Molecular profiling for acromegaly treatment: a validation study
Por:
Puig-Domingo, M, Gil, J, Sampedro-Nunez, M, Jorda, M, Webb, SM, Serra, G, Pons, L, Salinas, I, Blanco, A, Marques-Pamies, M, Valassi, E, Pico, A, Garcia-Martinez, A, Carrato, C, Buj, R, del Pozo, C, Obiols, G, Villabona, C, Camara, R, Fajardo-Montanana, C, Alvarez, CV, Bernabeu, I, Marazuela, M, REMAH Investigators
Publicada:
1 jun 2020
Resumen:
Pharmacologic treatment of acromegaly is currently based upon assay-error strategy, the first-generation somatostatin receptor ligands (SRL) being the first-line treatment. However, about 50% of patients do not respond adequately to SRL. Our objective was to evaluate the potential usefulness of different molecular markers as predictors of response to SRL. We used somatotropinoma tissue obtained after surgery from a national cohort of 100 acromegalic patients. Seventy-one patients were treated with SRL during at least 6 months under maximal therapeutic doses according to IGF1 values. We analyzed the expression of SSTR2, SSTR5, AIP, CDH1 (E-cadherin), MKI67 (Ki-67), KLK10, DRD2, ARRB1, GHRL, In1-Ghrelin, PLAGL1 and PEBP1 (RKIP) by RT-qPCR and mutations in GNAS gene by Sanger sequencing. The response to SRL was categorized as complete response (CR), partial (PR) or non-response (NR) if IGF1 was normal, between >2<3 SDS or >3 SDS IGF1 at 6 months of follow-up, respectively. From the 71 patients treated, there were 27 CR (38%), 18 PR (25%) and 26 NR (37%). SSTR2, Ki-67 and E-cadherin were associated with SRL response (P < 0.03, P < 0.01 and P < 0.003, respectively). E-cadherin was the best discriminator for response prediction (AUC = 0.74, P< 0.02, PPV of 83.7%, NPV of 72.6%), which was validated at protein level. SSTR5 expression was higher in patients pre-treated with SRL before surgery. We conclude that somatotropinomas showed heterogeneity in the expression of genes associated with SRL response. E-cadherin was the best molecular predictor of response to SRL. Thus, the inclusion of E-cadherin in subsequent treatment-decision after surgical failure may be useful in acromegaly.
Filiaciones:
Puig-Domingo, M:
Germans Trias & Pujol Univ Hosp, Dept Endocrinol & Nutr, Badalona, Spain
Germans Trias & Pujol Res Inst IGTP, Badalona, Spain
Autonomous Univ Barcelona, Dept Med, Barcelona, Spain
Inst Hlth Carlos III ISCIII, Biomed Res Networking Ctr Rare Dis CIBERER, Madrid, Spain
Gil, J:
Germans Trias & Pujol Res Inst IGTP, Badalona, Spain
Sampedro-Nunez, M:
Inst Hlth Carlos III ISCIII, Biomed Res Networking Ctr Rare Dis CIBERER, Madrid, Spain
Univ Autonoma Madrid, Hosp Princesa, Inst Princesa, Dept Endocrinol, Madrid, Spain
Jorda, M:
Germans Trias & Pujol Res Inst IGTP, Badalona, Spain
Webb, SM:
Univ Autonoma Barcelona, ISCIII, Res Ctr Pituitary Dis, Hosp St Pau,Dept Endocrinol Med,CIBERER U747,IIB, Barcelona, Spain
Serra, G:
Son Espases Univ Hosp, Dept Endocrinol, Palma De Mallorca, Balearic Island, Spain
Pons, L:
Germans Trias & Pujol Univ Hosp, Dept Pathol, Badalona, Spain
Salinas, I:
Germans Trias & Pujol Univ Hosp, Dept Endocrinol & Nutr, Badalona, Spain
Blanco, A:
Germans Trias & Pujol Univ Hosp, Dept Neurosurg, Badalona, Spain
Marques-Pamies, M:
Germans Trias & Pujol Univ Hosp, Dept Endocrinol & Nutr, Badalona, Spain
Valassi, E:
Univ Autonoma Barcelona, ISCIII, Res Ctr Pituitary Dis, Hosp St Pau,Dept Endocrinol Med,CIBERER U747,IIB, Barcelona, Spain
Pico, A:
Inst Hlth Carlos III ISCIII, Biomed Res Networking Ctr Rare Dis CIBERER, Madrid, Spain
Hosp Gen Univ Alicante, Inst Hlth & Biomed Res ISABIAL, Alicante, Spain
Miguel Hernandez Univ, Dept Clin Med, Elche, Spain
Garcia-Martinez, A:
Inst Hlth Carlos III ISCIII, Biomed Res Networking Ctr Rare Dis CIBERER, Madrid, Spain
Hosp Gen Univ Alicante, Inst Hlth & Biomed Res ISABIAL, Alicante, Spain
Carrato, C:
Germans Trias & Pujol Univ Hosp, Dept Pathol, Badalona, Spain
Buj, R:
Germans Trias & Pujol Res Inst IGTP, Badalona, Spain
Penn State Coll Med, Dept Cellular & Mol Physiol, Hershey, PA USA
del Pozo, C:
Hosp Univ Mutua Terrassa, Dept Endocrinol, Terrassa, Spain
Obiols, G:
Univ Autonoma Barcelona, Hosp Gen Univ Vall dHebron, Dept Endocrinol, Barcelona, Spain
Villabona, C:
Hosp Univ Bellvitge, Dept Endocrinol, Barcelona, Spain
Camara, R:
Hosp Univ & Politecn La Fe, Endocrinol Dept, Valencia, Spain
Fajardo-Montanana, C:
Hosp Univ La Ribera, Endocrinol Dept, Alzira, Spain
Alvarez, CV:
Univ Santiago de Compostela USC, Ctr Invest Med Mol & Enfermedades Cron CIMUS, Inst Invest Sanitaria Santiago IDIS, Neoplasia & Endocrine Differentiat P0L5, Santiago De Compostela, Spain
Bernabeu, I:
Complejo Hosp Univ Santiago de Compostela CHUS SE, Endocrinol Div, Santiago De Compostela, Spain
Marazuela, M:
Inst Hlth Carlos III ISCIII, Biomed Res Networking Ctr Rare Dis CIBERER, Madrid, Spain
Univ Autonoma Madrid, Hosp Princesa, Inst Princesa, Dept Endocrinol, Madrid, Spain
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