ESR1 gene amplification and MAP3K mutations are selected during adjuvant endocrine therapies in relapsing Hormone Receptor-positive, HER2-negative breast cancer (HR+ HER2- BC).
<h4>Background</h4>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 landscap...
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Public Library of Science (PLoS)
2023-01-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010563&type=printable |
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| author | Lorenzo Ferrando Andrea Vingiani Anna Garuti Claudio Vernieri Antonino Belfiore Luca Agnelli Gianpaolo Dagrada Diana Ivanoiu Giuseppina Bonizzi Elisabetta Munzone Luana Lippolis Martina Dameri Francesco Ravera Francesco Ravera Marco Colleoni Giuseppe Viale Luca Magnani Alberto Ballestrero Gabriele Zoppoli Giancarlo Pruneri |
| author_facet | Lorenzo Ferrando Andrea Vingiani Anna Garuti Claudio Vernieri Antonino Belfiore Luca Agnelli Gianpaolo Dagrada Diana Ivanoiu Giuseppina Bonizzi Elisabetta Munzone Luana Lippolis Martina Dameri Francesco Ravera Francesco Ravera Marco Colleoni Giuseppe Viale Luca Magnani Alberto Ballestrero Gabriele Zoppoli Giancarlo Pruneri |
| author_sort | Lorenzo Ferrando |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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. |
| format | Article |
| id | doaj-art-14b422e7ad2742c09e052fbd82eff010 |
| institution | Kabale University |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-14b422e7ad2742c09e052fbd82eff0102025-08-20T03:44:45ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042023-01-01191e101056310.1371/journal.pgen.1010563ESR1 gene amplification and MAP3K mutations are selected during adjuvant endocrine therapies in relapsing Hormone Receptor-positive, HER2-negative breast cancer (HR+ HER2- BC).Lorenzo FerrandoAndrea VingianiAnna GarutiClaudio VernieriAntonino BelfioreLuca AgnelliGianpaolo DagradaDiana IvanoiuGiuseppina BonizziElisabetta MunzoneLuana LippolisMartina DameriFrancesco RaveraFrancesco RaveraMarco ColleoniGiuseppe VialeLuca MagnaniAlberto BallestreroGabriele ZoppoliGiancarlo Pruneri<h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010563&type=printable |
| spellingShingle | Lorenzo Ferrando Andrea Vingiani Anna Garuti Claudio Vernieri Antonino Belfiore Luca Agnelli Gianpaolo Dagrada Diana Ivanoiu Giuseppina Bonizzi Elisabetta Munzone Luana Lippolis Martina Dameri Francesco Ravera Francesco Ravera Marco Colleoni Giuseppe Viale Luca Magnani Alberto Ballestrero Gabriele Zoppoli Giancarlo Pruneri ESR1 gene amplification and MAP3K mutations are selected during adjuvant endocrine therapies in relapsing Hormone Receptor-positive, HER2-negative breast cancer (HR+ HER2- BC). PLoS Genetics |
| title | ESR1 gene amplification and MAP3K mutations are selected during adjuvant endocrine therapies in relapsing Hormone Receptor-positive, HER2-negative breast cancer (HR+ HER2- BC). |
| title_full | ESR1 gene amplification and MAP3K mutations are selected during adjuvant endocrine therapies in relapsing Hormone Receptor-positive, HER2-negative breast cancer (HR+ HER2- BC). |
| title_fullStr | ESR1 gene amplification and MAP3K mutations are selected during adjuvant endocrine therapies in relapsing Hormone Receptor-positive, HER2-negative breast cancer (HR+ HER2- BC). |
| title_full_unstemmed | ESR1 gene amplification and MAP3K mutations are selected during adjuvant endocrine therapies in relapsing Hormone Receptor-positive, HER2-negative breast cancer (HR+ HER2- BC). |
| title_short | ESR1 gene amplification and MAP3K mutations are selected during adjuvant endocrine therapies in relapsing Hormone Receptor-positive, HER2-negative breast cancer (HR+ HER2- BC). |
| title_sort | esr1 gene amplification and map3k mutations are selected during adjuvant endocrine therapies in relapsing hormone receptor positive her2 negative breast cancer hr her2 bc |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010563&type=printable |
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