Plasma-Based Longitudinal Evaluation of ESR1 Epigenetic Status in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer
BackgroundEndocrine therapy (ET) is the mainstay of treatment for hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer; however, adaptive mechanisms emerge in about 25–30% of cases through alterations in the estrogen receptor ligand-binding doma...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-09-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2020.550185/full |
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| author | Lorenzo Gerratana Lorenzo Gerratana Debora Basile Debora Basile Alessandra Franzoni Lorenzo Allegri Davide Viotto Carla Corvaja Carla Corvaja Lucia Bortot Lucia Bortot Elisa Bertoli Elisa Bertoli Silvia Buriolla Silvia Buriolla Giada Targato Giada Targato Lucia Da Ros Stefania Russo Marta Bonotto Barbara Belletti Gustavo Baldassarre Giuseppe Damante Fabio Puglisi Fabio Puglisi |
| author_facet | Lorenzo Gerratana Lorenzo Gerratana Debora Basile Debora Basile Alessandra Franzoni Lorenzo Allegri Davide Viotto Carla Corvaja Carla Corvaja Lucia Bortot Lucia Bortot Elisa Bertoli Elisa Bertoli Silvia Buriolla Silvia Buriolla Giada Targato Giada Targato Lucia Da Ros Stefania Russo Marta Bonotto Barbara Belletti Gustavo Baldassarre Giuseppe Damante Fabio Puglisi Fabio Puglisi |
| author_sort | Lorenzo Gerratana |
| collection | DOAJ |
| description | BackgroundEndocrine therapy (ET) is the mainstay of treatment for hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer; however, adaptive mechanisms emerge in about 25–30% of cases through alterations in the estrogen receptor ligand-binding domain, with a consequent ligand-independent estrogen receptor activity. Epigenetic-mediated events are less known and potentially involved in alternative mechanisms of resistance. The aim of this study was to test the feasibility of estrogen receptor 1 (ESR1) epigenetic characterization through liquid biopsy and to show its potential longitudinal application for an early ET sensitivity assessment.MethodsA cohort of 49 women with hormone receptor-positive HER2-negative MBC was prospectively enrolled and characterized through circulating tumor DNA using methylation-specific droplet digital PCR (MS-ddPCR) before treatment start (BL) and after 3 months concomitantly with computed tomography (CT) scan restaging (EV1). ESR1 epigenetic status was defined by assessing the methylation of its main promoters (promA and promB). The most established cell-free tumor DNA (ctDNA) factors associated with ET resistance [ESR1 and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations] were assessed through next-generation sequencing. Associations were tested through Mann–Whitney U test, matched pairs variations through Wilcoxon signed rank test, and survival was analyzed by log-rank test.ResultsThe ET backbone was mainly based on aromatase inhibitors (AIs) (70.83%) in association with CDK4/6 inhibitors (93.75%). Significantly lower promA levels at baseline were observed in patients with liver metastases (P = 0.0212) and in patients with ESR1 mutations (P = 0.0091). No significant impact on PFS was observed for promA (P = 0.3777) and promB (P = 0.7455) dichotomized at the median while a ≥2-fold increase in promB or in either promA or promB at EV1 resulted in a significantly worse prognosis (respectively P = 0.0189, P = 0.0294). A significant increase at EV1 was observed for promB among patients with PIK3CA mutation (P = 0.0173). A trend was observed for promB in ESR1 wild-type patients and for promA in the ESR1 mutant subgroup.ConclusionThe study proofed the concept of an epigenetic characterization strategy based on ctDNA and is capable of being integrated in the current clinical workflow to give useful insights on treatment sensitivity. |
| first_indexed | 2024-12-22T01:25:04Z |
| format | Article |
| id | doaj.art-cc9ff308591747ecb18dbb45a2610636 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-22T01:25:04Z |
| publishDate | 2020-09-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Oncology |
| spelling | doaj.art-cc9ff308591747ecb18dbb45a26106362022-12-21T18:43:37ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-09-011010.3389/fonc.2020.550185550185Plasma-Based Longitudinal Evaluation of ESR1 Epigenetic Status in Hormone Receptor-Positive HER2-Negative Metastatic Breast CancerLorenzo Gerratana0Lorenzo Gerratana1Debora Basile2Debora Basile3Alessandra Franzoni4Lorenzo Allegri5Davide Viotto6Carla Corvaja7Carla Corvaja8Lucia Bortot9Lucia Bortot10Elisa Bertoli11Elisa Bertoli12Silvia Buriolla13Silvia Buriolla14Giada Targato15Giada Targato16Lucia Da Ros17Stefania Russo18Marta Bonotto19Barbara Belletti20Gustavo Baldassarre21Giuseppe Damante22Fabio Puglisi23Fabio Puglisi24Department of Medicine (DAME), University of Udine, Udine, ItalyDepartment of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, ItalyDepartment of Medicine (DAME), University of Udine, Udine, ItalyDepartment of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, ItalyInstitute of Human Genetics, ASUFC University Hospital, Udine, ItalyDepartment of Medicine (DAME), University of Udine, Udine, ItalyUnit of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, ItalyDepartment of Medicine (DAME), University of Udine, Udine, ItalyDepartment of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, ItalyDepartment of Medicine (DAME), University of Udine, Udine, ItalyDepartment of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, ItalyDepartment of Medicine (DAME), University of Udine, Udine, ItalyDepartment of Oncology, ASUFC University Hospital, Udine, ItalyDepartment of Medicine (DAME), University of Udine, Udine, ItalyDepartment of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, ItalyDepartment of Medicine (DAME), University of Udine, Udine, ItalyDepartment of Oncology, ASUFC University Hospital, Udine, ItalyDepartment of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, ItalyDepartment of Oncology, ASUFC University Hospital, Udine, ItalyDepartment of Oncology, ASUFC University Hospital, Udine, ItalyUnit of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, ItalyUnit of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, ItalyInstitute of Human Genetics, ASUFC University Hospital, Udine, ItalyDepartment of Medicine (DAME), University of Udine, Udine, ItalyDepartment of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, ItalyBackgroundEndocrine therapy (ET) is the mainstay of treatment for hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer; however, adaptive mechanisms emerge in about 25–30% of cases through alterations in the estrogen receptor ligand-binding domain, with a consequent ligand-independent estrogen receptor activity. Epigenetic-mediated events are less known and potentially involved in alternative mechanisms of resistance. The aim of this study was to test the feasibility of estrogen receptor 1 (ESR1) epigenetic characterization through liquid biopsy and to show its potential longitudinal application for an early ET sensitivity assessment.MethodsA cohort of 49 women with hormone receptor-positive HER2-negative MBC was prospectively enrolled and characterized through circulating tumor DNA using methylation-specific droplet digital PCR (MS-ddPCR) before treatment start (BL) and after 3 months concomitantly with computed tomography (CT) scan restaging (EV1). ESR1 epigenetic status was defined by assessing the methylation of its main promoters (promA and promB). The most established cell-free tumor DNA (ctDNA) factors associated with ET resistance [ESR1 and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations] were assessed through next-generation sequencing. Associations were tested through Mann–Whitney U test, matched pairs variations through Wilcoxon signed rank test, and survival was analyzed by log-rank test.ResultsThe ET backbone was mainly based on aromatase inhibitors (AIs) (70.83%) in association with CDK4/6 inhibitors (93.75%). Significantly lower promA levels at baseline were observed in patients with liver metastases (P = 0.0212) and in patients with ESR1 mutations (P = 0.0091). No significant impact on PFS was observed for promA (P = 0.3777) and promB (P = 0.7455) dichotomized at the median while a ≥2-fold increase in promB or in either promA or promB at EV1 resulted in a significantly worse prognosis (respectively P = 0.0189, P = 0.0294). A significant increase at EV1 was observed for promB among patients with PIK3CA mutation (P = 0.0173). A trend was observed for promB in ESR1 wild-type patients and for promA in the ESR1 mutant subgroup.ConclusionThe study proofed the concept of an epigenetic characterization strategy based on ctDNA and is capable of being integrated in the current clinical workflow to give useful insights on treatment sensitivity.https://www.frontiersin.org/article/10.3389/fonc.2020.550185/fullcirculating tumor DNADNA methylationendocrine treatmentESR1liquid biopsy |
| spellingShingle | Lorenzo Gerratana Lorenzo Gerratana Debora Basile Debora Basile Alessandra Franzoni Lorenzo Allegri Davide Viotto Carla Corvaja Carla Corvaja Lucia Bortot Lucia Bortot Elisa Bertoli Elisa Bertoli Silvia Buriolla Silvia Buriolla Giada Targato Giada Targato Lucia Da Ros Stefania Russo Marta Bonotto Barbara Belletti Gustavo Baldassarre Giuseppe Damante Fabio Puglisi Fabio Puglisi Plasma-Based Longitudinal Evaluation of ESR1 Epigenetic Status in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer Frontiers in Oncology circulating tumor DNA DNA methylation endocrine treatment ESR1 liquid biopsy |
| title | Plasma-Based Longitudinal Evaluation of ESR1 Epigenetic Status in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer |
| title_full | Plasma-Based Longitudinal Evaluation of ESR1 Epigenetic Status in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer |
| title_fullStr | Plasma-Based Longitudinal Evaluation of ESR1 Epigenetic Status in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer |
| title_full_unstemmed | Plasma-Based Longitudinal Evaluation of ESR1 Epigenetic Status in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer |
| title_short | Plasma-Based Longitudinal Evaluation of ESR1 Epigenetic Status in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer |
| title_sort | plasma based longitudinal evaluation of esr1 epigenetic status in hormone receptor positive her2 negative metastatic breast cancer |
| topic | circulating tumor DNA DNA methylation endocrine treatment ESR1 liquid biopsy |
| url | https://www.frontiersin.org/article/10.3389/fonc.2020.550185/full |
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