Mitotane treatment in adrenocortical carcinoma: mechanisms of action and predictive markers of response to therapy

2021 ◽  
Author(s):  
Barbara ALTIERI ◽  
Enzo LALLI ◽  
Antongiulio FAGGIANO
Keyword(s):  
Adrenocortical Carcinoma ◽  
Mechanisms Of Action ◽  
Predictive Markers ◽  
Response To Therapy

scholarly journals Effects of Germline CYP2W1*6 and CYP2B6*6 Single Nucleotide Polymorphisms on Mitotane Treatment in Adrenocortical Carcinoma: A Multicenter ENSAT Study

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 359 ◽  
Author(s):  
Barbara Altieri ◽  
Silviu Sbiera ◽  
Sabine Herterich ◽  
Silvia De Francia ◽  
Silvia Della Casa ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Therapeutic Range ◽  
Adrenocortical Carcinoma ◽  
Plasma Concentrations ◽  
Response To Therapy ◽  
Blood Levels ◽  
Individual Response ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Group B

Mitotane is the only approved drug for advanced adrenocortical carcinoma (ACC) and no biomarkers are available to predict attainment of therapeutic plasma concentrations and clinical response. Aim of the study was to evaluate the suitability of cytochrome P450(CYP)2W1 and CYP2B6 single nucleotide polymorphisms (SNPs) as biomarkers. A multicenter cohort study including 182 ACC patients (F/M = 121/61) treated with mitotane monotherapy after radical resection (group A, n = 103) or in not completely resectable, recurrent or advanced disease (group B, n = 79) was performed. CYP2W1*2, CYP2W1*6, CYP2B6*6 and CYP2B6 rs4803419 were genotyped in germline DNA. Mitotane blood levels were measured regularly. Response to therapy was evaluated as time to progression (TTP) and disease control rate (DCR). Among investigated SNPs, CYP2W1*6 and CYP2B6*6 correlated with mitotane treatment only in group B. Patients with CYP2W1*6 (n = 21) achieved less frequently therapeutic mitotane levels (>14 mg/L) than those with wild type (WT) allele (76.2% vs 51.7%, p = 0.051) and experienced shorter TTP (HR = 2.10, p = 0.019) and lower DCR (chi-square = 6.948, p = 0.008). By contrast, 55% of patients with CYP2B6*6 vs. 28.2% WT (p = 0.016) achieved therapeutic range. Combined, a higher rate of patients with CYP2W1*6WT+CYP2B6*6 (60.6%) achieved mitotane therapeutic range (p = 0.034). In not completely resectable, recurrent or advanced ACC, CYP2W1*6 SNP was associated with a reduced probability to reach mitotane therapeutic range and lower response rates, whereas CYP2B6*6 correlated with higher mitotane levels. The association of these SNPs may predict individual response to mitotane.

Circulating tumor cells as prognostic and predictive markers in neuroendocrine tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4123-4123 ◽  
Author(s):  
Mohid Shakil Khan ◽  
Theodora Tsigani ◽  
Jorge Garcia-Hernandez ◽  
John Anthony Hartley ◽  
Martyn E Caplin ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Neuroendocrine Tumors ◽  
Cox Regression ◽  
Somatostatin Analogues ◽  
Predictive Markers ◽  
Response To Therapy ◽  
Unknown Primary ◽  
Cellsearch System ◽  
Therapeutic Trials

4123 Background: Neuroendocrine tumors (NETs) are a heterogeneous group of tumors with variable survival. While Ki67 in tumour tissue is prognostic, there have been no prospectively validated circulating prognostic or predictive markers. Here we present results from a large prospective study of circulating tumor cells (CTCs) in patients with NETs. Methods: Patients about to commence therapy had a 7.5 ml blood sample taken at baseline with additional samples taken at 3-5 weeks after commencing treatment. CTCs were enumerated using the CellSearch system and counted independently by two observers. Radiological response was classified according to RECIST 1.1. PFS and OS were measured from start date of therapy, to date of progression and date of death, respectively. In order to define a prognostic cut off value for CTCs, 90 patients were enrolled in a training set and 85 patients in a validation set. The optimal cut-off level validated was CTC≥1. Prognostic factors including Ki67 were evaluated using Cox regression. Changes in CTCs after treatment were divided into tertiles. Results: 138 patients with metastatic NET (31 pancreatic, 81 midgut, 12 bronchopulmonary, 11 unknown primary, 3 hindgut) were recruited who were about to undergo treatment with somatostatin analogues(34), chemotherapy(28), PRRT(40), TAE(18), RFA(3), Sunitinib(4), interferon(4) and surgery(7). Median follow-up was 9.7 months (range 5-29). Patients with baseline CTC≥1 had significantly worse PFS (HR 4.3 95%CI 1.8-10.3), and OS (HR 6.1 95%CI 1.8-20.3) than those without CTCs. In multivariate analysis CTC presence was associated with worse PFS (HR 3.7 95%CI 1.5-8.9) and OS (HR 5.1 95%CI1.5-7.3). Changes in CTCs predicted response to therapy (Fisher’s exact p<0.001) and those with increase in CTCs by ≥33% post-therapy had significantly worse PFS (HR 23.1 95%CI 5.37-99.0) and OS (HR18.9 95%CI 2.4-146) than a fall or <33% increase. Conclusions: In metastatic NETs, CTCs are a promising prognostic marker and may be an early marker of response to therapy. Further evaluation of CTCs in the context of therapeutic trials is required.

scholarly journals SAT-175 Trial in Progress Interim Report: A Phase II Clinical Trial Using Single Agent Cabozantinib in Advanced Adrenocortical Carcinoma

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Sara Shokry Daniel Bedrose ◽  
Lina Altameemi ◽  
Marilyne Daher ◽  
Gina Tamsen De Rosa ◽  
Jeena Mary Varghese ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Phase Ii ◽  
Adrenocortical Carcinoma ◽  
Hypertensive Crisis ◽  
Response To Therapy ◽  
Phase Ii Clinical Trial ◽  
Study Endpoint ◽  
Close Monitoring ◽  
Grade 3

Abstract BACKGROUND: Adrenocortical carcinoma (ACC) in an aggressive malignancy with suboptimal response to frontline chemotherapy and without established second line treatment. cMET activation is associated with ACC resistance to chemotherapy. Cabozantinib is a multi-kinase inhibitor that targets the VEGFR, c-MET, AXL, and RET receptors. We report interim data about using cabozantinib in ACC through a prospective phase II clinical trial. Methods: This is an investigator-initiated, open label clinical trial to evaluate the efficacy and safety of cabozantinib in patients with unresectable/metastatic ACC (ClinicalTrials.gov Identifier: NCT03370718). The primary objective is 4-month progression-free survival rate (PFS4). Participants are ≥ 18 years old with histologically confirmed ACC. Subjects who used mitotane within 6 months of consent must have mitotane serum level of &lt; 2 mg/L. Cabozantinib starting dose is 60 mg daily with possible dose reductions. Subjects stopped treatment at time of disease progression, death, or occurrence of severe adverse events. Objective tumor responses were assessed per RECIST v.1.1 criteria. Adverse effects were graded per CTCAE v.4.03 Results: At time of data cut off (Oct 28, 2019), we screened 16 patients for enrollment. Ten patients (3 females) received cabozantinib out of whom 5 had history of mitotane use. Nine patients were eligible for response evaluation, defined as having at least one follow up imaging. One patient was taken off study after one week due to hypertensive crisis. Median age at time of diagnosis was 45 years (range 32 - 72). Five patients had hormonally active ACC. Median number of prior lines of systemic therapy was 2 (range 0 -5). Median duration of cabozantinib therapy was 6.6 months (range 0.7 -11.3). Eight patients (80%) were without evidence of progression at 4 months (achieved study endpoint). At time of data cut off, 1 patient had partial response (53% reduction over 8.8 months and ongoing), 3 patients had stable disease, and 5 patients had progressive disease. Nine patients were alive with disease and one patient died (not drug related). Grade 3/4 clinical adverse events included thromboembolic events (3 patients), severe hypertension (1 patient), intracranial hemorrhage secondary to hypertensive crisis (1 patient), weight loss (1 patient), and abdominal pain (1 patient). Grade 3/4 laboratory adverse events included increased AST (2 patient), increased ALT (1 patient), increased GGT, increased amylase (1 patient), increased lipase (1 patient) and hyponatremia (1 patient). Conclusions: In this interim analysis of phase II study, majority of subjects reached the study primary endpoint (PFS4). These data are in favor of continuing study accrual to assess magnitude of response to therapy and safety profile in ACC. Aggressive blood pressure management and close monitoring of liver enzymes are crucial to ensure the safety of study subjects.

Possible Predictive Markers of Response to Therapy in Esophageal Squamous Cell Cancer

2017 ◽  
Vol 25 (1) ◽  
pp. 279-288 ◽  
Author(s):  
Laszló Zoltan ◽  
Robert Farkas ◽  
Andrew V. Schally ◽  
Eva Pozsgai ◽  
Andras Papp ◽  
...  
Keyword(s):  
Squamous Cell ◽  
Squamous Cell Cancer ◽  
Cell Cancer ◽  
Predictive Markers ◽  
Response To Therapy ◽  
Esophageal Squamous Cell Cancer

520: Establishment of an Adrenocortical Carcinoma Cell Line (SO-RY), and its Characterization Including Adrenal Cortical Steroidogenesis

2005 ◽  
Vol 173 (4S) ◽  
pp. 141-142
Author(s):  
Yutaka Kamiyama ◽  
Hiroshi Okada ◽  
Koujiro Nishio ◽  
Takashi Yoshii ◽  
Keisuke Saito ◽  
...  
Keyword(s):  
Cell Line ◽  
Adrenocortical Carcinoma ◽  
Carcinoma Cell ◽  
Carcinoma Cell Line

Case Formulation and Design of Behavioral Treatment Programs

2003 ◽  
Vol 19 (3) ◽  
pp. 164-174 ◽  
Author(s):  
Stephen N. Haynes ◽  
Andrew E. Williams
Keyword(s):  
Functional Analysis ◽  
Behavior Problems ◽  
Behavioral Treatment ◽  
Clinical Case ◽  
Relative Magnitude ◽  
Mechanisms Of Action ◽  
Treatment Programs ◽  
Case Formulation ◽  
Functional Relations ◽  
Causal Variables

Summary: We review the rationale for behavioral clinical case formulations and emphasize the role of the functional analysis in the design of individualized treatments. Standardized treatments may not be optimally effective for clients who have multiple behavior problems. These problems can affect each other in complex ways and each behavior problem can be influenced by multiple, interacting causal variables. The mechanisms of action of standardized treatments may not always address the most important causal variables for a client's behavior problems. The functional analysis integrates judgments about the client's behavior problems, important causal variables, and functional relations among variables. The functional analysis aids treatment decisions by helping the clinician estimate the relative magnitude of effect of each causal variable on the client's behavior problems, so that the most effective treatments can be selected. The parameters of, and issues associated with, a functional analysis and Functional Analytic Clinical Case Models (FACCM) are illustrated with a clinical case. The task of selecting the best treatment for a client is complicated because treatments differ in their level of specificity and have unequally weighted mechanisms of action. Further, a treatment's mechanism of action is often unknown.

Enkephalin influences on behavioral and neural plasticity: Mechanisms of action.

1990 ◽  
Author(s):  
Joe L. Martinez ◽  
Patricia H. Janak ◽  
Susan B. Weinberger ◽  
Gery Schulteis
Keyword(s):  
Neural Plasticity ◽  
Mechanisms Of Action
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