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Preexisting Somatic Mutations of Estrogen Receptor Alpha (ESR1) in Early-Stage Primary Breast Cancer
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- Dahlgren, Malin (författare)
- Lund University,Lunds universitet,Translational Oncogenomics,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Transl onkogenomik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Transl oncogenomics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- George, Anthony (författare)
- Lund University,Lunds universitet,Translational Oncogenomics,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Transl onkogenomik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Transl oncogenomics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Brueffer, Christian (författare)
- Lund University,Lunds universitet,Translational Oncogenomics,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Transl onkogenomik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Transl oncogenomics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- (creator_code:org_t)
- 2021-04-22
- 2021
- Engelska.
- Ingår i: JNCI Cancer Spectrum. - : Oxford University Press (OUP). - 2515-5091. ; 5:2
- Tidskriftsartikel (refereegranskat)
Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Bioinformatik och systembiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Bioinformatics and Systems Biology (hsv//eng)
- NATURVETENSKAP -- Data- och informationsvetenskap -- Bioinformatik (hsv//swe)
- NATURAL SCIENCES -- Computer and Information Sciences -- Bioinformatics (hsv//eng)
Nyckelord
- ESR1
- Mutation
- RNA-seq
- dPCR
- Endocrine therapy
- Therapy resistance
- Breast cancer
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