Preexisting Somatic Mutations of Estrogen Receptor Alpha (ESR1) in Early-Stage Primary Breast Cancer
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/8e71ac7c-a7e7-4e8c-ae3f-b1c53f6e3db2
- author
- organization
-
- Transl oncogenomics
- LUCC: Lund University Cancer Centre
- Translational Oncogenomics (research group)
- Breastcancer-genetics
- Breast cancer treatment
- The Liquid Biopsy and Tumor Progression in Breast Cancer (research group)
- Breast Cancer Surgery (research group)
- Surgery (Lund)
- Tumor Cell Biology (research group)
- Division of Translational Cancer Research
- Division of Clinical Genetics
- Familial Breast Cancer (research group)
- publishing date
- 2021-04-22
- 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
- external identifiers
-
- pmid:33937624
- scopus:85122556946
- 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
- 2022-06-16 04:20:53
@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 < .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}}, keywords = {{ESR1; Mutation; RNA-seq; dPCR; Endocrine therapy; Therapy resistance; Breast cancer}}, 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}}, }