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Åke Borg

Åke Borg

Principal investigator

Åke Borg

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

Author

  • Kamila Kaminska
  • Nina Akrap
  • Johan Staaf
  • Carla L Alves
  • Anna Ehinger
  • Anna Ebbesson
  • Ingrid Hedenfalk
  • Lukas Beumers
  • Srinivas Veerla
  • Katja Harbst
  • Sidse Ehmsen
  • Signe Borgquist
  • Åke Borg
  • Alejandro Pérez-Fidalgo
  • Henrik J Ditzel
  • Ana Bosch
  • Gabriella Honeth
Show all

Summary, in English

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.

Department/s

  • Melanoma
  • LUCC: Lund University Cancer Centre
  • Molecular therapeutics in breast cancer
  • Breastcancer-genetics
  • Breast/lungcancer
  • Research Group Lung Cancer
  • Pathology, Lund
  • Department of Laboratory Medicine
  • Breast/ovarian cancer
  • Breast and Ovarian Cancer Genomics
  • Melanoma Genomics
  • Lund Melanoma Study Group
  • Breastcancer
  • Breast cancer prevention & intervention
  • Familial Breast Cancer

Publishing year

2021-02-18

Language

English

Pages

26-26

Publication/Series

Breast cancer research : BCR

Volume

23

Issue

1

Document type

Journal article

Publisher

BioMed Central (BMC)

Topic

  • Cancer and Oncology
  • Pharmaceutical Sciences

Status

Published

Research group

  • Molecular therapeutics in breast cancer
  • Research Group Lung Cancer
  • Breast and Ovarian Cancer Genomics
  • Melanoma Genomics
  • Lund Melanoma Study Group
  • Breast cancer prevention & intervention
  • Familial Breast Cancer

ISBN/ISSN/Other

  • ISSN: 1465-5411