PMID- 33072577
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220417
IS  - 2234-943X (Print)
IS  - 2234-943X (Electronic)
IS  - 2234-943X (Linking)
VI  - 10
DP  - 2020
TI  - Plasma-Based Longitudinal Evaluation of ESR1 Epigenetic Status in Hormone 
      Receptor-Positive HER2-Negative Metastatic Breast Cancer.
PG  - 550185
LID - 10.3389/fonc.2020.550185 [doi]
LID - 550185
AB  - BACKGROUND: Endocrine 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. 
      METHODS: A 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. RESULTS: The 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. CONCLUSION: The 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.
CI  - Copyright (c) 2020 Gerratana, Basile, Franzoni, Allegri, Viotto, Corvaja, Bortot, 
      Bertoli, Buriolla, Targato, Da Ros, Russo, Bonotto, Belletti, Baldassarre, 
      Damante and Puglisi.
FAU - Gerratana, Lorenzo
AU  - Gerratana L
AD  - Department of Medicine (DAME), University of Udine, Udine, Italy.
AD  - Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), 
      IRCCS, Aviano, Italy.
FAU - Basile, Debora
AU  - Basile D
AD  - Department of Medicine (DAME), University of Udine, Udine, Italy.
AD  - Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), 
      IRCCS, Aviano, Italy.
FAU - Franzoni, Alessandra
AU  - Franzoni A
AD  - Institute of Human Genetics, ASUFC University Hospital, Udine, Italy.
FAU - Allegri, Lorenzo
AU  - Allegri L
AD  - Department of Medicine (DAME), University of Udine, Udine, Italy.
FAU - Viotto, Davide
AU  - Viotto D
AD  - Unit of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), 
      IRCCS, Aviano, Italy.
FAU - Corvaja, Carla
AU  - Corvaja C
AD  - Department of Medicine (DAME), University of Udine, Udine, Italy.
AD  - Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), 
      IRCCS, Aviano, Italy.
FAU - Bortot, Lucia
AU  - Bortot L
AD  - Department of Medicine (DAME), University of Udine, Udine, Italy.
AD  - Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), 
      IRCCS, Aviano, Italy.
FAU - Bertoli, Elisa
AU  - Bertoli E
AD  - Department of Medicine (DAME), University of Udine, Udine, Italy.
AD  - Department of Oncology, ASUFC University Hospital, Udine, Italy.
FAU - Buriolla, Silvia
AU  - Buriolla S
AD  - Department of Medicine (DAME), University of Udine, Udine, Italy.
AD  - Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), 
      IRCCS, Aviano, Italy.
FAU - Targato, Giada
AU  - Targato G
AD  - Department of Medicine (DAME), University of Udine, Udine, Italy.
AD  - Department of Oncology, ASUFC University Hospital, Udine, Italy.
FAU - Da Ros, Lucia
AU  - Da Ros L
AD  - Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), 
      IRCCS, Aviano, Italy.
FAU - Russo, Stefania
AU  - Russo S
AD  - Department of Oncology, ASUFC University Hospital, Udine, Italy.
FAU - Bonotto, Marta
AU  - Bonotto M
AD  - Department of Oncology, ASUFC University Hospital, Udine, Italy.
FAU - Belletti, Barbara
AU  - Belletti B
AD  - Unit of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), 
      IRCCS, Aviano, Italy.
FAU - Baldassarre, Gustavo
AU  - Baldassarre G
AD  - Unit of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), 
      IRCCS, Aviano, Italy.
FAU - Damante, Giuseppe
AU  - Damante G
AD  - Institute of Human Genetics, ASUFC University Hospital, Udine, Italy.
FAU - Puglisi, Fabio
AU  - Puglisi F
AD  - Department of Medicine (DAME), University of Udine, Udine, Italy.
AD  - Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), 
      IRCCS, Aviano, Italy.
LA  - eng
PT  - Journal Article
DEP - 20200918
PL  - Switzerland
TA  - Front Oncol
JT  - Frontiers in oncology
JID - 101568867
PMC - PMC7531252
OTO - NOTNLM
OT  - DNA methylation
OT  - ESR1
OT  - circulating tumor DNA
OT  - endocrine treatment
OT  - liquid biopsy
EDAT- 2020/10/20 06:00
MHDA- 2020/10/20 06:01
PMCR- 2020/01/01
CRDT- 2020/10/19 05:58
PHST- 2020/04/08 00:00 [received]
PHST- 2020/08/20 00:00 [accepted]
PHST- 2020/10/19 05:58 [entrez]
PHST- 2020/10/20 06:00 [pubmed]
PHST- 2020/10/20 06:01 [medline]
PHST- 2020/01/01 00:00 [pmc-release]
AID - 10.3389/fonc.2020.550185 [doi]
PST - epublish
SO  - Front Oncol. 2020 Sep 18;10:550185. doi: 10.3389/fonc.2020.550185. eCollection 
      2020.