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Genomic alterations associated with resistance and circulating tumor DNA dynamics for early detection of progression on CDK4/6 inhibitor in advanced breast cancer

Kindt, Charlotte K. ; Alves, Carla L. LU ; Ehmsen, Sidse ; Kragh, Amalie ; Reinert, Thomas ; Vogsen, Marianne ; Kodahl, Annette R. ; Rønlev, Jeanette D. ; Ardik, Dilan and Sørensen, Anna L. , et al. (2024) In International Journal of Cancer 155(12). p.2211-2222
Abstract

Combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy significantly improves outcome for patients with estrogen receptor-positive (ER+) metastatic breast cancer, but drug resistance and thus disease progression inevitably occur. Herein, we aimed to identify genomic alterations associated with combined CDK4/6i and endocrine therapy resistance, and follow the levels of specific mutations in longitudinal circulating tumor DNA (ctDNA) for early detection of progression. From a cohort of 86 patients with ER+ metastatic breast cancer we performed whole exome sequencing or targeted sequencing of paired tumor (N = 8) or blood samples (N = 5) obtained before initiation of combined CDK4/6i and endocrine therapy and at disease progression.... (More)

Combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy significantly improves outcome for patients with estrogen receptor-positive (ER+) metastatic breast cancer, but drug resistance and thus disease progression inevitably occur. Herein, we aimed to identify genomic alterations associated with combined CDK4/6i and endocrine therapy resistance, and follow the levels of specific mutations in longitudinal circulating tumor DNA (ctDNA) for early detection of progression. From a cohort of 86 patients with ER+ metastatic breast cancer we performed whole exome sequencing or targeted sequencing of paired tumor (N = 8) or blood samples (N = 5) obtained before initiation of combined CDK4/6i and endocrine therapy and at disease progression. Mutations in oncogenic genes at progression were rare, while amplifications of growth-regulating genes were more frequent. The most frequently acquired alterations observed were PIK3CA and TP53 mutations and PDK1 amplification. Longitudinal ctDNA dynamics of mutant PIK3CA or private mutations revealed increased mutation levels at progression in 8 of 10 patients (80%). Impressively, rising levels of PIK3CA-mutated ctDNA were detected 4–17 months before imaging. Our data add to the growing evidence supporting longitudinal ctDNA analysis for real-time monitoring of CDK4/6i response and early detection of progression in advanced breast cancer. Further, our analysis suggests that amplification of growth-related genes may contribute to combined CDK4/6i and endocrine therapy resistance.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CDK4/6 inhibitor, ctDNA, estrogen receptor-positive breast cancer, genomic alterations, resistance
in
International Journal of Cancer
volume
155
issue
12
pages
12 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:39128978
  • scopus:85201047204
ISSN
0020-7136
DOI
10.1002/ijc.35126
language
English
LU publication?
yes
id
d82787bc-e495-40c8-b1e5-b41a8a946426
date added to LUP
2024-11-04 10:34:18
date last changed
2025-07-01 07:49:13
@article{d82787bc-e495-40c8-b1e5-b41a8a946426,
  abstract     = {{<p>Combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy significantly improves outcome for patients with estrogen receptor-positive (ER+) metastatic breast cancer, but drug resistance and thus disease progression inevitably occur. Herein, we aimed to identify genomic alterations associated with combined CDK4/6i and endocrine therapy resistance, and follow the levels of specific mutations in longitudinal circulating tumor DNA (ctDNA) for early detection of progression. From a cohort of 86 patients with ER+ metastatic breast cancer we performed whole exome sequencing or targeted sequencing of paired tumor (N = 8) or blood samples (N = 5) obtained before initiation of combined CDK4/6i and endocrine therapy and at disease progression. Mutations in oncogenic genes at progression were rare, while amplifications of growth-regulating genes were more frequent. The most frequently acquired alterations observed were PIK3CA and TP53 mutations and PDK1 amplification. Longitudinal ctDNA dynamics of mutant PIK3CA or private mutations revealed increased mutation levels at progression in 8 of 10 patients (80%). Impressively, rising levels of PIK3CA-mutated ctDNA were detected 4–17 months before imaging. Our data add to the growing evidence supporting longitudinal ctDNA analysis for real-time monitoring of CDK4/6i response and early detection of progression in advanced breast cancer. Further, our analysis suggests that amplification of growth-related genes may contribute to combined CDK4/6i and endocrine therapy resistance.</p>}},
  author       = {{Kindt, Charlotte K. and Alves, Carla L. and Ehmsen, Sidse and Kragh, Amalie and Reinert, Thomas and Vogsen, Marianne and Kodahl, Annette R. and Rønlev, Jeanette D. and Ardik, Dilan and Sørensen, Anna L. and Evald, Kirstine and Clemmensen, Mia L. and Staaf, Johan and Ditzel, Henrik J.}},
  issn         = {{0020-7136}},
  keywords     = {{CDK4/6 inhibitor; ctDNA; estrogen receptor-positive breast cancer; genomic alterations; resistance}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{2211--2222}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{International Journal of Cancer}},
  title        = {{Genomic alterations associated with resistance and circulating tumor DNA dynamics for early detection of progression on CDK4/6 inhibitor in advanced breast cancer}},
  url          = {{http://dx.doi.org/10.1002/ijc.35126}},
  doi          = {{10.1002/ijc.35126}},
  volume       = {{155}},
  year         = {{2024}},
}