{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T08:41:00Z","timestamp":1782549660706,"version":"3.54.5"},"reference-count":50,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T00:00:00Z","timestamp":1674000000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>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\u2019Orsola-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\u201389.7), the median PFS was 32.8 months (95%CI 17.2\u2013NA), 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\u2013NA] vs. 30.2 months [95%CI 15.2\u2013NA], respectively; RMST p = 0.005) and OS (median not reached [95%CI NA\u2013NA] vs. not reached [40.1\u2013NA], respectively; RMST p = 0.019). After adjusting for confounding factors, the MGMT-promoter methylation status was independently associated to the PFS. Numerically higher ORR (60% vs. 24%; p = 0.274) and DCR (100% vs. 88%; p = 1.00) were observed in the methylated vs. unmethylated MGMT group. TEM-based chemotherapy was well-tolerated (adverse events grade \u22653 &lt; 10%). In this prospective study, MGMT-promoter methylation predicted better outcomes to TEM-based chemotherapy in patients with NET.<\/jats:p>","DOI":"10.3390\/curroncol30020106","type":"journal-article","created":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T03:04:44Z","timestamp":1674011084000},"page":"1381-1394","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Prospective Evaluation of MGMT-Promoter Methylation Status and Correlations with Outcomes to Temozolomide-Based Chemotherapy in Well-Differentiated Neuroendocrine Tumors"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1187-5481","authenticated-orcid":false,"given":"Nicole","family":"Brighi","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \u201cDino Amadori\u201d, 47014 Meldola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3069-7630","authenticated-orcid":false,"given":"Giuseppe","family":"Lamberti","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine, Sant\u2019Orsola-Malpighi University Hospital, ENETS Center of Excellence, 40138 Bologna, Italy"},{"name":"Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via P. Albertoni 15, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2952-1507","authenticated-orcid":false,"given":"Elisa","family":"Andrini","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine, Sant\u2019Orsola-Malpighi University Hospital, ENETS Center of Excellence, 40138 Bologna, Italy"},{"name":"Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via P. Albertoni 15, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Mosconi","sequence":"additional","affiliation":[{"name":"Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Manuzzi","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine, Sant\u2019Orsola-Malpighi University Hospital, ENETS Center of Excellence, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giada","family":"Donati","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine, Sant\u2019Orsola-Malpighi University Hospital, ENETS Center of Excellence, 40138 Bologna, Italy"},{"name":"Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via P. Albertoni 15, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7724-7402","authenticated-orcid":false,"given":"Andrea","family":"Lisotti","sequence":"additional","affiliation":[{"name":"Gastroenterology Unit, Hospital of Imola, University of Bologna, 40026 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4615-7340","authenticated-orcid":false,"given":"Davide","family":"Campana","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine, Sant\u2019Orsola-Malpighi University Hospital, ENETS Center of Excellence, 40138 Bologna, Italy"},{"name":"Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via P. Albertoni 15, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1002\/cncr.25425","article-title":"First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas","volume":"117","author":"Strosberg","year":"2011","journal-title":"Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s00280-012-2055-z","article-title":"Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: The Pancreas Center at Columbia University experience","volume":"71","author":"Fine","year":"2013","journal-title":"Cancer Chemother. 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