Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors.
Clin Cancer Res
; 25(24): 7485-7496, 2019 12 15.
Article
em En
| MEDLINE
| ID: mdl-31548345
ABSTRACT
PURPOSE:
To investigate the presence of ESR1 mutations in primary estrogen-receptor-positive (ER+) breast cancer treated with extended (>4 weeks) neoadjuvant (presurgical) aromatase inhibitor (NAI) therapy and to identify patients who may gain less benefit from aromatase inhibition (AI) alone based upon on-treatment changes in gene expression. EXPERIMENTALDESIGN:
We evaluated ER, progesterone receptor, and Ki67 by immunostaining, ESR1 mutations by droplet-digital PCR and expression of over 800 key breast cancer genes in paired pre- and post-NAI tumor samples from 87 ER+ breast cancer patients.RESULTS:
Cell proliferation and estrogen-regulated genes (ERG) remained suppressed in most tumors indicative of persistent response to NAI. Enrichment of ESR1 mutations was found in five tumors and predominantly in patients receiving therapy for >6 months. ESR1-mutant tumors showed increased expression of ESR1 transcript and limited suppression of ERGs and proliferation-associated genes in response to NAI. ESR1 wild-type tumors with high residual proliferation (Ki67r ≥10%; 15/87 tumors) showed lower ESR1/ER expression pre- and post-therapy and lower ERGs. Tumors with ESR1 mutations or Ki67r ≥10% showed less inhibition of estrogen response, cell cycle, and E2F-target genes.CONCLUSIONS:
Ligand-independent ER signaling, as a result of ESR1 mutation or reduced ER dependence, identified after extended NAI therapy, can guide early selection of patients who would benefit from combination therapy.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
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Biomarcadores Tumorais
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Regulação Neoplásica da Expressão Gênica
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Receptor alfa de Estrogênio
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Inibidores da Aromatase
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Mutação
Limite:
Aged
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Aged80
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Female
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Humans
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Middle aged
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article