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Preexisting Somatic Mutations of Estrogen Receptor Alpha (ESR1) in Early-Stage Primary Breast Cancer

Dahlgren, Malin LU ; George, Anthony LU ; Brueffer, Christian LU ; Gladchuk, Sergii LU ; Chen, Yilun LU ; Vallon-Christersson, Johan LU ; Hegardt, Cecilia LU ; Häkkinen, Jari LU ; Ryden, Lisa LU and Malmberg, Martin LU , et al. (2021) In JNCI Cancer Spectrum 5(2).
Abstract
More than three-quarters of primary breast cancers are positive for estrogen receptor alpha (ER; encoded by the gene ESR1), the most important factor for directing anti-estrogenic endocrine therapy (ET). Recently, mutations in ESR1 were identified as acquired mechanisms of resistance to ET, found in 12% to 55% of metastatic breast cancers treated previously with ET. We analyzed 3217 population-based invasive primary (nonmetastatic) breast cancers (within the SCAN-B study, ClinicalTrials.gov NCT02306096), sampled from initial diagnosis prior to any treatment, for the presence of ESR1 mutations using RNA sequencing. Mutations were verified by droplet digital polymerase chain reaction on tumor and normal DNA. Patient outcomes were analyzed... (More)
More than three-quarters of primary breast cancers are positive for estrogen receptor alpha (ER; encoded by the gene ESR1), the most important factor for directing anti-estrogenic endocrine therapy (ET). Recently, mutations in ESR1 were identified as acquired mechanisms of resistance to ET, found in 12% to 55% of metastatic breast cancers treated previously with ET. We analyzed 3217 population-based invasive primary (nonmetastatic) breast cancers (within the SCAN-B study, ClinicalTrials.gov NCT02306096), sampled from initial diagnosis prior to any treatment, for the presence of ESR1 mutations using RNA sequencing. Mutations were verified by droplet digital polymerase chain reaction on tumor and normal DNA. Patient outcomes were analyzed using Kaplan-Meier estimation and a series of 2-factor Cox regression multivariable analyses. We identified ESR1 resistance mutations in 30 tumors (0.9%), of which 29 were ER positive (1.1%). In ET-treated disease, presence of ESR1 mutation was associated with poor relapse-free survival and overall survival (2-sided log-rank test P < .001 and P = .008, respectively), with hazard ratios of 3.00 (95% confidence interval = 1.56 to 5.88) and 2.51 (95% confidence interval = 1.24 to 5.07), respectively, which remained statistically significant when adjusted for other prognostic factors. These population-based results indicate that ESR1 mutations at diagnosis of primary breast cancer occur in about 1% of women and identify for the first time in the adjuvant setting that such preexisting mutations are associated to eventual resistance to standard hormone therapy. If replicated, tumor ESR1 screening should be considered in ER-positive primary breast cancer, and for patients with mutated disease, ER degraders such as fulvestrant or other therapeutic options may be considered as more appropriate. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ESR1, Mutation, RNA-seq, dPCR, Endocrine therapy, Therapy resistance, Breast cancer
in
JNCI Cancer Spectrum
volume
5
issue
2
article number
pkab028
publisher
Oxford University Press
ISSN
2515-5091
DOI
10.1093/jncics/pkab028
project
Sweden Cancerome Analysis Network - Breast (SCAN-B): a large-scale multicenter infrastructure towards implementation of breast cancer genomic analyses in the clinical routine
language
English
LU publication?
yes
id
8e71ac7c-a7e7-4e8c-ae3f-b1c53f6e3db2
date added to LUP
2021-04-26 19:32:02
date last changed
2021-04-28 15:25:55
@article{8e71ac7c-a7e7-4e8c-ae3f-b1c53f6e3db2,
  abstract     = {More than three-quarters of primary breast cancers are positive for estrogen receptor alpha (ER; encoded by the gene ESR1), the most important factor for directing anti-estrogenic endocrine therapy (ET). Recently, mutations in ESR1 were identified as acquired mechanisms of resistance to ET, found in 12% to 55% of metastatic breast cancers treated previously with ET. We analyzed 3217 population-based invasive primary (nonmetastatic) breast cancers (within the SCAN-B study, ClinicalTrials.gov NCT02306096), sampled from initial diagnosis prior to any treatment, for the presence of ESR1 mutations using RNA sequencing. Mutations were verified by droplet digital polymerase chain reaction on tumor and normal DNA. Patient outcomes were analyzed using Kaplan-Meier estimation and a series of 2-factor Cox regression multivariable analyses. We identified ESR1 resistance mutations in 30 tumors (0.9%), of which 29 were ER positive (1.1%). In ET-treated disease, presence of ESR1 mutation was associated with poor relapse-free survival and overall survival (2-sided log-rank test P &lt; .001 and P = .008, respectively), with hazard ratios of 3.00 (95% confidence interval = 1.56 to 5.88) and 2.51 (95% confidence interval = 1.24 to 5.07), respectively, which remained statistically significant when adjusted for other prognostic factors. These population-based results indicate that ESR1 mutations at diagnosis of primary breast cancer occur in about 1% of women and identify for the first time in the adjuvant setting that such preexisting mutations are associated to eventual resistance to standard hormone therapy. If replicated, tumor ESR1 screening should be considered in ER-positive primary breast cancer, and for patients with mutated disease, ER degraders such as fulvestrant or other therapeutic options may be considered as more appropriate.},
  author       = {Dahlgren, Malin and George, Anthony and Brueffer, Christian and Gladchuk, Sergii and Chen, Yilun and Vallon-Christersson, Johan and Hegardt, Cecilia and Häkkinen, Jari and Ryden, Lisa and Malmberg, Martin and Larsson, Christer and Gruvberger, Sofia and Ehinger, Anna and Loman, Niklas and Borg, Åke and Saal, Lao},
  issn         = {2515-5091},
  language     = {eng},
  month        = {04},
  number       = {2},
  publisher    = {Oxford University Press},
  series       = {JNCI Cancer Spectrum},
  title        = {Preexisting Somatic Mutations of Estrogen Receptor Alpha (ESR1) in Early-Stage Primary Breast Cancer},
  url          = {http://dx.doi.org/10.1093/jncics/pkab028},
  doi          = {10.1093/jncics/pkab028},
  volume       = {5},
  year         = {2021},
}