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Translational Results of Zo-NAnTax: A Phase II Trial of Neoadjuvant Zoledronic Acid in HER2-Positive Breast Cancer
Breast cancer is a heterogeneous disease with distinct clinical and molecular characteristics. Scientific advances in molecular subtype differentiation support the understanding of cellular signaling, crosstalk, proliferation, survival, migration, and invasion mechanisms, allowing the development of...
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Published in: | International journal of molecular sciences 2022-12, Vol.23 (24), p.15515 |
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description | Breast cancer is a heterogeneous disease with distinct clinical and molecular characteristics. Scientific advances in molecular subtype differentiation support the understanding of cellular signaling, crosstalk, proliferation, survival, migration, and invasion mechanisms, allowing the development of new molecular drug targets. The breast cancer subtype with super expression and/or amplification of human growth factor receptor 2 (HER2) is clinically aggressive, but prognosis significantly shifted with the advent of anti-HER2 targeted therapy. Zoledronic-acid (ZOL) combined with a neoadjuvant Trastuzumab-containing chemotherapy regimen (Doxorubicin, Cyclophosphamide followed by Docetaxel, Trastuzumab) increased the pCR rate in a RH-positive/ HER2-positive subgroup, according to the phase II Zo-NAnTax trial. To verify genes that could be related to this response, a microarray assay was performed finding 164 differentially expressed genes. Silico analysis of these genes showed signaling pathways related to growth factors, apoptosis, invasion, and metabolism, as well as differentially expressed genes related to estrogen response. In addition, the RAC3 gene was found to interact with the MVD gene, a member of the mevalonate pathway. Taken together, these results indicate that RH-positive/ HER2-positive patients present gene alterations before treatment, and these could be related to the improvement of pCR. |
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Scientific advances in molecular subtype differentiation support the understanding of cellular signaling, crosstalk, proliferation, survival, migration, and invasion mechanisms, allowing the development of new molecular drug targets. The breast cancer subtype with super expression and/or amplification of human growth factor receptor 2 (HER2) is clinically aggressive, but prognosis significantly shifted with the advent of anti-HER2 targeted therapy. Zoledronic-acid (ZOL) combined with a neoadjuvant Trastuzumab-containing chemotherapy regimen (Doxorubicin, Cyclophosphamide followed by Docetaxel, Trastuzumab) increased the pCR rate in a RH-positive/ HER2-positive subgroup, according to the phase II Zo-NAnTax trial. To verify genes that could be related to this response, a microarray assay was performed finding 164 differentially expressed genes. Silico analysis of these genes showed signaling pathways related to growth factors, apoptosis, invasion, and metabolism, as well as differentially expressed genes related to estrogen response. In addition, the RAC3 gene was found to interact with the MVD gene, a member of the mevalonate pathway. Taken together, these results indicate that RH-positive/ HER2-positive patients present gene alterations before treatment, and these could be related to the improvement of pCR.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms232415515</identifier><identifier>PMID: 36555156</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Angiogenesis ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Apoptosis ; Biomarkers ; Biopsy ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Cancer therapies ; Cell growth ; Chemotherapy ; Cyclophosphamide ; Cyclophosphamide - therapeutic use ; Cytochrome ; differential expression genes ; DNA microarrays ; Doxorubicin ; ErbB-2 protein ; Estrogens ; Female ; Gene expression ; Genes ; Growth factors ; HER2-positive ; Humans ; Kinases ; Metabolism ; Metabolites ; Metastasis ; Mevalonate pathway ; Monoclonal antibodies ; Neoadjuvant Therapy ; Patients ; Receptor, ErbB-2 - genetics ; Receptor, ErbB-2 - metabolism ; Signal transduction ; Subgroups ; Therapeutic targets ; Trastuzumab ; Trastuzumab - therapeutic use ; Treatment Outcome ; Tumors ; Zoledronic acid ; Zoledronic Acid - therapeutic use</subject><ispartof>International journal of molecular sciences, 2022-12, Vol.23 (24), p.15515</ispartof><rights>2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). 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Scientific advances in molecular subtype differentiation support the understanding of cellular signaling, crosstalk, proliferation, survival, migration, and invasion mechanisms, allowing the development of new molecular drug targets. The breast cancer subtype with super expression and/or amplification of human growth factor receptor 2 (HER2) is clinically aggressive, but prognosis significantly shifted with the advent of anti-HER2 targeted therapy. Zoledronic-acid (ZOL) combined with a neoadjuvant Trastuzumab-containing chemotherapy regimen (Doxorubicin, Cyclophosphamide followed by Docetaxel, Trastuzumab) increased the pCR rate in a RH-positive/ HER2-positive subgroup, according to the phase II Zo-NAnTax trial. To verify genes that could be related to this response, a microarray assay was performed finding 164 differentially expressed genes. Silico analysis of these genes showed signaling pathways related to growth factors, apoptosis, invasion, and metabolism, as well as differentially expressed genes related to estrogen response. In addition, the RAC3 gene was found to interact with the MVD gene, a member of the mevalonate pathway. Taken together, these results indicate that RH-positive/ HER2-positive patients present gene alterations before treatment, and these could be related to the improvement of pCR.</description><subject>Angiogenesis</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Apoptosis</subject><subject>Biomarkers</subject><subject>Biopsy</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Cancer therapies</subject><subject>Cell growth</subject><subject>Chemotherapy</subject><subject>Cyclophosphamide</subject><subject>Cyclophosphamide - therapeutic use</subject><subject>Cytochrome</subject><subject>differential expression genes</subject><subject>DNA microarrays</subject><subject>Doxorubicin</subject><subject>ErbB-2 protein</subject><subject>Estrogens</subject><subject>Female</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Growth factors</subject><subject>HER2-positive</subject><subject>Humans</subject><subject>Kinases</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Metastasis</subject><subject>Mevalonate pathway</subject><subject>Monoclonal antibodies</subject><subject>Neoadjuvant Therapy</subject><subject>Patients</subject><subject>Receptor, ErbB-2 - genetics</subject><subject>Receptor, ErbB-2 - metabolism</subject><subject>Signal transduction</subject><subject>Subgroups</subject><subject>Therapeutic targets</subject><subject>Trastuzumab</subject><subject>Trastuzumab - therapeutic use</subject><subject>Treatment Outcome</subject><subject>Tumors</subject><subject>Zoledronic acid</subject><subject>Zoledronic Acid - therapeutic use</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNpd0s1rFDEYBvBBFPuhR68S8OJlNB-TZOJBWJdqF0otZb14CW8y77QZZidtMrPof99pt5aup4S8Px4S8hTFO0Y_CWHo59BtMhe8YlIy-aI4ZBXnJaVKv3y2PyiOcu4onaE0r4sDoeQ9V4dFWicYcg9jiAP05BLz1I-ZxJb8juX5YljDny9kQS6uISNZrcg6hZnN43OM0HTTFoZxpj02KQ7Bk4UPDQkDOT255OVFzGEMWyTfEkIeyRIGj-lN8aqFPuPbx_W4-PX9ZL08Lc9-_lgtF2elr2o2loqzBphwGr1WlVNM8rqR0msjBVCGzmkqFKKhaLDhtTGOGSUqVTdg2roRx8Vql9tE6OxNChtIf22EYB8OYrqykMbge7QoVN2i81o7VwnFjZMgDXCsnam8r-asr7usm8ltsPE4jAn6vdD9yRCu7VXcWqO1qRifAz4-BqR4O2Ee7SZkj30PA8YpW65lzShjTM70w3-0i1Oaf-dBKS3qmrJZlTvlU8w5Yft0GUbtfTPsXjNm__75C570vyqIO9Hws4c</recordid><startdate>20221208</startdate><enddate>20221208</enddate><creator>Crocamo, Susanne</creator><creator>Binato, Renata</creator><creator>Dos Santos, Everton Cruz</creator><creator>de Paula, Bruno</creator><creator>Abdelhay, Eliana</creator><general>MDPI AG</general><general>MDPI</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-5463-5517</orcidid><orcidid>https://orcid.org/0000-0002-3412-5325</orcidid><orcidid>https://orcid.org/0000-0001-6427-229X</orcidid></search><sort><creationdate>20221208</creationdate><title>Translational Results of Zo-NAnTax: A Phase II Trial of Neoadjuvant Zoledronic Acid in HER2-Positive Breast Cancer</title><author>Crocamo, Susanne ; Binato, Renata ; Dos Santos, Everton Cruz ; de Paula, Bruno ; Abdelhay, Eliana</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c481t-621da13b7ec764b61528d55c7953a01ebb7036ee90e9ed2899b1963468da9f8d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Angiogenesis</topic><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Apoptosis</topic><topic>Biomarkers</topic><topic>Biopsy</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - metabolism</topic><topic>Cancer therapies</topic><topic>Cell growth</topic><topic>Chemotherapy</topic><topic>Cyclophosphamide</topic><topic>Cyclophosphamide - therapeutic use</topic><topic>Cytochrome</topic><topic>differential expression genes</topic><topic>DNA microarrays</topic><topic>Doxorubicin</topic><topic>ErbB-2 protein</topic><topic>Estrogens</topic><topic>Female</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Growth factors</topic><topic>HER2-positive</topic><topic>Humans</topic><topic>Kinases</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Metastasis</topic><topic>Mevalonate pathway</topic><topic>Monoclonal antibodies</topic><topic>Neoadjuvant Therapy</topic><topic>Patients</topic><topic>Receptor, ErbB-2 - genetics</topic><topic>Receptor, ErbB-2 - 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Scientific advances in molecular subtype differentiation support the understanding of cellular signaling, crosstalk, proliferation, survival, migration, and invasion mechanisms, allowing the development of new molecular drug targets. The breast cancer subtype with super expression and/or amplification of human growth factor receptor 2 (HER2) is clinically aggressive, but prognosis significantly shifted with the advent of anti-HER2 targeted therapy. Zoledronic-acid (ZOL) combined with a neoadjuvant Trastuzumab-containing chemotherapy regimen (Doxorubicin, Cyclophosphamide followed by Docetaxel, Trastuzumab) increased the pCR rate in a RH-positive/ HER2-positive subgroup, according to the phase II Zo-NAnTax trial. To verify genes that could be related to this response, a microarray assay was performed finding 164 differentially expressed genes. 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subjects | Angiogenesis Antineoplastic Combined Chemotherapy Protocols - adverse effects Apoptosis Biomarkers Biopsy Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Cancer therapies Cell growth Chemotherapy Cyclophosphamide Cyclophosphamide - therapeutic use Cytochrome differential expression genes DNA microarrays Doxorubicin ErbB-2 protein Estrogens Female Gene expression Genes Growth factors HER2-positive Humans Kinases Metabolism Metabolites Metastasis Mevalonate pathway Monoclonal antibodies Neoadjuvant Therapy Patients Receptor, ErbB-2 - genetics Receptor, ErbB-2 - metabolism Signal transduction Subgroups Therapeutic targets Trastuzumab Trastuzumab - therapeutic use Treatment Outcome Tumors Zoledronic acid Zoledronic Acid - therapeutic use |
title | Translational Results of Zo-NAnTax: A Phase II Trial of Neoadjuvant Zoledronic Acid in HER2-Positive Breast Cancer |
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