Molecular profiling for acromegaly treatment: a validation study
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 diff...
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| Veröffentlicht in: | Endocrine-related cancer 2020-06, Vol.27 (6), p.375-389 |
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| creator | Puig-Domingo, Manel Gil, Joan Sampedro-Nuñez, Miguel Jordà, Mireia Webb, Susan M Serra, Guillermo Pons, Laura Salinas, Isabel Blanco, Alberto Marques-Pamies, Montserrat Valassi, Elena Picó, Antonio García-Martínez, Araceli Carrato, Cristina Buj, Raquel del Pozo, Carlos Obiols, Gabriel Villabona, Carles Cámara, Rosa Fajardo-Montañana, Carmen Alvarez, Clara V Bernabéu, Ignacio Marazuela, Mónica |
| description | 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 >23 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 |
| doi_str_mv | 10.1530/ERC-18-0565 |
| format | Article |
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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.</description><identifier>ISSN: 1351-0088</identifier><identifier>EISSN: 1479-6821</identifier><identifier>DOI: 10.1530/ERC-18-0565</identifier><identifier>PMID: 32302973</identifier><language>eng</language><publisher>BRISTOL: Bioscientifica Ltd</publisher><subject>Endocrinology & Metabolism ; Life Sciences & Biomedicine ; Oncology ; Science & Technology</subject><ispartof>Endocrine-related cancer, 2020-06, Vol.27 (6), p.375-389</ispartof><rights>2020 Society for Endocrinology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>38</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000536143800011</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-b434t-29530650174e706868b9f2af114cf9d51175b031c2792e1566250381f0131d5a3</citedby><cites>FETCH-LOGICAL-b434t-29530650174e706868b9f2af114cf9d51175b031c2792e1566250381f0131d5a3</cites><orcidid>0000-0003-1500-4058 ; 0000-0003-1030-9119 ; 0000-0003-0784-4110 ; 0000-0002-8355-6666 ; 0000-0002-6744-7195 ; 0000-0001-7052-6436 ; 0000-0003-1158-9618 ; 0000-0002-0784-0761</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,3954,27933,27934,28257</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32302973$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Puig-Domingo, Manel</creatorcontrib><creatorcontrib>Gil, Joan</creatorcontrib><creatorcontrib>Sampedro-Nuñez, Miguel</creatorcontrib><creatorcontrib>Jordà, Mireia</creatorcontrib><creatorcontrib>Webb, Susan M</creatorcontrib><creatorcontrib>Serra, Guillermo</creatorcontrib><creatorcontrib>Pons, Laura</creatorcontrib><creatorcontrib>Salinas, Isabel</creatorcontrib><creatorcontrib>Blanco, Alberto</creatorcontrib><creatorcontrib>Marques-Pamies, Montserrat</creatorcontrib><creatorcontrib>Valassi, Elena</creatorcontrib><creatorcontrib>Picó, Antonio</creatorcontrib><creatorcontrib>García-Martínez, Araceli</creatorcontrib><creatorcontrib>Carrato, Cristina</creatorcontrib><creatorcontrib>Buj, Raquel</creatorcontrib><creatorcontrib>del Pozo, Carlos</creatorcontrib><creatorcontrib>Obiols, Gabriel</creatorcontrib><creatorcontrib>Villabona, Carles</creatorcontrib><creatorcontrib>Cámara, Rosa</creatorcontrib><creatorcontrib>Fajardo-Montañana, Carmen</creatorcontrib><creatorcontrib>Alvarez, Clara V</creatorcontrib><creatorcontrib>Bernabéu, Ignacio</creatorcontrib><creatorcontrib>Marazuela, Mónica</creatorcontrib><creatorcontrib>REMAH Investigators</creatorcontrib><title>Molecular profiling for acromegaly treatment: a validation study</title><title>Endocrine-related cancer</title><addtitle>ENDOCR-RELAT CANCER</addtitle><addtitle>Endocr Relat Cancer</addtitle><description>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. 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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. 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| subjects | Endocrinology & Metabolism Life Sciences & Biomedicine Oncology Science & Technology |
| title | Molecular profiling for acromegaly treatment: a validation study |
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