Efficacy and safety of aranoza-based therapy in neuroendocrine neoplasms. Prognostic role of O6-methylguanine DNA methyltransferase expression in tumor tissue

2016 ◽  
Vol 21 (6) ◽  
pp. 293-299
Author(s):  
Svetlana A. Polozkova ◽  
V. A Gorbunova ◽  
V. V Delektorskaya ◽  
N. F Orel ◽  
N. A Kozlov ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Tumor Tissue ◽  
Objective Response ◽  
Chemotherapy Resistance ◽  
Progression Free Survival ◽  
Neuroendocrine Neoplasms ◽  
Mgmt Expression ◽  
Methylguanine Dna Methyltransferase ◽  
Tumor Focus ◽  
The Impact

Aranoza (3-a-L-arabinopyranosyl-1-methyl-nitrosourea) is nitrosourea derivative, as streptozotocin STZ. O6-methylguanine DNA methyltransferase (MGMT) is an enzyme involved in chemotherapy resistance to alkalyting agents. Material and methods. There were observed 117patients with neuroendocrine neoplasms (NENs) received Aranoza-based therapy. They included 52 cases with pancreatic neuroendocrine tumors (P-NETs), 52 patients with non-pancreatic (notP-NETs, 13 NET patients with metastases without revealed primary tumor focus). There was investigated the radiologic response to the treatment according to Response Evaluation Criteria In Solid Tumors (RECIST) Score, version 1.0), biochemical response, median progression-free survival (PFS) by Kaplan-Meier estimator), toxicity (according to Common Terminology Criteria for Adverse Events (CTCAE), version 3.0) and the impact of MGMT expression (immunohistochemistry method) in tumor tissue on the efficacy of the treatment. Results. Objective response rate (ORR) in PNET cases accounted for 39% (20/52) whereas in nonP-NETpatients - 12% (6/52) (p = 0.0032). Median PFS accounted for 15.3 months in PNET patients and 16.6 months in non-PNET cases (p = 0.78). The most common types of the toxicity grade III-IV included thrombocytopenia (17from 871 courses) and neutropenia (11 from 871 courses). In samples of the tumor tissue the lack of MGMT expression was observed in 29 out of 35 P-NET cases, 12 out of 31 non-PNET cases (p = 0,0006). Objective response was recorded in 20 of 44 patients with MGMT-deficient tumors and in 1 out of 27patients with MGMT intact tumors (p = 0.0001). In the lack and presence of the MGMT expression in the tumor tissue median PFS accounted for 20.6 months and 14.4 months correspondingly (p = 0,022). Conclusion. Aranoza-based therapy demonstrated an antitumor activity and good safety profile in NENpatientss. MGMT deficiency in PNETs was more common than in non-PNETs and explained the susceptibility of some PNETs to treatment.

scholarly journals Activity and safety of temozolomide in advanced adrenocortical carcinoma patients

2019 ◽  
Vol 181 (6) ◽  
pp. 681-689 ◽  
Author(s):  
Deborah Cosentini ◽  
Giuseppe Badalamenti ◽  
Salvatore Grisanti ◽  
Vittoria Basile ◽  
Ida Rapa ◽  
...  
Keyword(s):  
Disease Control ◽  
Dna Methyltransferase ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Disease Control Rate ◽  
Adrenocortical Cancer ◽  
Disease Response ◽  
Methylguanine Dna Methyltransferase

Objective Temozolomide has shown a significant anti-proliferative activity on adrenocortical cancer (ACC) cells in vitro. Design On the basis of these results the drug was prescribed as second/third line in advanced metastatic ACC patients in four referral centers in Italy. Methods We retrospectively collected anagraphic, clinical and pathological data of patients with advanced ACC with disease progression to standard chemotherapy plus mitotane who were treated with temozolomide at the dose of 200 mg/m2/die given for 5 consecutive days every 28 days. The primary endpoint was the disease control rate, defined as objective response or disease stabilization after 3 months. Secondary endpoints were overall survival (OS), progression-free survival (PFS) and drug safety. Results Twenty-eight patients have been included in the study. Ten patients (35.8%, 95% CI: 17.8–53.8) obtained a disease control from temozolomide treatment. In particular, 1 patient had a complete response, 5 patients a partial response and 4 patients stable disease. Median PFS was 3.5 months and median OS was 7.2 months. Disease response was more frequently observed in patients with methylation of O6-methylguanine-DNA methyltransferase (MGMT) gene. Temozolomide therapy was well tolerated and most toxicities were limited to grade G1–2 according to WHO criteria. Conclusion Temozolomide was found active in the management of advanced ACC patients. The disease control rate obtained, however, was short-lived and the prognosis of treated patients was poor.

scholarly journals Successful Second-Line Metronomic Temozolomide in Metastatic Paraganglioma: Case Reports and Review of the Literature

2018 ◽  
Vol 12 ◽  
pp. 117955491876336 ◽  
Author(s):  
Isabel Tena ◽  
Garima Gupta ◽  
Marcos Tajahuerce ◽  
Marta Benavent ◽  
Manuel Cifrián ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Tumor Tissue ◽  
Metabolic Response ◽  
Case Reports ◽  
Progression Free Survival ◽  
High Dose ◽  
Disease Treatment ◽  
Free Survival ◽  
Methylguanine Dna Methyltransferase

Metastatic pheochromocytoma and paraganglioma (mPHEO/PGL) are frequently associated with succinate dehydrogenase B ( SDHB) mutations. Cyclophosphamide-dacarbazine-vincristine (CVD) regimen is recommended as standard chemotherapy for advanced mPHEO/PGL. There is limited evidence to support the role of metronomic schemes (MS) of chemotherapy in mPHEO/PGL treatment. We report 2 patients with SDHB-related mPGL who received a regimen consisting of MS temozolomide (TMZ) and high-dose lanreotide after progression on both CVD chemotherapy and high-dose lanreotide. Molecular profiling of the tumor tissue from both patients revealed hypermethylation of the O6-methylguanine-DNA-methyltransferase ( MGMT) promoter. In one patient, progression-free survival was 13 months and the second patient remained under treatment after 27 months of stabilization of metabolic response of his disease. Treatment was well tolerated, and adverse effects were virtually absent. A modification in the scheme of TMZ from standard schemes to MS is safe and feasible and can be considered in patients with progressive mPHEO/PGL refractory to dacarbazine in standard doses.

Correlation Between O6-Methylguanine-DNA Methyltransferase and Survival in Inoperable Newly Diagnosed Glioblastoma Patients Treated With Neoadjuvant Temozolomide

2007 ◽  
Vol 25 (12) ◽  
pp. 1470-1475 ◽  
Author(s):  
Olivier L. Chinot ◽  
Maryline Barrié ◽  
Stephane Fuentes ◽  
Nathalie Eudes ◽  
Sophie Lancelot ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Mgmt Expression ◽  
Methylguanine Dna Methyltransferase ◽  
Common Grade ◽  
Newly Diagnosed Glioblastoma ◽  
Grade 3 ◽  
Dose Dense

Purpose This phase II study evaluated the efficacy and safety of a 7-day on/7-day off regimen of temozolomide before radiotherapy (RT) in patients with inoperable newly diagnosed glioblastoma. Patients and Methods Patients received temozolomide (150 mg/m2/d on days 1 to 7 and days 15 to 21 every 28 days; 7 days on/7 days off) for up to four cycles before conventional RT (2-Gy fractions to a total of 60 Gy) and for four cycles thereafter or until disease progression. The primary end point was tumor response. Tumor tissue from 25 patients was analyzed for O6-methylguanine-DNA methyltransferase (MGMT) expression. Results Twenty-nine patients with a median age of 60 years were treated, and 28 were assessable for response. Seven (24%) of 29 patients had a partial response, nine patients (31%) had stable disease, and 12 patients (41%) had progressive disease. Median progression-free survival (PFS) time was 3.8 months, and median overall survival (OS) time was 6.1 months. Patients with low MGMT expression, compared with patients with high MGMT expression, had a significantly higher response rate (55% v 7%, respectively; P = .004) and improved PFS (median, 5.5 v 1.9 months, respectively; P = .009) and OS (median, 16 v 5 months, respectively; P = .003). The most common grade 3 and 4 toxicities were thrombocytopenia (20%) and neutropenia (17%). Conclusion This dose-dense temozolomide regimen resulted in modest antitumor activity with an acceptable safety profile in the neoadjuvant setting, and expression of MGMT correlated with response to temozolomide. However, this treatment approach seems to be inferior to standard concomitant RT plus temozolomide.

scholarly journals MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors

2016 ◽  
Vol 23 (8) ◽  
pp. 625-633 ◽  
Author(s):  
J Cros ◽  
O Hentic ◽  
V Rebours ◽  
M Zappa ◽  
N Gille ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Stable Disease ◽  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Tumor Response ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Pancreatic Neuroendocrine Tumors ◽  
Mgmt Expression

Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). LowO6-methylguanine-DNA methyltransferase (MGMT) expression andMGMTpromoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression andMGMTpromoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0–300) andMGMTpromoter methylation by pyrosequencing. Forty-three patients (21 men, 58years (27–84)) with grade 1 WDPNET (n=6) or 2 (n=36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P=0.04) and better progression-free survival (PFS) (HR=0.35 (0.15–0.81),P=0.01). Disease control rate at 18months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. HighMGMTpromoter methylation was associated with a low MGMT expression and longer PFS (HR=0.37 (0.29–1.08),P=0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50–100) seems to be associated with prolonged stable disease.

Alkylating agent rechallenge in metastatic pancreatic neuroendocrine tumours

2021 ◽  
Author(s):  
Ophelie De Rycke ◽  
Thomas Walter ◽  
Marine Perrier ◽  
Olivia Hentic ◽  
Catherine Lombard-Bohas ◽  
...  
Keyword(s):  
Neuroendocrine Tumours ◽  
Objective Response ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Tumor Control ◽  
Free Survival ◽  
Mgmt Expression ◽  
Pancreatic Neuroendocrine Tumours

A rechallenge is common after initial efficacy of alkylating-based chemotherapy (ALK) in pancreatic neuroendocrine tumors (PanNET). High MGMT expression seems associated with lower response to ALK. We aimed to evaluate the efficacy and toxicity of ALK rechallenge in PanNET. Secondly, to assess the evolution of MGMT expression under ALK. All consecutive patients with advanced PanNETs who received initial ALK (achieving tumor control) followed by a pause > 3 months, then an ALK rechallenge (ALK2) upon progression were retrospectively studied (Cohort A). Primary endpoint was progression-free survival under ALK2 (PFS2). The MGMT expression was retrospectively assessed by immunohistochemistry (H-score) in consecutive PanNET surgically resected following ALK (Cohort B). We foud that cohort A included 62 patients (median Ki67 8%), for which ALK1 followed by pause achieved an objective response rate of 55%, and a PFS1 of 23.7 months (95% IC, 19.8-27.6). ALK2 achieved no objective response, and stability in 62% of patients. The median PFS2 was 9.2 months (IC 95% 7.1-11.3). At multivariable analysis, a hormonal syndrome (p=0.032) and a pause longer than 12 months (p=0.041) were associated with a longer PFS2. In the cohort B (17 patients), the median MGMT H-score increased from 45 (IQR 18-105) before ALK, to 100 (IQR 56-180) after ALK (p=0.003). We conclude that after initial efficacy of ALK treatment, a pause followed by ALK rechallenge might be appropriate to prolong tumor control, improve quality of life and limit long-term adverse events. Increased MGMT expression under ALK might explain low efficacy of ALK rechallenge.

Association of statins and nivolumab activity in patients with metastatic renal cell carcinoma (mRCC): Results from the phase II nivoren—GETUG AFU 26 trial.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 359-359
Author(s):  
Emeline Colomba ◽  
Ronan Flippot ◽  
Cécile Dalban ◽  
Sylvie Negrier ◽  
Christine Chevreau ◽  
...  
Keyword(s):  
Phase Ii ◽  
Immune Modulation ◽  
Performance Status ◽  
Objective Response ◽  
Progression Free Survival ◽  
Population Based ◽  
Metabolic Reprogramming ◽  
Oncogenic Signaling ◽  
Grade 3 ◽  
The Impact

359 Background: Statins are HMG-CoA inhibitors that regulate several mechanisms involved in tumor growth, including mitochondrial metabolism, activation of oncogenic signaling pathways, and immune modulation. Population-based studies showed that statin intake may be negatively associated with RCC onset. The impact of statins on response to immunotherapy in mRCC is unknown. Herein we study the association between statin administration and outcomes in patients with mRCC treated with nivolumab in the NIVOREN-GETUG AFU 26 phase II trial (NCT03013335). Methods: Patients with mRCC who failed previous VEGFR inhibitors were included. We assessed nivolumab activity, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) according to statin intake at baseline. Toxicity was assessed using CTCAE v4.0. Results: Overall,133 patients were treated with statins at baseline among 702 evaluable for concomitant therapies (19%). Among them, median age was 68 (49-90), 84% were male, 85% had a performance status ≥ 80%, 42% were overweight and 20% obese. Patients treated with statins had mostly good (23%) or intermediate (58%) IMDC risk, 64% had grade 3 or 4 tumors, and nivolumab was given in a third line setting or more in 55%. Median follow-up was 23.9 months (95%CI 23.0-24.5) in the overall cohort. The ORR was 26% in patients treated with statins, PFS 5.0 months (CI95% 3.0 – 5.5), OS 27.9 months (CI95% 19.4-30.3). Outcomes of patients with or without statins did not differ significantly. Similar rates of grade 3-5 TRAE were reported in patients with (20%) or without (18%) statin intake. Conclusions: This is the first study to evaluate statin intake and outcomes with nivolumab in patients with mRCC. Despite numerically higher ORR, statins were not significantly associated with improved outcomes. These data require other analyzes considering other factors such as BMI and other comorbidities. Further studies may help better understand the interplay between immunity and metabolic reprogramming in RCC.

scholarly journals Promising Immunotherapy in Metastatic Testicular Sex Cord Stromal Tumours After First-Line Chemotherapy

2022 ◽  
Vol 12 ◽  
Author(s):  
Bingqing Shang ◽  
Chuanzhen Cao ◽  
Weixing Jiang ◽  
Hongzhe Shi ◽  
Xingang Bi ◽  
...  
Keyword(s):  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Chemotherapy Resistance ◽  
Progression Free Survival ◽  
Retroperitoneal Lymph Node Dissection ◽  
First Line ◽  
Experienced Grade ◽  
Line Chemotherapy

BackgroundTesticular sex cord stromal tumours (TSCSTs) are rare, with few studies focusing on the metastatic TSCST prognosis. The value of treatments, including radical orchiectomy (RO) and retroperitoneal lymph node dissection (RPLND), in preventing metastasis is controversial. Additionally, metastatic TSCSTs are resistant to chemotherapy. We aimed to assess the effectiveness and safety of immunotherapy in metastatic TSCSTs after first-line chemotherapy.MethodsWe retrospectively screened patients with testicular tumours undergoing testis surgery between January 2005 and January 2019. Patients with TSCSTs who had undergone testis-sparing surgery (TSS) or RO were identified. The malignant type was defined as metastasis confirmed by pathology. Treatment responses, progression-free survival (PFS), overall survival (OS) and safety were analysed.ResultsAmong the 494 testicular tumour patients who received TSS or RO, 11 (2.2%) patients with histologically proven TSCSTs were identified. At the last follow-up, 7 patients survived without tumours, and 4 patients developed metastasis and received first-line cisplatin-based chemotherapy, with 1 of them achieving an objective response. Their PFS times were 1.5, 2.2, 9.0, and 17.0 months, respectively. Two patients received immune checkpoint inhibitors (ICIs) after developing chemotherapy resistance and achieved a partial response up to the last follow-up; one of them experienced Grade 1 adverse events, and the other experienced Grade 2 adverse events during immunotherapy. The median OS time of the 4 patients with metastatic TSCSTs was 32 months.ConclusionsTSCSTs are rare, and most are benign with a good prognosis. ICIs represent a promising option for improving clinical outcomes in metastatic TSCSTs.

scholarly journals MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

2020 ◽  
Author(s):  
Barbara Oldrini ◽  
Nuria Vaquero-Siguero ◽  
Quanhua Mu ◽  
Paula Kroon ◽  
Ying Zhang ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Chemotherapy Resistance ◽  
Glioma Cells ◽  
Promoter Hypermethylation ◽  
Dna Adduct ◽  
Genomic Rearrangements ◽  
Low Grade ◽  
Methylguanine Dna Methyltransferase

AbstractTemozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo. Lastly, we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.

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