Molecular profiling for acromegaly treatment: a validation study

in Endocrine-Related Cancer
View More View Less
  • 1 Department of Endocrinology and Nutrition, Germans Trias i Pujol University Hospital, Badalona, Spain
  • 2 Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
  • 3 Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain
  • 4 Biomedical Research Networking Center in Rare Diseases (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain
  • 5 Department of Endocrinology, Hospital de la Princesa, Universidad Autónoma de Madrid, Instituto Princesa, Madrid, Spain
  • 6 Department of Endocrinology/Medicine, CIBERER U747, ISCIII, Research Center for Pituitary Diseases, Hospital Sant Pau, IIB-SPau, Universitat Autònoma de Barcelona, Barcelona, Spain
  • 7 Department of Endocrinology, Son Espases University Hospital, Palma de Mallorca, Balearic Islands, Spain
  • 8 Department of Pathology, Germans Trias i Pujol University Hospital, Badalona, Spain
  • 9 Department of Neurosurgery, Germans Trias i Pujol University Hospital, Badalona, Spain
  • 10 Hospital General Universitario de Alicante-Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
  • 11 Department of Clinical Medicine, Miguel Hernández University, Elche, Spain
  • 12 Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania, USA
  • 13 Department of Endocrinology, Hospital Universitari Mutua Terrassa, Terrassa, Spain
  • 14 Department of Endocrinology, Hospital General Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
  • 15 Department of Endocrinology, Hospital Universitari de Bellvitge, Barcelona, Spain
  • 16 Endocrinology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain
  • 17 Endocrinology Department, Hospital Universitario de La Ribera, Alzira, Spain
  • 18 Neoplasia & Endocrine Differentiation P0L5, Centro de Investigacion en Medicina Molecular y Enfermedades Cronicas (CIMUS), Instituto de Investigacion Sanitaria de Santiago (IDIS), Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain
  • 19 Endocrinology Division, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS)-SERGAS, Santiago de Compostela, Spain

Correspondence should be addressed to M Puig-Domingo: mpuigd@igtp.cat

*(M Puig-Domingo and J Gil contributed equally to this work)

Restricted access

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.

Supplementary Materials

    • Supplementary Table 1. Statistical measures of correlations between each molecular marker and SRL response.
    • Supplementary Figure 1. H-score of SSTR2 (a) and % positive Ki-67 cells (b) in complete responders (CR), partial responders (PR) and non-responders (NR) (N = 47).

 

      Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 1138 1138 79
Full Text Views 45 45 7
PDF Downloads 34 34 7
  • Al-Brahim NYY & Asa SL 2006 My approach to pathology of the pituitary gland. Journal of Clinical Pathology 59 12451253. (https://doi.org/10.1136/jcp.2005.031187)

    • Search Google Scholar
    • Export Citation
  • Bakhtiar Y, Hirano H, Arita K, Yunoue S, Fujio S, Tominaga A, Sakoguchi T, Sugiyama K, Kurisu K, Yasufuku-Takano J, et al. 2010 Relationship between cytokeratin staining patterns and clinico-pathological features in somatotropinomae. European Journal of Endocrinology 163 531539. (https://doi.org/10.1530/EJE-10-0586)

    • Search Google Scholar
    • Export Citation
  • Casar-Borota O, Heck A, Schulz S, Nesland JM, Ramm-Pettersen J, Lekva T, Alafuzoff I & Bollerslev J 2013 Expression of SSTR2a, but not of SSTRs 1, 3, or 5 in somatotroph adenomas assessed by monoclonal antibodies was reduced by octreotide and correlated with the acute and long-term effects of octreotide. Journal of Clinical Endocrinology and Metabolism 98 E1730E1739. (https://doi.org/10.1210/jc.2013-2145)

    • Search Google Scholar
    • Export Citation
  • Chahal HS, Trivellin G, Leontiou CA, Alband N, Fowkes RC, Tahir A, Igreja SC, Chapple JP, Jordan S, Lupp A, et al. 2012 Somatostatin analogs modulate AIP in somatotroph adenomas: the role of the ZAC1 pathway. Journal of Clinical Endocrinology and Metabolism 97 E1411E1420. (https://doi.org/10.1210/jc.2012-1111)

    • Search Google Scholar
    • Export Citation
  • Chanson P & Salenave S 2008 Acromegaly. Orphanet Journal of Rare Diseases 3 17. (https://doi.org/10.1186/1750-1172-3-17)

  • Coelho MCA, Vasquez ML, Wildemberg LE, Vázquez-Borrego MC, Bitana L, Camacho AHDS, Silva D, Ogino LL, Ventura N, Chimelli L, et al. 2018 Molecular evidence and clinical importance of β-arrestins expression in patients with acromegaly. Journal of Cellular and Molecular Medicine 22 21102116. (https://doi.org/10.1111/jcmm.13427)

    • Search Google Scholar
    • Export Citation
  • Efstathiadou ZA, Bargiota A, Chrisoulidou A, Kanakis G, Papanastasiou L, Theodoropoulou A, Tigas SK, Vassiliadi DA, Alevizaki M & Tsagarakis S 2015 Impact of gsp mutations in somatotroph pituitary adenomas on growth hormone response to somatostatin analogs: a meta-analysis. Pituitary 18 861867. (https://doi.org/10.1007/s11102-015-0662-5)

    • Search Google Scholar
    • Export Citation
  • Fougner SL, Bollerslev J, Latif F, Hald JK, Lund T, Ramm-Pettersen J & Berg JP 2008 Low levels of raf kinase inhibitory protein in growth hormone-secreting pituitary adenomas correlate with poor response to octreotide treatment. Journal of Clinical Endocrinology and Metabolism 93 12111216. (https://doi.org/10.1210/jc.2007-2272)

    • Search Google Scholar
    • Export Citation
  • Fougner SL, Lekva T, Borota OC, Hald JK, Bollerslev J & Berg JP 2010 The expression of E-cadherin in somatotroph pituitary adenomas is related to tumor size, invasiveness, and somatostatin analog response. Journal of Clinical Endocrinology and Metabolism 95 23342342. (https://doi.org/10.1210/jc.2009-2197)

    • Search Google Scholar
    • Export Citation
  • Fougner SL, Casar-Borota O, Heck A, Berg JP & Bollerslev J 2012 Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly. Clinical Endocrinology 76 96102. (https://doi.org/10.1111/j.1365-2265.2011.04163.x)

    • Search Google Scholar
    • Export Citation
  • Franck SE, Gatto F, van der Lely AJ, Janssen JAMJL, Dallenga AHG, Nagtegaal AP, Hofland LJ & Neggers SJCMM 2017 Somatostatin receptor expression in GH-secreting pituitary adenomas treated with long-acting somatostatin analogues in combination with pegvisomant. Neuroendocrinology 105 4453. (https://doi.org/10.1159/000448429)

    • Search Google Scholar
    • Export Citation
  • Freda PU 2002 Somatostatin analogs in acromegaly. Journal of Clinical Endocrinology and Metabolism 87 30133018. (https://doi.org/10.1210/jcem.87.7.8665)

    • Search Google Scholar
    • Export Citation
  • Gadelha MR 2015 A paradigm shift in the medical treatment of acromegaly: from a ‘trial and error’ to a personalized therapeutic decision-making process. Clinical Endocrinology 83 12. (https://doi.org/10.1111/cen.12797)

    • Search Google Scholar
    • Export Citation
  • Gadelha MR, Kasuki L & Korbonits M 2013 Novel pathway for somatostatin analogs in patients with acromegaly. Trends in Endocrinology and Metabolism 24 238246. (https://doi.org/10.1016/j.tem.2012.11.007)

    • Search Google Scholar
    • Export Citation
  • Gadelha MR, Wildemberg LE, Bronstein MD, Gatto F & Ferone D 2017 Somatostatin receptor ligands in the treatment of acromegaly. Pituitary 20 100108. (https://doi.org/10.1007/s11102-017-0791-0)

    • Search Google Scholar
    • Export Citation
  • Gatto F, Feelders RA, van der Pas R, Kros JM, Waaijers M, Sprij-Mooij D, Neggers SJCMM, van der Lelij AJ, Minuto F, Lamberts SWJ, et al. 2013 Immunoreactivity score using an anti-sst2A receptor monoclonal antibody strongly predicts the biochemical response to adjuvant treatment with somatostatin analogs in acromegaly. Journal of Clinical Endocrinology and Metabolism 98 E66E71. (https://doi.org/10.1210/jc.2012-2609)

    • Search Google Scholar
    • Export Citation
  • Gatto F, Biermasz NR, Feelders RA, Kros JM, Dogan F, van der Lely AJ, Neggers SJCMM, Lamberts SWJ, Pereira AM, Ferone D, et al. 2016 Low beta-arrestin expression correlates with the responsiveness to long-term somatostatin analog treatment in acromegaly. European Journal of Endocrinology 174 651662. (https://doi.org/10.1530/EJE-15-0391)

    • Search Google Scholar
    • Export Citation
  • Gatto F, Feelders RA, Franck SE, van Koetsveld PM, Dogan F, Kros JM, Neggers SJCMM, van der Lely AJ, Lamberts SWJ, Ferone D, et al. 2017 In vitro head-to-head comparison Between octreotide and pasireotide in GH-secreting pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 102 20092018. (https://doi.org/10.1210/jc.2017-00135)

    • Search Google Scholar
    • Export Citation
  • Gonzalez B, Vargas G, Ramirez C, Asa S, Cheng S, Sandoval C & Mercado M 2014 Cytoplasmic expression of SSTR2 and 5 by immunohistochemistry and by RT/PCR is not associated with the pharmacological response to octreotide. Endocrinologia y Nutricion 61 523530. (https://doi.org/10.1016/j.endonu.2014.05.006)

    • Search Google Scholar
    • Export Citation
  • Ibáñez-Costa A, Gahete MD, Rivero-Cortés E, Rincón-Fernández D, Nelson R, Beltrán M, de la Riva A, Japón MA, Venegas-Moreno E, Gálvez , et al. 2015 In1-ghrelin splicing variant is overexpressed in pituitary adenomas and increases their aggressive features. Scientific Reports 5 8714. (https://doi.org/10.1038/srep08714)

    • Search Google Scholar
    • Export Citation
  • Kasuki L, Wildemberg LEA, Neto LV, Marcondes J, Takiya CM & Gadelha MR 2013 Ki-67 is a predictor of acromegaly control with octreotide LAR independent of SSTR2 status and relates to cytokeratin pattern. European Journal of Endocrinology 169 217223. (https://doi.org/10.1530/EJE-13-0349)

    • Search Google Scholar
    • Export Citation
  • Kasuki L, Wildemberg LE & Gadelha MR 2018 MANAGEMENT of ENDOCRINE DISEASE: Personalized medicine in the treatment of acromegaly. European Journal of Endocrinology 178 R89R100. (https://doi.org/10.1530/EJE-17-1006)

    • Search Google Scholar
    • Export Citation
  • Katznelson L, Laws ER, Melmed S, Molitch ME, Murad MH, Utz A, Wass JAH & Endocrine Society 2014 Acromegaly: an endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 99 39333951. (https://doi.org/10.1210/jc.2014-2700)

    • Search Google Scholar
    • Export Citation
  • Kiseljak-Vassiliades K, Xu M, Mills TS, Smith EE, Silveira LJ, Lillehei KO, Kerr JM, Kleinschmidt-DeMasters BK & Wierman ME 2015a Differential somatostatin receptor (SSTR) 1-5 expression and downstream effectors in histologic subtypes of growth hormone pituitary tumors. Molecular and Cellular Endocrinology 417 7383. (https://doi.org/10.1016/j.mce.2015.09.016)

    • Search Google Scholar
    • Export Citation
  • Kiseljak-Vassiliades K, Carlson NE, Borges MT, Kleinschmidt-DeMasters BK, Lillehei KO, Kerr JM & Wierman ME 2015b Growth hormone tumor histological subtypes predict response to surgical and medical therapy. Endocrine 49 231241. (https://doi.org/10.1007/s12020-014-0383-y)

    • Search Google Scholar
    • Export Citation
  • Lekva T, Berg JP, Fougner SL, Olstad OK, Ueland T & Bollerslev J 2012 Gene expression profiling identifies ESRP1 as a potential regulator of epithelial mesenchymal transition in somatotroph adenomas from a large cohort of patients with acromegaly. Journal of Clinical Endocrinology and Metabolism 97 E1506E1514. (https://doi.org/10.1210/jc.2012-1760)

    • Search Google Scholar
    • Export Citation
  • Lekva T, Berg JP, Heck A, Lyngvi Fougner S, Olstad OK, Ringstad G, Bollerslev J & Ueland T 2013 Attenuated RORC expression in the presence of EMT progression in somatotroph adenomas following treatment with somatostatin analogs is associated with poor clinical recovery. PLoS ONE 8 e66927. (https://doi.org/10.1371/journal.pone.0066927)

    • Search Google Scholar
    • Export Citation
  • Liu W, Xie L, He M, Shen M, Zhu J, Yang Y, Wang M, Hu J, Ye H, Li Y, et al. 2017 Expression of somatostatin receptor 2 in somatotropinoma correlated with the short-term efficacy of somatostatin analogues. International Journal of Endocrinology 2017 9606985. (https://doi.org/10.1155/2017/9606985)

    • Search Google Scholar
    • Export Citation
  • Luque RM, Ibáñez-Costa A, Neto LV, Taboada GF, Hormaechea-Agulla D, Kasuki L, Venegas-Moreno E, Moreno-Carazo A, Gálvez , Soto-Moreno A, et al. 2015 Truncated somatostatin receptor variant sst5TMD4 confers aggressive features (proliferation, invasion and reduced octreotide response) to somatotropinomas. Cancer Letters 359 299306. (https://doi.org/10.1016/j.canlet.2015.01.037)

    • Search Google Scholar
    • Export Citation
  • Mallona I, Díez-Villanueva A, Martín B & Peinado MA 2017 Chainy: an universal tool for standardized relative quantification in real-time PCR. Bioinformatics 33 14111413. (https://doi.org/10.1093/bioinformatics/btw839)

    • Search Google Scholar
    • Export Citation
  • Melmed S 2006 Medical progress: acromegaly. New England Journal of Medicine 355 25582573. (https://doi.org/10.1056/NEJMra062453)

  • Melmed S, Bronstein MD, Chanson P, Klibanski A, Casanueva FF, Wass JAH, Strasburger CJ, Luger A, Clemmons DR & Giustina A 2018 A Consensus Statement on acromegaly therapeutic outcomes. Nature Reviews: Endocrinology 14 552561. (https://doi.org/10.1038/s41574-018-0058-5)

    • Search Google Scholar
    • Export Citation
  • Puig Domingo M 2015 Treatment of acromegaly in the era of personalized and predictive medicine. Clinical Endocrinology 83 314. (https://doi.org/10.1111/cen.12731)

    • Search Google Scholar
    • Export Citation
  • Puig-Domingo M, Resmini E, Gomez-Anson B, Nicolau J, Mora M, Palomera E, Martí C, Halperin I & Webb SM 2010 Magnetic resonance imaging as a predictor of response to somatostatin analogs in acromegaly after surgical failure. Journal of Clinical Endocrinology and Metabolism 95 49734978. (https://doi.org/10.1210/jc.2010-0573)

    • Search Google Scholar
    • Export Citation
  • Reid TJ, Post KD, Bruce JN, Nabi Kanibir M, Reyes-Vidal CM & Freda PU 2010 Features at diagnosis of 324 patients with acromegaly did not change from 1981 to 2006: acromegaly remains under-recognized and under-diagnosed. Clinical Endocrinology 72 203208. (https://doi.org/10.1111/j.1365-2265.2009.03626.x)

    • Search Google Scholar
    • Export Citation
  • Rochette C, Castinetti F & Brue T 2016 Acromegaly and Cushing’s disease: persistence of comorbidities after the control of hypersecretion. Annales d’Endocrinologie 77 (Supplement 1) S19S28. (https://doi.org/10.1016/S0003-4266(17)30074-4)

    • Search Google Scholar
    • Export Citation
  • Rotondo F, Di Ieva A, Kovacs K, Cusimano MD, Syro LV, Diamandis EP & Yousef GM 2015 Human kallikrein 10 in surgically removed human pituitary adenomas. Hormones 14 272279. (https://doi.org/10.14310/horm.2002.1558)

    • Search Google Scholar
    • Export Citation
  • Taboada GF, Luque RM, Bastos W, Guimarães RFC, Marcondes JB, Chimelli LMC, Fontes R, Mata PJP, Filho PN, Carvalho DP, et al. 2007 Quantitative analysis of somatostatin receptor subtype (SSTR1-5) gene expression levels in somatotropinomas and non-functioning pituitary adenomas. European Journal of Endocrinology 156 6574. (https://doi.org/10.1530/eje.1.02313)

    • Search Google Scholar
    • Export Citation
  • Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A & Speleman F 2002 Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biology 3 RESEARCH0034. (https://doi.org/10.1186/gb-2002-3-7-research0034)

    • Search Google Scholar
    • Export Citation
  • Venegas-Moreno E, Vazquez-Borrego MC, Dios E, Gros-Herguido N, Flores-Martinez A, Rivero-Cortés E, Madrazo-Atutxa A, Japón MA, Luque RM, Castaño JP, et al. 2018 Association between dopamine and somatostatin receptor expression and pharmacological response to somatostatin analogues in acromegaly. Journal of Cellular and Molecular Medicine 22 16401649. (https://doi.org/10.1111/jcmm.13440)

    • Search Google Scholar
    • Export Citation
  • Wildemberg LEA, Vieira Neto L, Costa DF, Nasciutti LE, Takiya CM, Alves LM & Gadelha MR 2012 Validation of immunohistochemistry for somatostatin receptor subtype 2A in human somatotropinomas: comparison between quantitative real time RT-PCR and immunohistochemistry. Journal of Endocrinological Investigation 35 580584. (https://doi.org/10.3275/7906)

    • Search Google Scholar
    • Export Citation
  • Wildemberg LEA, Neto LV, Costa DF, Nasciuti LE, Takiya CM, Alves LM, Rebora A, Minuto F, Ferone D & Gadelha MR 2013 Low somatostatin receptor subtype 2, but not dopamine receptor subtype 2 expression predicts the lack of biochemical response of somatotropinomas to treatment with somatostatin analogs. Journal of Endocrinological Investigation 36 3843. (https://doi.org/10.3275/8305)

    • Search Google Scholar
    • Export Citation