ECE2018 Oral Communications The curious case of growth hormone (5 abstracts)
Molecular profiling for assistance to pharmacological treatment of acromegaly
Manuel Puig-Domingo 1 , Joan Gil 1 , Miguel Sampedro 2 , Susan M Webb 3 , Guillermo Serra 4 , Isabel Salinas 5 , Alberto Blanco 5 , Montse Marques-Pamies 6 , Antonio Pico 6 , Araceli García-Martínez 8 , Concepción Blanco 7 , Carlos Del Pozo 8 , Gabriel Obiols 9 , Cristina Alvarez-Escolá 10 , Rosa Cámara 11 , Carmen Fajardo 12 , Raúl Luque 13 , Justo Castaño 13 , Mercedes Robledo 14 , Mireia Jordà 15 , Ignacio Bernabéu 16 & Mónica Marazuela 17
1Institut Germans Trias i Pujol, Badalona, Spain; 2Hospital La Princesa, Madrid, Spain; 3Hospital de Sant Pau, Barcelona, Spain; 4Hospital Son Espases, Palma de Mallorca, Spain; 5Hospital Germans Trias, Badalona, Spain; 6Hospital General Universitario, Alicante, Spain; 7Hospital Príncipe de Asturias, Alacalá de Henares, Spain; 8Hospital Mutua, Terrassa, Spain; 9Hospital Vall d’Hebron, Barcelona, Spain; 10Hospital La Paz, Madrid, Spain; 11Hospital La Fe, Valencia, Spain; 12Hospital de la Ribera, Alzira, Spain; 13IMIBIC, Córdoba, Spain; 14CNIO, Madrid, Spain; 15Institut Germans Trias, Badalona, Spain; 16Complexo Hospitalario, Santiago de Compostela, Spain; 17Hospital de la Princesa, Madrid, Spain.
Pharmacologic treatment of acromegaly is currently based upon assay-error strategy in which first generation somatostatin analogs (SSA) is the first-line treatment. However, about 50% of patients do no respond adequately to SSA. We aimed to evaluate the potential usefulness of including studies of molecular markers identifying poor response to SSA for prescription of pharmacologic treatment in acromegalic patients in which SSA was prescribed before surgical therapy.
Methods: Retrospective study in which 68 acromegalic patients (59% females, median age 44) from a national cohort from 12 hospitals participated. All patients were treated with SSA preoperatively during at least 6 months under maximal effective therapeutic doses according to IGF-I values normalization. Response to SSA treatment was categorized as: complete response (C) when IGF-I achieved normal values; partial (P) response if IGF-I was between >2<3 SDS requiring combined treatment with pegvisomant or non-responders (NR) when IGF-I was >3 SDS and patient required monotherapy with pegvisomant. Somatotropinoma tissue from surgical specimen was obtained, RNA-later embedded and further processed for evaluation of the expression of 11 genes related to SSA response: SSTR2, SSTR5, AIP, e-cadherin (CDH1), Ki67, Kallikrein 10 (KLK10), arrestin beta-1 (ARRB1), ghrelin (GHRL), intron 1 Ghrelin (in1-Ghrelin), ZAC1 (PLAGL1) and Raf Kinase inhibitory protein (PEBP1). Measurements were made by RT-qPCR and obtained levels were normalized by the expression of MRPL19, TBP and PGK1 as reference genes. Furthermore, we analysed the gene GNAS (gsp) looking for mutations in the 201 and 227 codons using conventional PCR and Sanger Sequencing.
Results: According to therapeutic response there were 26 patients (38%) with complete, 17 (25%) with partial response and 25 (37%) no response. SSTR2 expression and CDH1 were associated to complete response (P=0.05 and P<0.001, respectively). Moreover, CDH1 was able to discriminate between the three different therapeutic response categories (C, P, NR) None of the other previously described genes related to SSA therapeutic response showed statistically significant different expression between C, P or NR patients. The best discriminator between C and NR was CDH1 (ROC AUC=0.74, P<0.01).
Conclusions: Somatotropinomas are heterogeneous tumours depicting a high variable molecular expression of genes associated to SSA response. CDH1 is the best molecular discriminator of therapeutic response to SSA. Thus, it may be useful in subsequent treatment decision after surgical failure in acromegalic patients.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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