In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 19, No. 1 ( 2023-1-3), p. e1010563-
Abstract:
Previous studies have provided a comprehensive picture of genomic alterations in primary and metastatic Hormone Receptor (HR)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer (HR+ HER2- BC). However, the evolution of the genomic landscape of HR+ HER2- BC during adjuvant endocrine therapies (ETs) remains poorly investigated. Methods and findings We performed a genomic characterization of surgically resected HR+ HER2- BC patients relapsing during or at the completion of adjuvant ET. Using a customized panel, we comprehensively evaluated gene mutations and copy number variation (CNV) in paired primary and metastatic specimens. After retrieval and quality/quantity check of tumor specimens from an original cohort of 204 cases, 74 matched tumor samples were successfully evaluated for DNA mutations and CNV analysis. Along with previously reported genomic alterations, including PIK3CA , TP53 , CDH1 , GATA3 and ESR1 mutations/deletions, we found that ESR1 gene amplification (confirmed by FISH) and MAP3K mutations were enriched in metastatic lesions as compared to matched primary tumors. These alterations were exclusively found in patients treated with adjuvant aromatase inhibitors or LHRH analogs plus tamoxifen, but not in patients treated with tamoxifen alone. Patients with tumors bearing MAP3K mutations in metastatic lesions had significantly worse distant relapse-free survival (hazard ratio [HR] 3.4, 95% CI 1.52–7.70, p value 0.003) and worse overall survival (HR 5.2, 95% CI 2.10–12.8, p-value 〈 0.001) independently of other clinically relevant patient- and tumor-related variables. Conclusions ESR1 amplification and activating MAP3K mutations are potential drivers of acquired resistance to adjuvant ETs employing estrogen deprivation in HR+ HER2- BC. MAP3K mutations are associated with worse prognosis in patients with metastatic disease.
Type of Medium:
Online Resource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1010563
DOI:
10.1371/journal.pgen.1010563.g001
DOI:
10.1371/journal.pgen.1010563.g002
DOI:
10.1371/journal.pgen.1010563.g003
DOI:
10.1371/journal.pgen.1010563.g004
DOI:
10.1371/journal.pgen.1010563.t001
DOI:
10.1371/journal.pgen.1010563.s001
DOI:
10.1371/journal.pgen.1010563.s002
DOI:
10.1371/journal.pgen.1010563.s003
DOI:
10.1371/journal.pgen.1010563.s004
DOI:
10.1371/journal.pgen.1010563.s005
DOI:
10.1371/journal.pgen.1010563.s006
DOI:
10.1371/journal.pgen.1010563.s007
DOI:
10.1371/journal.pgen.1010563.s008
DOI:
10.1371/journal.pgen.1010563.s009
DOI:
10.1371/journal.pgen.1010563.r001
DOI:
10.1371/journal.pgen.1010563.r002
DOI:
10.1371/journal.pgen.1010563.r003
DOI:
10.1371/journal.pgen.1010563.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2186725-2
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