Alternative Lengthening of Telomeres and Loss of DAXX/ATRX Expression Predicts Metastatic Disease and Poor Survival in Patients with Pancreatic Neuroendocrine Tumors

Abstract Purpose of Review Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism used by some types of malignancies, including pancreatic neuroendocrine tumors, to overcome the issue of telomere shortening, thus supporting tumor growth and cell proliferation. This review is focused on the most important achievements and opportunities deriving from ALT assessment in PanNET onco-pathology, highlighting the most promising fields in which such biomarker could be implemented in clinical practice. Recent Findings In pancreatic neuroendocrine tumors (PanNET), ALT is strongly correlated with the mutational status of two chromatin remodeling genes, DAXX and ATRX. Recent advances in tumor biology permitted to uncover important roles of ALT in the landscape of PanNET, potentially relevant for introducing this biomarker into clinical practice. Indeed, ALT emerged as a reliable indicator of worse prognosis for PanNET, helping in clinical stratification and identification of “high-risk” patients. Furthermore, it is a very specific marker supporting the pancreatic origin of neuroendocrine neoplasms and can be used for improving the diagnostic workflow of patients presenting with neuroendocrine metastasis from unknown primary. The activation of this process can be determined by specific FISH analysis. Summary ALT should be introduced in clinical practice for identifying “high-risk” PanNET patients and improving their clinical management, and as a marker of pancreatic origin among neuroendocrine tumors.

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Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors

Modern Pathology ◽

10.1038/modpathol.2012.53 ◽

2012 ◽

Vol 25 (7) ◽

pp. 1033-1039 ◽

Cited By ~ 96

Author(s):

Roeland F de Wilde ◽

Christopher M Heaphy ◽

Anirban Maitra ◽

Alan K Meeker ◽

Barish H Edil ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Small Subset ◽

Pancreatic Neuroendocrine Tumors ◽

Alternative Lengthening Of Telomeres ◽

Men 1 ◽

Alternative Lengthening

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CT Radiogenomic Characterization of the Alternative Lengthening of Telomeres Phenotype in Pancreatic Neuroendocrine Tumors

American Journal of Roentgenology ◽

10.2214/ajr.17.19490 ◽

2018 ◽

Vol 211 (5) ◽

pp. 1020-1025 ◽

Cited By ~ 3

Author(s):

Jonathan M. McGovern ◽

Aatur D. Singhi ◽

Amir A. Borhani ◽

Alessandro Furlan ◽

Kevin M. McGrath ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Pancreatic Neuroendocrine Tumors ◽

Alternative Lengthening Of Telomeres ◽

Alternative Lengthening

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Alternative lengthening of telomeres in pancreatic neuroendocrine tumors is associated with more aggressive clinicopathologic features and increased risk of recurrence

HPB ◽

10.1016/j.hpb.2021.06.058 ◽

2021 ◽

Vol 23 ◽

pp. S478

Author(s):

H. Gudmundsdottir ◽

R.P. Graham ◽

R.L. Smoot ◽

M.J. Truty ◽

M.L. Kendrick ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Clinicopathologic Features ◽

Pancreatic Neuroendocrine Tumors ◽

Alternative Lengthening Of Telomeres ◽

Risk Of Recurrence ◽

Alternative Lengthening ◽

Increased Risk

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Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors

Endocrine Related Cancer ◽

10.1530/erc-16-0147 ◽

2016 ◽

Vol 23 (9) ◽

pp. 759-767 ◽

Cited By ~ 57

Author(s):

M Cives ◽

M Ghayouri ◽

B Morse ◽

M Brelsford ◽

M Black ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Proliferative Activity ◽

Dna Methyltransferase ◽

Predictive Biomarkers ◽

Pancreatic Neuroendocrine Tumors ◽

Mgmt Expression ◽

Methylguanine Dna Methyltransferase ◽

Response Predictors ◽

Alternative Lengthening ◽

Pathway Activation

The capecitabine and temozolomide (CAPTEM) regimen is active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30 to 70%. Small retrospective studies suggest that O6-methylguanine DNA methyltransferase (MGMT) deficiency predicts response to temozolomide. High tumor proliferative activity is also commonly perceived as a significant predictor of response to cytotoxic chemotherapy. It is unclear whether chromosomal instability (CIN), which correlates with alternative lengthening of telomeres (ALT), is a predictive factor. In this study, we evaluated 143 patients with advanced pNET who underwent treatment with CAPTEM for radiographic and biochemical response. MGMT expression (n=52), grade (n=128) and ALT activation (n=46) were investigated as potential predictive biomarkers. Treatment with CAPTEM was associated with an overall response rate (ORR) of 54% by RECIST 1.1. Response to CAPTEM was not influenced by MGMT expression, proliferative activity or ALT pathway activation. Based on these results, no biomarker-driven selection criteria for use of the CAPTEM regimen can be recommended at this time.

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Pancreatic neuroendocrine tumors: A population-based analysis of epidemiology and outcomes.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.401 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 401-401 ◽

Cited By ~ 3

Author(s):

Samer Alsidawi ◽

Gustavo Figueiredo Marcondes Westin ◽

Timothy J. Hobday ◽

Thorvardur Ragnar Halfdanarson

Keyword(s):

Neuroendocrine Tumors ◽

Metastatic Disease ◽

Early Stage ◽

Population Based ◽

Annual Incidence ◽

Pancreatic Neuroendocrine Tumors ◽

New Therapies ◽

Study Duration ◽

Younger Age ◽

Localized Disease

401 Background: Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms comprising less than 2% of pancreatic tumors. Outcomes of PNETs vary by stage, grade, and clinical presentation. New therapies may have improved outcomes. We present an analysis of the epidemiology and prognosis of patients (pts) with PNETs evaluating a more recent period than previously reported. Methods: Using data from the SEER registry, we identified adults with PNETs between 2000 and 2013. Cases were identified using a combination of ICD-O-3 site and histology codes. The JMP and SEER*STAT 8.3.2 were used for statistical analysis. Overall survival (OS) was analyzed using the Kaplan–Meier method. The prognostic effect of variables was studied using multivariate Cox proportional hazards models. Results: We identified 5993 pts with PNETs. Over the study duration, there was an increase in the annual incidence from 0.3 to 1.2 per 100.000. This was largely explained by the increase in number of pts with localized disease. The OS for the entire cohort was 54 months (95%; CI 50-58) and 5-year OS rates in localized, locally advanced and metastatic disease were 81.7%, 62% and 26% respectively. New therapies were increasingly implemented after 2008 such as sunitinib, everolimus and capecitabine/temozolomide. OS was better for pts diagnosed after 2008 (HR 0.73; 95% CI, 0.69-0.79; P < 0.0001) and this remained significant after excluding pts with localized disease (HR 0.85; 95% CI, 0.78-0.92; P = 0.0002). Factors found to favorably affect OS included younger age, female sex, early stage, low grade, and surgery. In metastatic disease, pts who had surgery had better OS and this was significant after adjusting for possible confounders (HR 0.36; 95% CI, 0.3-0.45). Conclusions: In this large population-based study, we saw an increase in the annual incidence of PNETs mainly due to an increased number of pts with localized disease. The OS has improved over the study duration likely due to both stage migration and new therapies used in advanced disease. Younger age, female gender, low histologic grade, early stage and surgery were found to be factors that favorably affected survival. Surgery was found to be a predictor of better outcomes in metastatic disease.

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Should all pancreatic neuroendocrine tumors (PNET) over 1 cm be resected?

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4108 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4108-4108

Author(s):

Diana Hsu ◽

Sidney Le ◽

Alex Chang ◽

Austin Spitzer ◽

George Kazantsev ◽

...

Keyword(s):

Overall Survival ◽

Surgical Resection ◽

Neuroendocrine Tumors ◽

Metastatic Disease ◽

Tumor Size ◽

Cox Regression ◽

Metastatic Spread ◽

Rank Test ◽

Pancreatic Neuroendocrine Tumors ◽

Localized Disease

4108 Background: Pancreatic neuroendocrine tumors (PNET) are a heterogeneous group of tumors that represent 1-2% of all pancreatic neoplasms. Their biologic behaviors are unpredictable with high grade, nodal metastasis, or liver metastasis lending an unfavorable prognosis. Current guidelines recommend resection for functioning tumors and those 2 cm or larger but are less straightforward regarding tumors < 2 cm in size. Previous data show that observation for nonfunctioning tumors < 2 cm can be safe and feasible; however, a significant portion of these patients may have nodal involvement or metastatic disease. Methods: A retrospective review was undertaken to identify patients with pancreatic neuroendocrine tumors treated at Northern California Kaiser Permanente (KP-NCAL) between February 2010 and December 2018. Univariate and multivariate analyses were performed with the log-rank test and Cox regression. Chi-squared test of relevant clinicopathologic factors determined which factors were predictive for overall survival (OS). Results: Mean age was 61 years in our cohort of 354 patients, with 29% over the age of 70. Mean tumor size was 3.43 cm; 32% of tumors were 2 cm or smaller. 51% of the patients had localized disease; 32% of the patients presented with metastatic disease. The pancreatic tail was the most common tumor location (38%), followed by the head of the pancreas (24%). On multivariate survival analysis, stage, location of the tumor, and surgical resection were statistically significant in terms of overall survival ( p<.001). Mean OS for patients with localized and metastatic disease was 93 months versus 37 months ( p<.001). Surgery was utilized in 8.9% of patients with metastatic disease ( p<.001). All patients with PNET smaller than 1 cm in our study group had localized disease only. However, in patients with tumor size between 1 and 2 cm, 11% had nodal or metastatic spread. Conclusions: PNETs are indolent but have malignant potential at any size. In our retrospective study, all of the patients with tumor size < 1 cm had localized disease. For those with PNETs 1-2 cm in size, 11% had nodal or metastatic spread. Based on our findings, we suggest a more aggressive surgical resection size criteria of 1 cm.[Table: see text]

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