and IL1 receptor antagonist (IL1Ra) with endometrial cancer risk and second to examine to which extent these markers can influence the association between obesity and endometrial cancer. We conducted a case–control study, nested within the European Prospective Investigation into Cancer and Nutrition, which comprised 305 incident cases of endometrial cancer and 574 matched controls. CRP, IL6, and IL1Ra were measured in prospectively collected blood specimens by immunoassays. Data were analyzed using conditional logistic regression. All statistical tests were two-sided, and P values <0.05 were considered statistically significant. We observed a significant increase in risk of endometrial cancer with elevated levels of CRP (odds ratio (OR) for top versus bottom quartile: 1.58, 95% confidence interval (CI): 1.03–2.41, Ptrend=0.02), IL6 (OR for top versus bottom quartile: 1.66, 95% CI: 1.08–2.54, Ptrend=0.008), and IL1Ra (OR for top versus bottom quartile: 1.82, 95% CI: 1.22–2.73, Ptrend=0.004). After adjustment for body mass index (BMI), the estimates were strongly reduced and became non-significant. The association between BMI and endometrial cancer was also substantially attenuated ( 10–20%) after adjustment for inflammatory markers, even when the effects of C-peptide or estrone had already been taken into account. We provided epidemiological evidence that chronic inflammation might mediate the association between obesity and endometrial cancer and that endometrial carcinogenesis could be promoted by an inflammatory milieu.

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