Multivariable Prediction Model for Biochemical Response to First-Generation Somatostatin Receptor Ligands in Acromegaly

Abstract Context First-generation somatostatin receptor ligands (fg-SRLs) represent the mainstay of medical therapy for acromegaly, but they provide biochemical control of disease in only a subset of patients. Various pretreatment biomarkers might affect biochemical response to fg-SRLs. Objective To identify clinical predictors of the biochemical response to fg-SRLs monotherapy defined as biochemical response (insulin-like growth factor (IGF)-1 ≤ 1.3 × ULN (upper limit of normal)), partial response (>20% relative IGF-1 reduction without normalization), and nonresponse (≤20% relative IGF-1 reduction), and IGF-1 reduction. Design Retrospective multicenter study. Setting Eight participating European centers. Methods We performed a meta-analysis of participant data from 2 cohorts (Rotterdam and Liège acromegaly survey, 622 out of 3520 patients). Multivariable regression models were used to identify predictors of biochemical response to fg-SRL monotherapy. Results Lower IGF-1 concentration at baseline (odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.72–0.95 IGF-1 ULN, P = .0073) and lower bodyweight (OR = 0.99, 95% CI 0.98–0.99 kg, P = .038) were associated with biochemical response. Higher IGF-1 concentration at baseline (OR = 1.40, (1.19–1.65) IGF-1 ULN, P ≤ .0001), the presence of type 2 diabetes (oral medication OR = 2.48, (1.43–4.29), P = .0013; insulin therapy OR = 2.65, (1.02–6.70), P = .045), and higher bodyweight (OR = 1.02, (1.01–1.04) kg, P = .0023) were associated with achieving partial response. Younger patients at diagnosis are more likely to achieve nonresponse (OR = 0.96, (0.94–0.99) year, P = .0070). Baseline IGF-1 and growth hormone concentration at diagnosis were associated with absolute IGF-1 reduction (β = 0.90, standard error (SE) = 0.02, P ≤ .0001 and β = 0.002, SE = 0.001, P = .014, respectively). Conclusion Baseline IGF-1 concentration was the best predictor of biochemical response to fg-SRL, followed by bodyweight, while younger patients were more likely to achieve nonresponse.

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MRI follow‐up of patients with acromegaly treated after surgery with first‐generation somatostatin receptor ligands

Clinical Endocrinology ◽

10.1111/cen.14539 ◽

2021 ◽

Author(s):

Naia Grandgeorge ◽

Giovanni Barchetti ◽

Solange Grunenwald ◽

Fabrice Bonneville ◽

Philippe Caron

Keyword(s):

First Generation ◽

Somatostatin Receptor ◽

Receptor Ligands ◽

Somatostatin Receptor Ligands

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MON-320 Inter-Rater Reliability of T2 MRI Intensity of Somatotroph Adenomas; Endocrinologists vs. Neuroradiologist Pilot Study

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.970 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Elena V Varlamov ◽

José Miguel Hinojosa-Amaya ◽

Dawn Lim Shao Ting ◽

Maria Fleseriu ◽

Joao Prola

Keyword(s):

White Matter ◽

Pilot Study ◽

Medical Therapy ◽

Somatostatin Receptor ◽

Biochemical Response ◽

Receptor Ligands ◽

Rater Reliability ◽

Post Surgery ◽

Somatostatin Receptor Ligands ◽

T2 Mri

Abstract Background MRI T2 hypointensity of growth hormone (GH) secreting pituitary adenomas (PA) has been associated with better biochemical response to somatostatin receptor ligands and has been suggested to be useful in selecting patients with expected favorable response for pre- and post-surgery medical therapy. However, in most imaging centers, T2 intensity measurement is not part of standard neuroradiologist (NR) reporting. Objective To assess whether endocrinologists (Es) can reliably measure PA T2 signal intensity by calculating inter-rater reliability between Es and NR. Methods Retrospective review of MRI in 20 patients with pituitary somatotroph macroadenoma randomly selected from an IRB-approved PA database who had preoperative MRI available. T2 MRI intensity of the solid portion of the PA was compared to the temporal gray matter (GM) and white matter (WM): hypo- (PA< WM), hyper- (PA> GM), and isointense (WM <PA <GM). Measurements were performed separately by a NR and by two Es trained to take measurements by the same NR. Statistics: SPSS 25; Cohen kappa (κ). Results Patient mean age was 47 ± 20 years, with 12 females; mean largest PA diameter was 22.6 mm (range 11-45 mm). NR measured 12 hyper-, 7 iso- and 1 hypo-intense PA. Agreement was moderate between NR and E#1 (κ 0.72, 95%CI 0.751-1.0, p<0.001) and NR and E#2 (κ 0.638, 95%CI 0.351-0976, p<0.001) and strong between E#1 and E#2 (κ=0.90, 95%CI 0.309-0.903, p=0.001). Hypointense PA (by NR) was read by both Es as isointense. One hyperintense PA (by NR) was read by both Es as isointense. One isointense PA was read by E#2 as hypointense. Overall adenomas were; 9 densely granulated GH, 5 sparsely granulated GH, 3 mixed GH and prolactin, 1 plurihormonal, 1 not classified, and 1 no surgical intervention. Discussion Inter-rater reliability between the 2 Es was strong, however, it was moderate between each E and the NR. Factors that likely contributed to difference in measurement are heterogeneity of the PA, MRI quality, selection bias in choosing “most appropriate” site to measure intensity of adenoma, gray and white matter. Es could be trained to interpret the T2 intensity, although reliability with NR is only moderate. Interestingly, in this sample majority of T2 PA were hyperintense, but densely granulated, suggesting that preoperative identification of densely granulated tumors, which are also predictive of favorable SRL response, might be limited. More studies are needed to assess T2 correlation with pathology. Conclusion As T2 intensity (hyper-, hypo- or iso-) on MRI might be predictive of biochemical response to medical therapy in some patients with PA, we recommend T2 intensity to be part of neuroradiology reporting protocol. Our pilot study showed that endocrinologists could read MRIs after adequate training, but there is only moderate correlation with neuroradiologists.

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The future of somatostatin receptor ligands in acromegaly

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab726 ◽

2021 ◽

Author(s):

Monica R Gadelha ◽

Luiz Eduardo Wildemberg ◽

Leandro Kasuki

Keyword(s):

Precision Medicine ◽

First Generation ◽

Somatostatin Receptor ◽

New Drugs ◽

Response To Treatment ◽

Tumor Shrinkage ◽

Receptor Ligands ◽

Biochemical Control ◽

Somatostatin Receptor Ligands ◽

The Future

Abstract Currently, first-generation somatostatin receptor ligands (fg-SRLs), octreotide LAR and lanreotide autogel, are the mainstays of acromegaly treatment and achieve biochemical control in approximately 40% of patients and tumor shrinkage in over 60% of patients. Pasireotide, a second-generation SRL, shows higher efficacy with respect to both biochemical control and tumor shrinkage but has a worse safety profile. In this review, we discuss the future perspectives of currently available SRLs, focusing on the use of biomarkers of response and precision medicine, new formulations of these SRLs and new drugs, which are under development. Precision medicine, which is based on biomarkers of response to treatment, will help guide the decision-making process by allowing physicians to choose the appropriate drug for each patient and improving response rates. New formulations of available SRLs, such as oral, subcutaneous depot and nasal octreotide, may improve patients’ adherence to treatment and quality of life since there will be more options available that better suit each patient. Finally, new drugs, such as paltusotine, somatropin, ONO-5788 and ONO-ST-468, may improve treatment adherence and present higher efficacy than currently available drugs.

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Machine Learning-based Prediction Model for Treatment of Acromegaly With First-generation Somatostatin Receptor Ligands

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab125 ◽

2021 ◽

Author(s):

Luiz Eduardo Wildemberg ◽

Aline Helen da Silva Camacho ◽

Renan Lyra Miranda ◽

Paula C L Elias ◽

Nina R de Castro Musolino ◽

...

Keyword(s):

Machine Learning ◽

Support Vector Machine ◽

Prediction Model ◽

Predictive Value ◽

First Generation ◽

Somatostatin Receptor ◽

Support Vector ◽

Receptor Ligands ◽

Somatostatin Receptor Ligands ◽

Igf I

Abstract Context Artificial intelligence (AI), in particular machine learning (ML), may be used to deeply analyze biomarkers of response to first-generation somatostatin receptor ligands (fg-SRLs) in the treatment of acromegaly. Objective To develop a prediction model of therapeutic response of acromegaly to fg-SRL. Methods Patients with acromegaly not cured by primary surgical treatment and who had adjuvant therapy with fg-SRL for at least 6 months after surgery were included. Patients were considered controlled if they presented growth hormone (GH) <1.0 ng/mL and normal age-adjusted insulin-like growth factor (IGF)-I levels. Six AI models were evaluated: logistic regression, k-nearest neighbor classifier, support vector machine, gradient-boosted classifier, random forest, and multilayer perceptron. The features included in the analysis were age at diagnosis, sex, GH, and IGF-I levels at diagnosis and at pretreatment, somatostatin receptor subtype 2 and 5 (SST2 and SST5) protein expression and cytokeratin granulation pattern (GP). Results A total of 153 patients were analyzed. Controlled patients were older (P = .002), had lower GH at diagnosis (P = .01), had lower pretreatment GH and IGF-I (P < .001), and more frequently harbored tumors that were densely granulated (P = .014) or highly expressed SST2 (P < .001). The model that performed best was the support vector machine with the features SST2, SST5, GP, sex, age, and pretreatment GH and IGF-I levels. It had an accuracy of 86.3%, positive predictive value of 83.3% and negative predictive value of 87.5%. Conclusion We developed a ML-based prediction model with high accuracy that has the potential to improve medical management of acromegaly, optimize biochemical control, decrease long-term morbidities and mortality, and reduce health services costs.

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A Phase 3 Large International Noninferiority Trial (MPOWERED): Assessing Maintenance of Response to Oral Octreotide Capsules in Comparison to Injectable Somatostatin Receptor Ligands

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1056 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A517-A517

Author(s):

Maria Fleseriu ◽

Alexander V Dreval ◽

Yulia Pokramovich ◽

Irina Bondar ◽

Elena Isaeva ◽

...

Keyword(s):

Somatostatin Receptor ◽

Safety Data ◽

Biochemical Response ◽

Receptor Ligands ◽

Phase 3 ◽

Landmark Analysis ◽

End Point ◽

Noninferiority Trial ◽

Somatostatin Receptor Ligands ◽

Igf I

Abstract Background: MPOWERED, a large phase 3 trial, assessed maintenance of response to oral octreotide capsules (OOC; MYCAPSSA®) compared to injectable somatostatin receptor ligands (iSRLs) in patients with acromegaly who responded to OOC and iSRLs (octreotide or lanreotide). OOC were recently approved in the US for patients with acromegaly who responded to and tolerated iSRLs. Methods: Eligibility criteria included age 18-75 years at screening, acromegaly diagnosis, disease evidence, biochemical control (insulin-like growth factor I [IGF-I] <1.3 × upper limit of normal [ULN] and mean integrated growth hormone [GH] <2.5 ng/mL) at screening, and ≥6 months’ iSRL treatment. Effective OOC dose was determined in a 26-week Run-in phase. Eligible patients (IGF-I <1.3 × ULN and mean integrated GH <2.5 ng/mL, week 24) were randomized to a 36-week controlled treatment phase (RCT), receiving OOC or iSRLs starting at week 26. The primary end point was a noninferiority assessment of proportion of patients biochemically controlled in the RCT (IGF-I <1.3 × ULN using time-weighted average). Other end points included nonresponse imputation of the primary end point, landmark analysis using proportion of responders based on average of last 2 IGF-I values at end of RCT, and change from baseline RCT (week 26) IGF-I and GH levels. Results: Of 146 enrolled patients, 92 entered the RCT (OOC, n=55; iSRLs, n=37). Both arms were well balanced for age, sex, and acromegaly duration. OOC demonstrated noninferiority to iSRLs in maintaining biochemical response, with 91% (CI, 80%-97%) of OOC and 100% (CI, 91%-100%) of iSRL groups maintaining control during the RCT. Of those responding at end of Run-in, 96% of patients on OOC maintained response during RCT. Using nonresponse imputation, 89% of OOC and 95% of iSRL groups were biochemically controlled in RCT. Landmark analysis of those respnding at end of Run-in showed that 94% of patients in each group maintained response at RCT end. In both groups, IGF-I levels were stable in the RCT, average IGF-I at baseline and RCT end being 0.9 × ULN (OOC) and 0.8 × ULN (iSRL). Mean change in GH from RCT start to RCT end was -0.03 ng/mL (OOC) and +0.29 ng/mL (iSRL). Safety data were mostly similar between groups; the OOC group did not experience injection site reactions. Conclusion: In this noninferiority trial in patients with acromegaly, OOC demonstrated maintenance of biochemical response compared to iSRLs. Results support the efficacy of OOC as a possible iSRL alternative.

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gsp Mutation Is Not a Molecular Biomarker of Long-Term Response to First-Generation Somatostatin Receptor Ligands in Acromegaly

Cancers ◽

10.3390/cancers13194857 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4857

Author(s):

Luiz Eduardo Wildemberg ◽

Daniel Henriques ◽

Paula C. L. Elias ◽

Carlos Henrique de A. Lima ◽

Nina R. de Castro Musolino ◽

...

Keyword(s):

First Generation ◽

Somatostatin Receptor ◽

Receptor Ligands ◽

Biochemical Control ◽

Molecular Biomarker ◽

Α Subunit ◽

Cavernous Sinus Invasion ◽

Somatostatin Receptor Ligands ◽

Term Response

Background: It is still controversial if activating mutations in the stimulatory G-protein α subunit (gsp mutation) are a biomarker of response to first generation somatostatin receptor ligands (fg-SRL) treatment in acromegaly. Thus, we aimed to evaluate whether gsp mutation predicts long-term response to fg-SRL treatment and to characterize the phenotype of patients harboring gsp mutations. Methods: GNAS1 sequencing was performed by Sanger. SST2 and SST5 were analyzed by immunohistochemistry (IHC) and real-time RT-PCR. The cytokeratin granulation pattern was evaluated by IHC. Biochemical control was defined as GH < 1.0 ng/mL and normal age-adjusted IGF-I levels. Results: gsp mutation was found in 54 out of 136 patients evaluated. Biochemical control with fg-SRL treatment was similar in gsp+ and gsp- patients (37% vs. 25%, p = 0.219). Tumors harboring gsp mutation were smaller (p = 0.035) and had a lower chance of invading cavernous sinuses (p = 0.001). SST5 protein (p = 0.047) and mRNA (p = 0.013) expression levels were higher in wild-type tumors. Conclusions: In this largest series available in the literature, we concluded that gsp is not a molecular biomarker of response to fg-SRL treatment in acromegaly. However, the importance of its negative association with cavernous sinus invasion and SST5 expression needs to be further investigated.

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Pasireotide in the Personalized Treatment of Acromegaly

Frontiers in Endocrinology ◽

10.3389/fendo.2021.648411 ◽

2021 ◽

Vol 12 ◽

Author(s):

Manel Puig-Domingo ◽

Ignacio Bernabéu ◽

Antonio Picó ◽

Betina Biagetti ◽

Joan Gil ◽

...

Keyword(s):

First Generation ◽

Somatostatin Receptor ◽

Receptor Ligands ◽

First Line ◽

First Line Therapy ◽

Somatostatin Receptor Ligands ◽

Therapeutic Algorithm ◽

Surgical Failure ◽

Positive Effect ◽

T2 Mri

The delay in controlling the disease in patients who do not respond to first-line treatment with first generation somatostatin receptor ligands (first-generation SRLs) can be quantified in years, as every modification in the medical therapy requires some months to be fully evaluated. Considering this, acromegaly treatment should benefit from personalized medicine therapeutic approach by using biomarkers identifying drug response. Pasireotide has been positioned mostly as a compound to be used in first-generation SRLs resistant patients and after surgical failure, but sufficient data are now available to indicate it is a first line therapy for patients with certain characteristics. Pasireotide has been proved to be useful in patients in which hyperintensity T2 MRI signal is shown and in those depicting low SST2 and high expression of SST5, low or mutated AIP condition and sparsely granulated immunohistochemical pattern. This combination of clinical and pathological characteristics is unique for certain patients and seems to cluster in the same cases, strongly suggesting an etiopathogenic link. Thus, in this paper we propose to include this clinico-pathologic phenotype in the therapeutic algorithm, which would allow us to use as first line medical treatment those compounds with the highest potential for achieving the fastest control of GH hypersecretion as well as a positive effect upon tumor shrinkage, therefore accelerating the implementation of precision medicine for acromegaly. Moreover, we suggest the development, validation and clinical use of a pasireotide acute test, able to identify patients responsive to pasireotide LAR as the acute octreotide test is able to do for SRLs.

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Clinical and Radiological Predictors of Biochemical Response to First-Line Treatment With Somatostatin Receptor Ligands in Acromegaly: A Real-Life Perspective

Frontiers in Endocrinology ◽

10.3389/fendo.2021.677919 ◽

2021 ◽

Vol 12 ◽

Author(s):

Federica Nista ◽

Giuliana Corica ◽

Lara Castelletti ◽

Keyvan Khorrami ◽

Claudia Campana ◽

...

Keyword(s):

Logistic Regression ◽

Somatostatin Receptor ◽

Biochemical Response ◽

Line Treatment ◽

Receptor Ligands ◽

First Line ◽

Multivariable Logistic Regression ◽

Somatostatin Receptor Ligands ◽

Younger Age ◽

First Line Treatment

BackgroundFirst-generation somatostatin receptor ligands (fg-SRLs) represent the first-line medical treatment for acromegaly, recommended in patients with persistent disease after neurosurgery, or when surgical approach is not feasible. Despite the lack of strong recommendations from guidelines and consensus statements, data from national Registries report an increasing use of medical therapy as first-line treatment in acromegaly.ObjectiveWe retrospectively evaluated the potential role of a large number of clinical and radiological parameters in predicting the biochemical response to 6-month treatment with fg-SRLs, in a cohort of naïve acromegaly patients referred to a single tertiary center for pituitary diseases.MethodsUnivariable and multivariable logistic regression and linear regression analyses were performed. Biochemical response was defined based on IGF-1 levels, represented as both categorical (tight control, control, >50% reduction) and continuous (linear % reduction) variables.ResultsFifty-one patients (33 females, median age 57 years) were included in the study. At univariable logistic regression analysis, we found that younger age (≤ 40 years; OR 0.04, p=0.045) and higher BMI (OR 0.866, p=0.034) were associated with a lower chance of achieving >50% IGF-1 reduction. On the contrary, higher IGF-1 xULN values at diagnosis (OR 2.304, p=0.007) and a T2-hypointense tumor (OR 18, p=0.017) were associated with a significantly higher likelihood of achieving >50% IGF-1 reduction after SRL therapy. Of note, dichotomized age, IGF1 xULN at diagnosis, and T2-hypointense signal of the tumor were retained as significant predictors by our multivariable logistic regression model. Furthermore, investigating the presence of predictors to the linear % IGF-1 reduction, we found a negative association with younger age (≤ 40 years; β -0.533, p<0.0001), while a positive association was observed with both IGF-1 xULN levels at diagnosis (β 0.330, p=0.018) and the presence of a T2-hypointense pituitary tumor (β 0.466, p=0.019). All these variables were still significant predictors at multivariable analysis.ConclusionsDichotomized age, IGF-1 levels at diagnosis, and tumor T2-weighted signal are reliable predictors of both >50% IGF-1 reduction and linear % IGF-1 reduction after 6 month fg-SRL treatment in naïve acromegaly patients. These parameters should be considered in the light of an individualized treatment for acromegaly patients.

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COMPARATIVE EFFICACY OF MEDICAL TREATMENT FOR ACROMEGALY: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS OF INTEGRATED RANDOMIZED TRIALS AND OBSERVATIONAL STUDIES

Endocrine Practice ◽

10.4158/ep-2019-0528 ◽

2020 ◽

Vol 26 (4) ◽

pp. 454-462 ◽

Cited By ~ 1

Author(s):

Nidan Qiao ◽

Min He ◽

Ming Shen ◽

Qilin Zhang ◽

Zhaoyun Zhang ◽

...

Keyword(s):

Growth Factor ◽

Observational Studies ◽

Randomized Trials ◽

Meta Analysis ◽

Somatostatin Receptor ◽

Credible Interval ◽

Receptor Ligands ◽

Somatostatin Receptor Ligands ◽

The Mean ◽

Long Acting

Objective: Comprehensive evidence comparing different medications for acromegaly is scarce. The aim of this study was to perform a network meta-analysis based on evidence from both randomized trials and observational studies of medical treatments for acromegaly. Methods: Electronic databases were searched for both observational studies and randomized trials that enrolled acromegaly patients treated with medications of interest. Simulated trials were generated by a machine learning algorithm and then synthesized with Bayesian random-effects network meta-analyses. The main outcome was the rate of insulin-like growth factor 1 (IGF-1) control after medical treatment. Results: We included 90 studies (100 arms, 4,523 patients) before matching. After matching, 28 simulated trials were generated. Balance of matched arms was checked by spatial distance and correlation matrix. Cotreatment with somatostatin receptor ligands and pegvisomant was the most effective treatment compared with other treatments. In unselected patients, pegvisomant was better than octreotide long-acting release (logOR, 0.85; 95% credible interval [CrI], 0.05 to 1.65) or lanreotide (logOR, 1.09, 95% CrI, 0.05 to 2.14), and the mean absolute IGF-1 control rate ranged from 40 to 60%. In partially responsive patients, cotreatment with somatostatin receptor ligands and pegvisomant was similar to pegvisomant monotherapy, ranking as the most two effective treatments, and the mean absolute IGF-1 control rate was over 60%. Conclusion: Our analysis suggested that the combination of data from observational studies and randomized trials in network meta-analysis was feasible. The findings of this network meta-analysis provided robust evidence supporting the current guidelines in treatment strategy for acromegaly. Abbreviations: CrI = credible interval; DA = dopamine agonist; GH = growth hormone; IGF-1 = insulin-like growth factor 1; ITT = intention-to-treat; LAN = lanreotide; LAN-ATG = lanreotide autogel; OCT = octreotide; OCT-LAR = octreotide long acting repeatable; OR = odds ratio; PEG = pegvisomant; PP = per-protocol; SRL = somatostatin receptor ligand

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