Clinical and Genomic Characteristics of Patients with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer Following Progression on Cyclin-Dependent Kinase 4 and 6 Inhibitors
©2023 The Authors; Published by the American Association for Cancer Research..
PURPOSE: We explored the clinical and genomic characteristics of hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC) after progression on cyclin-dependent kinase 4 and 6 inhibitors (CDK4 and 6i) ± endocrine therapy (ET) to understand potential resistance mechanisms that may aid in identifying treatment options.
EXPERIMENTAL DESIGN: Patients in the United States with HR+, HER2- MBC had tumor biopsies collected from a metastatic site during routine care following progression on a CDK4 and 6i ± ET (CohortPost) or prior to initiating CDK4 and 6i treatment (CohortPre) and analyzed using a targeted mutation panel and RNA-sequencing. Clinical and genomic characteristics were described.
RESULTS: The mean age at MBC diagnosis was 59 years in CohortPre (n = 133) and 56 years in CohortPost (n = 223); 14% and 45% of patients had prior chemotherapy/ET, and 35% and 26% had de novo stage IV MBC, respectively. The most common biopsy site was liver (CohortPre, 23%; CohortPost, 56%). CohortPost had significantly higher tumor mutational burden (TMB; median 3.16 vs. 1.67 Mut/Mb, P < 0.0001), ESR1 alteration frequency (mutations: 37% vs. 10%, FDR < 0.0001; fusions: 9% vs. 2%, P = 0.0176), and higher copy-number amplification of genes on chr12q15, including MDM2, FRS2, and YEATS4 versus patients in the CohortPre group. In addition, CDK4 copy-number gain on chr12q13 was significantly higher in CohortPost versus CohortPre (27% vs. 11%, P = 0.0005).
CONCLUSIONS: Distinct mechanisms potentially associated with resistance to CDK4 and 6i ± ET, including alterations in ESR1 and amplification of chr12q15 and CDK4 copy-number gain, were identified.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:29 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 29(2023), 17 vom: 01. Sept., Seite 3372-3383 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rao, Xi [VerfasserIn] |
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| Links: |
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| Themen: |
Cyclin-Dependent Kinase 4 |
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| Anmerkungen: |
Date Completed 04.09.2023 Date Revised 06.09.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-22-3843 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM357910141 |
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| 100 | 1 | |a Rao, Xi |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Clinical and Genomic Characteristics of Patients with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer Following Progression on Cyclin-Dependent Kinase 4 and 6 Inhibitors |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Revised 06.09.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2023 The Authors; Published by the American Association for Cancer Research. | ||
| 520 | |a PURPOSE: We explored the clinical and genomic characteristics of hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC) after progression on cyclin-dependent kinase 4 and 6 inhibitors (CDK4 and 6i) ± endocrine therapy (ET) to understand potential resistance mechanisms that may aid in identifying treatment options | ||
| 520 | |a EXPERIMENTAL DESIGN: Patients in the United States with HR+, HER2- MBC had tumor biopsies collected from a metastatic site during routine care following progression on a CDK4 and 6i ± ET (CohortPost) or prior to initiating CDK4 and 6i treatment (CohortPre) and analyzed using a targeted mutation panel and RNA-sequencing. Clinical and genomic characteristics were described | ||
| 520 | |a RESULTS: The mean age at MBC diagnosis was 59 years in CohortPre (n = 133) and 56 years in CohortPost (n = 223); 14% and 45% of patients had prior chemotherapy/ET, and 35% and 26% had de novo stage IV MBC, respectively. The most common biopsy site was liver (CohortPre, 23%; CohortPost, 56%). CohortPost had significantly higher tumor mutational burden (TMB; median 3.16 vs. 1.67 Mut/Mb, P < 0.0001), ESR1 alteration frequency (mutations: 37% vs. 10%, FDR < 0.0001; fusions: 9% vs. 2%, P = 0.0176), and higher copy-number amplification of genes on chr12q15, including MDM2, FRS2, and YEATS4 versus patients in the CohortPre group. In addition, CDK4 copy-number gain on chr12q13 was significantly higher in CohortPost versus CohortPre (27% vs. 11%, P = 0.0005) | ||
| 520 | |a CONCLUSIONS: Distinct mechanisms potentially associated with resistance to CDK4 and 6i ± ET, including alterations in ESR1 and amplification of chr12q15 and CDK4 copy-number gain, were identified | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Beyrer, Julie |e verfasserin |4 aut | |
| 700 | 1 | |a Nash Smyth, Emily |e verfasserin |4 aut | |
| 700 | 1 | |a Morato Guimaraes, Claudia |e verfasserin |4 aut | |
| 700 | 1 | |a Litchfield, Lacey M |e verfasserin |4 aut | |
| 700 | 1 | |a Bowman, Lee |e verfasserin |4 aut | |
| 700 | 1 | |a Lawrence, Garreth W |e verfasserin |4 aut | |
| 700 | 1 | |a Aggarwal, Amit |e verfasserin |4 aut | |
| 700 | 1 | |a Andre, Fabrice |e verfasserin |4 aut | |
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