Prospective Evaluation of <i>MGMT</i>-Promoter Methylation Status and Correlations with Outcomes to Temozolomide-Based Chemotherapy in Well-Differentiated Neuroendocrine Tumors
Temozolomide (TEM) as a single agent or in combination with capecitabine (CAPTEM) is active in well-differentiated advanced neuroendocrine tumors (NETs) of gastro-entero-pancreatic and thoracic origin. The predictive role of MGMT-promoter methylation in this setting is controversial. We sought to pr...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | Current Oncology |
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| Online Access: | https://www.mdpi.com/1718-7729/30/2/106 |
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| author | Nicole Brighi Giuseppe Lamberti Elisa Andrini Cristina Mosconi Lisa Manuzzi Giada Donati Andrea Lisotti Davide Campana |
| author_facet | Nicole Brighi Giuseppe Lamberti Elisa Andrini Cristina Mosconi Lisa Manuzzi Giada Donati Andrea Lisotti Davide Campana |
| author_sort | Nicole Brighi |
| collection | DOAJ |
| description | Temozolomide (TEM) as a single agent or in combination with capecitabine (CAPTEM) is active in well-differentiated advanced neuroendocrine tumors (NETs) of gastro-entero-pancreatic and thoracic origin. The predictive role of MGMT-promoter methylation in this setting is controversial. We sought to prospectively evaluate the MGMT-promoter methylation status ability to predict outcomes to TEM-based chemotherapy in patients with NET. A single-center, prospective, observational study has been conducted at the ENETS Center-of-Excellence Outpatient Clinic of the IRCCS Policlinico Sant’Orsola-Malpighi in Bologna, Italy. Patients with advanced, gastro-entero-pancreatic or lung well-differentiated NETs candidate to TEM-based chemotherapy and with available tumor samples for MGMT-promoter methylation assessment were included. The MGMT-promoter methylation status was analyzed by using pyrosequencing. The primary endpoint was progression-free survival (PFS) by the MGMT-promoter methylation status. Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Survival outcomes were compared by restricted mean survival time (RMST) difference. Of 26 screened patients, 22 were finally enrolled in the study. The most frequent NET primary sites were the pancreas (64%) and the lung (23%). MGMT promoter was methylated in five tumors (23%). At a median follow-up time of 47.2 months (95%CI 29.3–89.7), the median PFS was 32.8 months (95%CI 17.2–NA), while the median OS was not reached. Patients in the methylated MGMT group, when compared to those in the unmethylated MGMT group, had longer PFS (median not reached [95%CI NA–NA] vs. 30.2 months [95%CI 15.2–NA], respectively; RMST <i>p</i> = 0.005) and OS (median not reached [95%CI NA–NA] vs. not reached [40.1–NA], respectively; RMST <i>p</i> = 0.019). After adjusting for confounding factors, the MGMT-promoter methylation status was independently associated to the PFS. Numerically higher ORR (60% vs. 24%; <i>p</i> = 0.274) and DCR (100% vs. 88%; <i>p</i> = 1.00) were observed in the methylated vs. unmethylated MGMT group. TEM-based chemotherapy was well-tolerated (adverse events grade ≥3 < 10%). In this prospective study, MGMT-promoter methylation predicted better outcomes to TEM-based chemotherapy in patients with NET. |
| first_indexed | 2024-03-11T08:58:17Z |
| format | Article |
| id | doaj.art-cf7e4e02ab344cf889febb7e58d3a49a |
| institution | Directory Open Access Journal |
| issn | 1198-0052 1718-7729 |
| language | English |
| last_indexed | 2024-03-11T08:58:17Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Current Oncology |
| spelling | doaj.art-cf7e4e02ab344cf889febb7e58d3a49a2023-11-16T19:57:22ZengMDPI AGCurrent Oncology1198-00521718-77292023-01-013021381139410.3390/curroncol30020106Prospective Evaluation of <i>MGMT</i>-Promoter Methylation Status and Correlations with Outcomes to Temozolomide-Based Chemotherapy in Well-Differentiated Neuroendocrine TumorsNicole Brighi0Giuseppe Lamberti1Elisa Andrini2Cristina Mosconi3Lisa Manuzzi4Giada Donati5Andrea Lisotti6Davide Campana7Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine, Sant’Orsola-Malpighi University Hospital, ENETS Center of Excellence, 40138 Bologna, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine, Sant’Orsola-Malpighi University Hospital, ENETS Center of Excellence, 40138 Bologna, ItalyDepartment of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine, Sant’Orsola-Malpighi University Hospital, ENETS Center of Excellence, 40138 Bologna, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine, Sant’Orsola-Malpighi University Hospital, ENETS Center of Excellence, 40138 Bologna, ItalyGastroenterology Unit, Hospital of Imola, University of Bologna, 40026 Bologna, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine, Sant’Orsola-Malpighi University Hospital, ENETS Center of Excellence, 40138 Bologna, ItalyTemozolomide (TEM) as a single agent or in combination with capecitabine (CAPTEM) is active in well-differentiated advanced neuroendocrine tumors (NETs) of gastro-entero-pancreatic and thoracic origin. The predictive role of MGMT-promoter methylation in this setting is controversial. We sought to prospectively evaluate the MGMT-promoter methylation status ability to predict outcomes to TEM-based chemotherapy in patients with NET. A single-center, prospective, observational study has been conducted at the ENETS Center-of-Excellence Outpatient Clinic of the IRCCS Policlinico Sant’Orsola-Malpighi in Bologna, Italy. Patients with advanced, gastro-entero-pancreatic or lung well-differentiated NETs candidate to TEM-based chemotherapy and with available tumor samples for MGMT-promoter methylation assessment were included. The MGMT-promoter methylation status was analyzed by using pyrosequencing. The primary endpoint was progression-free survival (PFS) by the MGMT-promoter methylation status. Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Survival outcomes were compared by restricted mean survival time (RMST) difference. Of 26 screened patients, 22 were finally enrolled in the study. The most frequent NET primary sites were the pancreas (64%) and the lung (23%). MGMT promoter was methylated in five tumors (23%). At a median follow-up time of 47.2 months (95%CI 29.3–89.7), the median PFS was 32.8 months (95%CI 17.2–NA), while the median OS was not reached. Patients in the methylated MGMT group, when compared to those in the unmethylated MGMT group, had longer PFS (median not reached [95%CI NA–NA] vs. 30.2 months [95%CI 15.2–NA], respectively; RMST <i>p</i> = 0.005) and OS (median not reached [95%CI NA–NA] vs. not reached [40.1–NA], respectively; RMST <i>p</i> = 0.019). After adjusting for confounding factors, the MGMT-promoter methylation status was independently associated to the PFS. Numerically higher ORR (60% vs. 24%; <i>p</i> = 0.274) and DCR (100% vs. 88%; <i>p</i> = 1.00) were observed in the methylated vs. unmethylated MGMT group. TEM-based chemotherapy was well-tolerated (adverse events grade ≥3 < 10%). In this prospective study, MGMT-promoter methylation predicted better outcomes to TEM-based chemotherapy in patients with NET.https://www.mdpi.com/1718-7729/30/2/106neuroendocrine neoplasmschemotherapybiomarkersepigeneticgastroenteropancreatic |
| spellingShingle | Nicole Brighi Giuseppe Lamberti Elisa Andrini Cristina Mosconi Lisa Manuzzi Giada Donati Andrea Lisotti Davide Campana Prospective Evaluation of <i>MGMT</i>-Promoter Methylation Status and Correlations with Outcomes to Temozolomide-Based Chemotherapy in Well-Differentiated Neuroendocrine Tumors Current Oncology neuroendocrine neoplasms chemotherapy biomarkers epigenetic gastroenteropancreatic |
| title | Prospective Evaluation of <i>MGMT</i>-Promoter Methylation Status and Correlations with Outcomes to Temozolomide-Based Chemotherapy in Well-Differentiated Neuroendocrine Tumors |
| title_full | Prospective Evaluation of <i>MGMT</i>-Promoter Methylation Status and Correlations with Outcomes to Temozolomide-Based Chemotherapy in Well-Differentiated Neuroendocrine Tumors |
| title_fullStr | Prospective Evaluation of <i>MGMT</i>-Promoter Methylation Status and Correlations with Outcomes to Temozolomide-Based Chemotherapy in Well-Differentiated Neuroendocrine Tumors |
| title_full_unstemmed | Prospective Evaluation of <i>MGMT</i>-Promoter Methylation Status and Correlations with Outcomes to Temozolomide-Based Chemotherapy in Well-Differentiated Neuroendocrine Tumors |
| title_short | Prospective Evaluation of <i>MGMT</i>-Promoter Methylation Status and Correlations with Outcomes to Temozolomide-Based Chemotherapy in Well-Differentiated Neuroendocrine Tumors |
| title_sort | prospective evaluation of i mgmt i promoter methylation status and correlations with outcomes to temozolomide based chemotherapy in well differentiated neuroendocrine tumors |
| topic | neuroendocrine neoplasms chemotherapy biomarkers epigenetic gastroenteropancreatic |
| url | https://www.mdpi.com/1718-7729/30/2/106 |
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