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

2010 ◽  
Vol 17 (4) ◽  
pp. 847-856 ◽  
Author(s):  
Dermot O'Toole ◽  
Anne Couvelard ◽  
Vinciane Rebours ◽  
Magali Zappa ◽  
Olivia Hentic ◽  
...  
Keyword(s):  
Treatment Response ◽  
Neuroendocrine Tumors ◽  
Systemic Chemotherapy ◽  
Objective Response ◽  
Response Rates ◽  
Mismatch Repair Gene ◽  
Pancreatic Neuroendocrine Tumors ◽  
Repair Gene ◽  
Ki 67 ◽  
Response To Chemotherapy

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).

Subgroup analysis by Ki-67 and baseline CgA of the randomized, placebo-controlled phase 3 study of surufatinib in advanced well-differentiated pancreatic neuroendocrine tumors (SANET-p).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4111-4111
Author(s):  
Xianjun Yu ◽  
Jianming Xu ◽  
Lin Shen ◽  
Chunmei Bai ◽  
Jie Li ◽  
...  
Keyword(s):  
Partial Response ◽  
Neuroendocrine Tumors ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Pancreatic Neuroendocrine Tumors ◽  
Phase 3 ◽  
Ki 67 ◽  
Meaningful Improvement ◽  
Well Differentiated

4111 Background: In the phase 3 SANET-p trial (NCT02589821), surufatinib significantly increased progression-free survival (PFS) compared with placebo in patients with progressive, well-differentiated (grade 1 or 2), advanced pancreatic neuroendocrine tumors (NETs). Here we report the relationship of Ki-67 and baseline Chromogranin A (CgA) on efficacy outcomes. Methods: A total of 172 patients with advanced pancreatic NETs were randomized to surufatinib or placebo in a 2:1 ratio. Investigator-assessed PFS and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 were used for the analysis. The post-hoc subgroup analyses were performed on Ki-67 subcategory: < 5% (n = 40 vs 21), 5-10% (n = 57 vs 31), > 10% (n = 16 vs 7), and baseline CgA subcategory: ≤ 2 times of upper limit of normal (ULN) (n = 59 vs 31), > 2 × ULN (n = 44 vs 24). Results: In the intent-to-treat population, surufatinib was superior to placebo, median PFS (mPFS) of 10.9 vs 3.7 months (mo) ( p = 0.0011), with a stratified hazard ratio (HR) of 0.491 (95% confidence interval [CI]: 0.319, 0.755). mPFS was statistically significantly longer in the surufatinib arm versus that in the placebo arm in subgroups of Ki-67 5-10% (11.0 vs 3.7 mo, HR = 0.33, p= 0.0002), Ki-67 > 10% (11.1 vs 2.8 mo, HR = 0.04, p = 0.0003) and CgA > 2 × ULN (11.0 vs 3.7 mo, HR = 0.36, p = 0.0036). There was numerical PFS improvement with surufatinib compared to placebo in subgroup of Ki-67 < 5% (9.3 vs 5.6 mo, HR = 0.91, p = 0.8015) and CgA ≤ 2 × ULN (9.4 vs 3.7 mo, HR = 0.61, p = 0.0809). ORRs in the subgroups of Ki-67 < 5%, 5-10%, and > 10% with surufatinib were 15.8%, 24.0% and 12.5% respectively. There was only one partial response in the placebo arm (with Ki-67 < 5%). ORRs in the subgroups of CgA ≤ 2 × ULN and > 2 × ULN with surufatinib were 18.9% and 21.4%, while also only one partial response in the placebo arm with CgA ≤ 2 × ULN. Conclusions: Surufatinib showed statistically significant and clinically meaningful improvement in PFS compared to placebo in patients with advanced, progressive, well-differentiated pancreatic NETs. From this exploratory analysis, surufatinib demonstrated benefit irrespective of Ki-67 expression levels or baseline CgA. Clinical trial information: NCT02589821.

Erratum to: KI-67 heterogeneity in well differentiated gastro-entero-pancreatic neuroendocrine tumors: when is biopsy reliable for grade assessment?

Endocrine ◽  
2017 ◽  
Vol 57 (3) ◽  
pp. 503-503
Author(s):  
Federica Grillo ◽  
Luca Valle ◽  
Diego Ferone ◽  
Manuela Albertelli ◽  
Maria Pia Brisigotti ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Pancreatic Neuroendocrine Tumors ◽  
Ki 67 ◽  
Well Differentiated ◽  
Grade Assessment

scholarly journals Expression of the phosphorylated variant of the AKT1-kinase (p-AKT1) in well-differentiated pancreatic neuroendocrine tumors: immunohistochemical evaluation

2018 ◽  
Vol 46 (4) ◽  
pp. 314-322
Author(s):  
V. V. Delektorskaya ◽  
O. N. Solov'eva ◽  
G. Yu. Chemeris ◽  
Yu. I. Patyutko
Keyword(s):  
Liver Metastases ◽  
Neuroendocrine Tumors ◽  
Treatment Effectiveness ◽  
Disease Free Survival ◽  
Immunohistochemical Analysis ◽  
Pancreatic Neuroendocrine Tumors ◽  
Ki 67 ◽  
New Treatment ◽  
Well Differentiated ◽  
High Level

Background:Well-differentiated pancreatic neuroendocrine tumors (pNETs) represent a group of rare epithelial neoplasms with a highly variable clinical course. AKT1 is one of the most frequently activated protein kinases in pNETs, which promotes the tumor growth and is of interest as a prognostic factor and a target for new treatment approaches.Aim:To study the expression of the phosphorylated variant of AKT1-kinase (p-AKT1) in primary pNETs and their liver metastases and to correlate the results with various clinical and pathological parameters and the disease prognosis.Materials and methods:P-AKT1 expression was studied by the immunohistochemical analysis of the primary lesions and liver metastases in 52 pNETs patients.Results:A high level of cytoplasmic and/or nuclear immunoreactivity was detected in 24/52 of the primary pNETs (46.2%) and in 16/27 of their liver metastases (59.3%). p-AKT1 expression was observed in 3 (21.4%) of NET grade (G) 1, in 14 (46.7%) of NET G2, and in 7 (87.5%) of NET G3. p-AKT1 expression was more frequently identified in pNET G3 category and increased during the tumor progression in metachronous liver metastases, as compared to the corresponding primary tumor. In addition, p-AKT1 positivity was significantly associated with an increase of grade from G1 to G3 (p = 0.004), the Ki-67 index (p = 0.029), the pTNM stage (p = 0.0008), perineural invasion (p = 0.031) and a decrease in disease-free survival (p = 0.05).Conclusion:The results suggest that p-АКТ1 plays an important role in the pathogenesis of pNETs and may be an additional criterion for assessment of the prognosis and treatment effectiveness in this type of tumors.

Are Cystic Pancreatic Neuroendocrine Tumors an Indolent Entity Results from a Single-Center Surgical Series

2017 ◽  
Vol 106 (3) ◽  
pp. 234-241 ◽  
Author(s):  
Salvatore Paiella ◽  
Giovanni Marchegiani ◽  
Marco Miotto ◽  
Anna Malpaga ◽  
Harmony Impellizzeri ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Postoperative Outcome ◽  
Tumor Diameter ◽  
Pancreatic Neuroendocrine Tumors ◽  
Ki 67 ◽  
Excellent Outcome ◽  
Comparison Results ◽  
Well Differentiated

Introduction: Cystic pancreatic neuroendocrine tumors (CPanNETs) represent an uncommon variant of pancreatic neuroendocrine tumors (PanNETs). Due to their rarity, there is a lack of knowledge with regard to clinical features and postoperative outcome. Methods: The prospectively maintained surgical database of a high-volume institution was queried, and 46 resected CPanNETs were detected from 1988 to 2015. Clinical, demographic, and pathological features and survival outcomes of CPanNETs were described and matched with a population of 92 solid PanNETs (SPanNETs) for comparison. Results: CPanNETs accounted for 7.8% of the overall number of resected PanNETs (46/587). CPanNETs were mostly sporadic (n = 42, 91%) and nonfunctioning (39%). Two functioning CPanNETs were detected (4.3%), and they were 2 gastrinomas. The median tumor diameter was 30 mm (range 10-120). All tumors were well differentiated, with 38 (82.6%) G1 and 8 (17.4%) G2 tumors. Overall, no CPanNET showed a Ki-67 >5%. A correct preoperative diagnosis of a CPanNET was made in half of the cases. After a median follow-up of >70 months, the 5- and 10-year overall survival of resected CPanNETs was 93.8 and 62.5%, respectively, compared to 92.7 and 84.6% for SPanNETs (p > 0.05). The 5- and 10-year disease-free survival rates were 94.5 and 88.2% for CPanNETs and 81.8 and 78.9% for SPanNETs, respectively (p > 0.05). Conclusion: In the setting of a surgical cohort, CPanNETs are rare, nonfunctional, and well-differentiated neoplasms. After surgical resection, they share the excellent outcome of their well-differentiated solid counterparts for both survival and recurrence.

Grade 2 pancreatic neuroendocrine tumors: overbroad scope of Ki-67 index according to MRI features

2018 ◽  
Vol 43 (11) ◽  
pp. 3016-3024 ◽  
Author(s):  
Yabin Hu ◽  
Shengxiang Rao ◽  
Xiaolin Xu ◽  
Yibo Tang ◽  
Mengsu Zeng
Keyword(s):  
Neuroendocrine Tumors ◽  
Pancreatic Neuroendocrine Tumors ◽  
Ki 67 ◽  
Mri Features
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