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Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer

Kaminska, Kamila LU ; Akrap, Nina LU ; Staaf, Johan LU ; Alves, Carla L ; Ehinger, Anna LU ; Ebbesson, Anna LU ; Hedenfalk, Ingrid LU ; Beumers, Lukas LU ; Veerla, Srinivas LU and Harbst, Katja LU , et al. (2021) In Breast cancer research : BCR 23(1). p.26-26
Abstract

BACKGROUND: Resistance to endocrine treatment in metastatic breast cancer is a major clinical challenge. Clinical tools to predict both drug resistance and possible treatment combination approaches to overcome it are lacking. This unmet need is mainly due to the heterogeneity underlying both the mechanisms involved in resistance development and breast cancer itself.

METHODS: To study the complexity of the mechanisms involved in the resistance to the selective estrogen receptor degrader (SERD) fulvestrant, we performed comprehensive biomarker analyses using several in vitro models that recapitulate the heterogeneity of developed resistance. We further corroborated our findings in tissue samples from patients treated with... (More)

BACKGROUND: Resistance to endocrine treatment in metastatic breast cancer is a major clinical challenge. Clinical tools to predict both drug resistance and possible treatment combination approaches to overcome it are lacking. This unmet need is mainly due to the heterogeneity underlying both the mechanisms involved in resistance development and breast cancer itself.

METHODS: To study the complexity of the mechanisms involved in the resistance to the selective estrogen receptor degrader (SERD) fulvestrant, we performed comprehensive biomarker analyses using several in vitro models that recapitulate the heterogeneity of developed resistance. We further corroborated our findings in tissue samples from patients treated with fulvestrant.

RESULTS: We found that different in vitro models of fulvestrant resistance show variable stability in their phenotypes, which corresponded with distinct genomic alterations. Notably, the studied models presented adaptation at different cell cycle nodes to facilitate progression through the cell cycle and responded differently to CDK inhibitors. Cyclin E2 overexpression was identified as a biomarker of a persistent fulvestrant-resistant phenotype. Comparison of pre- and post-treatment paired tumor biopsies from patients treated with fulvestrant revealed an upregulation of cyclin E2 upon development of resistance. Moreover, overexpression of this cyclin was found to be a prognostic factor determining resistance to fulvestrant and shorter progression-free survival.

CONCLUSIONS: These data highlight the complexity of estrogen receptor positive breast cancer and suggest that the development of diverse resistance mechanisms dictate levels of ER independence and potentially cross-resistance to CDK inhibitors.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Breast cancer research : BCR
volume
23
issue
1
pages
26 - 26
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85101221232
  • pmid:33602273
ISSN
1465-5411
DOI
10.1186/s13058-021-01402-1
language
English
LU publication?
yes
id
c370313e-e31e-48ef-83aa-8fb4a7218293
date added to LUP
2021-03-01 16:40:00
date last changed
2021-06-16 04:30:44
@article{c370313e-e31e-48ef-83aa-8fb4a7218293,
  abstract     = {<p>BACKGROUND: Resistance to endocrine treatment in metastatic breast cancer is a major clinical challenge. Clinical tools to predict both drug resistance and possible treatment combination approaches to overcome it are lacking. This unmet need is mainly due to the heterogeneity underlying both the mechanisms involved in resistance development and breast cancer itself.</p><p>METHODS: To study the complexity of the mechanisms involved in the resistance to the selective estrogen receptor degrader (SERD) fulvestrant, we performed comprehensive biomarker analyses using several in vitro models that recapitulate the heterogeneity of developed resistance. We further corroborated our findings in tissue samples from patients treated with fulvestrant.</p><p>RESULTS: We found that different in vitro models of fulvestrant resistance show variable stability in their phenotypes, which corresponded with distinct genomic alterations. Notably, the studied models presented adaptation at different cell cycle nodes to facilitate progression through the cell cycle and responded differently to CDK inhibitors. Cyclin E2 overexpression was identified as a biomarker of a persistent fulvestrant-resistant phenotype. Comparison of pre- and post-treatment paired tumor biopsies from patients treated with fulvestrant revealed an upregulation of cyclin E2 upon development of resistance. Moreover, overexpression of this cyclin was found to be a prognostic factor determining resistance to fulvestrant and shorter progression-free survival.</p><p>CONCLUSIONS: These data highlight the complexity of estrogen receptor positive breast cancer and suggest that the development of diverse resistance mechanisms dictate levels of ER independence and potentially cross-resistance to CDK inhibitors.</p>},
  author       = {Kaminska, Kamila and Akrap, Nina and Staaf, Johan and Alves, Carla L and Ehinger, Anna and Ebbesson, Anna and Hedenfalk, Ingrid and Beumers, Lukas and Veerla, Srinivas and Harbst, Katja and Ehmsen, Sidse and Borgquist, Signe and Borg, Åke and Pérez-Fidalgo, Alejandro and Ditzel, Henrik J and Bosch, Ana and Honeth, Gabriella},
  issn         = {1465-5411},
  language     = {eng},
  month        = {02},
  number       = {1},
  pages        = {26--26},
  publisher    = {BioMed Central (BMC)},
  series       = {Breast cancer research : BCR},
  title        = {Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer},
  url          = {http://dx.doi.org/10.1186/s13058-021-01402-1},
  doi          = {10.1186/s13058-021-01402-1},
  volume       = {23},
  year         = {2021},
}