Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix
<p>Neuroendocrine carcinoma of the cervix (NEC) is a rare and highly aggressive cervical malignancy. Given that no targeted therapy has been approved specifically to NEC, we investigated the presence of novel, potentially targetable biomarkers in a large cohort of NEC. Sixty-two NEC were molec...
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2021
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| _version_ | 1864513560224202752 |
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| author | Adela Cimic (14908512) |
| author2 | Semir Vranic (3353012) David Arguello (3353000) Elma Contreras (16561296) Zoran Gatalica (3353003) Jeffrey Swensen (4760673) |
| author2_role | author author author author author |
| author_facet | Adela Cimic (14908512) Semir Vranic (3353012) David Arguello (3353000) Elma Contreras (16561296) Zoran Gatalica (3353003) Jeffrey Swensen (4760673) |
| author_role | author |
| dc.creator.none.fl_str_mv | Adela Cimic (14908512) Semir Vranic (3353012) David Arguello (3353000) Elma Contreras (16561296) Zoran Gatalica (3353003) Jeffrey Swensen (4760673) |
| dc.date.none.fl_str_mv | 2021-04-01T00:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1097/pai.0000000000000884 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Molecular_Profiling_Reveals_Limited_Targetable_Biomarkers_in_Neuroendocrine_Carcinoma_of_the_Cervix/23701659 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Oncology and carcinogenesis cervix neuroendocrine carcinoma molecular profiling sequencing targeted therapy |
| dc.title.none.fl_str_mv | Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p>Neuroendocrine carcinoma of the cervix (NEC) is a rare and highly aggressive cervical malignancy. Given that no targeted therapy has been approved specifically to NEC, we investigated the presence of novel, potentially targetable biomarkers in a large cohort of NEC. Sixty-two NEC were molecularly profiled for biomarkers of targeted therapies including antibody-drug conjugates [delta-like canonical notch ligand 3 (DLL3), a trophoblast cell surface antigen 2 (TROP-2), and folate receptor 1 (FOLR1)], <em>NTRK1-3</em> gene fusions, and immune checkpoint inhibitors [programmed death-ligand 1 (PD-L1), tumor mutational burden, and microsatellite instability] using immunohistochemistry and DNA/RNA next-generation sequencing assays. A cohort of squamous cell carcinomas of the cervix (n=599) was used for comparison for immune-oncology biomarkers. DLL3 expression was observed in 81% of the cases. DLL3 expression was inversely correlated with commonly observed pathogenic mutations in <em>PIK3CA</em> (17%) (<em>P</em>=0.018) and <em>PTEN</em> (10%) (<em>P</em>=0.006). Other more frequently seen pathogenic mutations (<em>TP53</em> 17%, <em>KRAS</em> 11%, and <em>CTNNB1</em> 5%) were not associated with DLL3 expression. TROP-2 expression was detected in only 1 case and no case expressed FOLR1. Although NTRK protein expression was observed in 21% of the cases, none of these had <em>an NTRK</em> gene fusion. PD-L1 expression (10%) and high tumor mutational burden (3%) were significantly less frequent in NEC compared with the squamous cell carcinoma cohort (79% and 11%, respectively). None of the NEC exhibited high microsatellite instability status. Despite frequent DLL3 expression in NEC, a potential therapeutic benefit of DLL3-targeted drugs remains uncertain given the recent failure of the Rova-T therapeutic trial in small cell lung carcinomas. Small cohorts of NEC enriched in PIK3CA/PTEN/AKT and programmed cell death protein 1/PD-L1 alterations indicate therapeutic roles for their respective inhibitors.</p> <h2>Other Information</h2> <p>Published in: Applied Immunohistochemistry & Molecular Morphology<br> License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by-nc-nd/4.0/</a><br> See article on publisher's website: <a href="http://dx.doi.org/10.1097/pai.0000000000000884" target="_blank">http://dx.doi.org/10.1097/pai.0000000000000884</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_2697301ea3e761685b1b911a60fd4377 |
| identifier_str_mv | 10.1097/pai.0000000000000884 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/23701659 |
| publishDate | 2021 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the CervixAdela Cimic (14908512)Semir Vranic (3353012)David Arguello (3353000)Elma Contreras (16561296)Zoran Gatalica (3353003)Jeffrey Swensen (4760673)Biomedical and clinical sciencesOncology and carcinogenesiscervixneuroendocrine carcinomamolecular profilingsequencingtargeted therapy<p>Neuroendocrine carcinoma of the cervix (NEC) is a rare and highly aggressive cervical malignancy. Given that no targeted therapy has been approved specifically to NEC, we investigated the presence of novel, potentially targetable biomarkers in a large cohort of NEC. Sixty-two NEC were molecularly profiled for biomarkers of targeted therapies including antibody-drug conjugates [delta-like canonical notch ligand 3 (DLL3), a trophoblast cell surface antigen 2 (TROP-2), and folate receptor 1 (FOLR1)], <em>NTRK1-3</em> gene fusions, and immune checkpoint inhibitors [programmed death-ligand 1 (PD-L1), tumor mutational burden, and microsatellite instability] using immunohistochemistry and DNA/RNA next-generation sequencing assays. A cohort of squamous cell carcinomas of the cervix (n=599) was used for comparison for immune-oncology biomarkers. DLL3 expression was observed in 81% of the cases. DLL3 expression was inversely correlated with commonly observed pathogenic mutations in <em>PIK3CA</em> (17%) (<em>P</em>=0.018) and <em>PTEN</em> (10%) (<em>P</em>=0.006). Other more frequently seen pathogenic mutations (<em>TP53</em> 17%, <em>KRAS</em> 11%, and <em>CTNNB1</em> 5%) were not associated with DLL3 expression. TROP-2 expression was detected in only 1 case and no case expressed FOLR1. Although NTRK protein expression was observed in 21% of the cases, none of these had <em>an NTRK</em> gene fusion. PD-L1 expression (10%) and high tumor mutational burden (3%) were significantly less frequent in NEC compared with the squamous cell carcinoma cohort (79% and 11%, respectively). None of the NEC exhibited high microsatellite instability status. Despite frequent DLL3 expression in NEC, a potential therapeutic benefit of DLL3-targeted drugs remains uncertain given the recent failure of the Rova-T therapeutic trial in small cell lung carcinomas. Small cohorts of NEC enriched in PIK3CA/PTEN/AKT and programmed cell death protein 1/PD-L1 alterations indicate therapeutic roles for their respective inhibitors.</p> <h2>Other Information</h2> <p>Published in: Applied Immunohistochemistry & Molecular Morphology<br> License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by-nc-nd/4.0/</a><br> See article on publisher's website: <a href="http://dx.doi.org/10.1097/pai.0000000000000884" target="_blank">http://dx.doi.org/10.1097/pai.0000000000000884</a></p>2021-04-01T00:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1097/pai.0000000000000884https://figshare.com/articles/journal_contribution/Molecular_Profiling_Reveals_Limited_Targetable_Biomarkers_in_Neuroendocrine_Carcinoma_of_the_Cervix/23701659CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/237016592021-04-01T00:00:00Z |
| spellingShingle | Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix Adela Cimic (14908512) Biomedical and clinical sciences Oncology and carcinogenesis cervix neuroendocrine carcinoma molecular profiling sequencing targeted therapy |
| status_str | publishedVersion |
| title | Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix |
| title_full | Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix |
| title_fullStr | Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix |
| title_full_unstemmed | Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix |
| title_short | Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix |
| title_sort | Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix |
| topic | Biomedical and clinical sciences Oncology and carcinogenesis cervix neuroendocrine carcinoma molecular profiling sequencing targeted therapy |