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Endothelial Cell pY397-FAK Expression Predicts the Risk of Breast Cancer Recurrences after Radiotherapy in the SweBCG91-RT Cohort

Drake, Rebecca J.G. ; Landén, Amalia H. ; Holmberg, Erik ; Tullberg, Axel Stenmark ; Killander, Fredrika LU ; Niméus, Emma LU ; Jordan, Alexander ; McGuinness, Jennifer ; Karlsson, Per and Hodivala-Dilke, Kairbaan (2025) In Clinical Cancer Research 31(7). p.1323-1332
Abstract

Purpose: Identifying biomarkers of radiotherapy (RT) response is important for optimizing the treatment of early breast cancer. In this study, we tested the interaction between endothelial cell (EC) expression of phospho-Tyr397-FAK (pY397-FAK) and adjuvant-RT on clinical outcomes after breast-conserving surgery (BCS) within a randomized study. Preclinical data suggest an enhanced effect of RT on low EC_pY397-FAK expression. Experimental Design: We analyzed tissue microarrays from the Swedish Breast Cancer Group 91 Radiotherapy (stage I–II, lymph node–negative) breast cancer cohort, consisting of 1,178 patients randomly assigned to receive either BCS alone or BCS plus adjuvant-RT. Tissue microarray sections were immunostained for... (More)

Purpose: Identifying biomarkers of radiotherapy (RT) response is important for optimizing the treatment of early breast cancer. In this study, we tested the interaction between endothelial cell (EC) expression of phospho-Tyr397-FAK (pY397-FAK) and adjuvant-RT on clinical outcomes after breast-conserving surgery (BCS) within a randomized study. Preclinical data suggest an enhanced effect of RT on low EC_pY397-FAK expression. Experimental Design: We analyzed tissue microarrays from the Swedish Breast Cancer Group 91 Radiotherapy (stage I–II, lymph node–negative) breast cancer cohort, consisting of 1,178 patients randomly assigned to receive either BCS alone or BCS plus adjuvant-RT. Tissue microarray sections were immunostained for pY397-FAK, CD31, α-smooth muscle actin, and pan-cytokeratin. HALO analysis scored mean pY397-FAK intensity in CD31+ ECs, pan-cytokeratin–positive tumor epithelial cells, and α-smooth muscle actin + mural/stromal cells per core. For 822 patients, multivariable Cox regression analysis was performed for the primary and secondary 5-year endpoints, locoregional recurrence and all recurrence, respectively, as dependent variables and RT and EC_pY397-FAK as independent variables. Results: EC_pY397-FAK expression was not predictive for the primary endpoint locoregional recurrence (P ¼ 0.098), but the direction of the RT effect was in line with preclinical findings. For the secondary endpoint all recurrence, there was a significant interaction (P ¼ 0.026) between EC_pY397-FAK and RT. Without RT, higher EC_pY397-FAK expression resulted in a lower risk for all recurrence (HR ¼ 0.74 per SD; 95% confidence interval ¼ 0.57–0.96; P ¼ 0.026). Conclusions: Within the first 5 years following BCS, patients with low EC_pY397-FAK expression derive greater benefit from RT than patients with high EC_pY397-FAK expression. However, without RT, low EC_pY397-FAK expression is associated with a higher risk of recurrence.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Clinical Cancer Research
volume
31
issue
7
pages
10 pages
publisher
American Association for Cancer Research Inc.
external identifiers
  • pmid:39908003
  • scopus:105002447250
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-24-2939
language
English
LU publication?
yes
additional info
Publisher Copyright: ©2025 The Authors.
id
c1636ac8-d08a-47af-ac03-1abb89ffdba3
date added to LUP
2025-08-22 13:52:33
date last changed
2025-10-03 17:55:59
@article{c1636ac8-d08a-47af-ac03-1abb89ffdba3,
  abstract     = {{<p>Purpose: Identifying biomarkers of radiotherapy (RT) response is important for optimizing the treatment of early breast cancer. In this study, we tested the interaction between endothelial cell (EC) expression of phospho-Tyr397-FAK (pY397-FAK) and adjuvant-RT on clinical outcomes after breast-conserving surgery (BCS) within a randomized study. Preclinical data suggest an enhanced effect of RT on low EC_pY397-FAK expression. Experimental Design: We analyzed tissue microarrays from the Swedish Breast Cancer Group 91 Radiotherapy (stage I–II, lymph node–negative) breast cancer cohort, consisting of 1,178 patients randomly assigned to receive either BCS alone or BCS plus adjuvant-RT. Tissue microarray sections were immunostained for pY397-FAK, CD31, α-smooth muscle actin, and pan-cytokeratin. HALO analysis scored mean pY397-FAK intensity in CD31<sup>+</sup> ECs, pan-cytokeratin–positive tumor epithelial cells, and α-smooth muscle actin + mural/stromal cells per core. For 822 patients, multivariable Cox regression analysis was performed for the primary and secondary 5-year endpoints, locoregional recurrence and all recurrence, respectively, as dependent variables and RT and EC_pY397-FAK as independent variables. Results: EC_pY397-FAK expression was not predictive for the primary endpoint locoregional recurrence (P ¼ 0.098), but the direction of the RT effect was in line with preclinical findings. For the secondary endpoint all recurrence, there was a significant interaction (P ¼ 0.026) between EC_pY397-FAK and RT. Without RT, higher EC_pY397-FAK expression resulted in a lower risk for all recurrence (HR ¼ 0.74 per SD; 95% confidence interval ¼ 0.57–0.96; P ¼ 0.026). Conclusions: Within the first 5 years following BCS, patients with low EC_pY397-FAK expression derive greater benefit from RT than patients with high EC_pY397-FAK expression. However, without RT, low EC_pY397-FAK expression is associated with a higher risk of recurrence.</p>}},
  author       = {{Drake, Rebecca J.G. and Landén, Amalia H. and Holmberg, Erik and Tullberg, Axel Stenmark and Killander, Fredrika and Niméus, Emma and Jordan, Alexander and McGuinness, Jennifer and Karlsson, Per and Hodivala-Dilke, Kairbaan}},
  issn         = {{1078-0432}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{7}},
  pages        = {{1323--1332}},
  publisher    = {{American Association for Cancer Research Inc.}},
  series       = {{Clinical Cancer Research}},
  title        = {{Endothelial Cell pY397-FAK Expression Predicts the Risk of Breast Cancer Recurrences after Radiotherapy in the SweBCG91-RT Cohort}},
  url          = {{http://dx.doi.org/10.1158/1078-0432.CCR-24-2939}},
  doi          = {{10.1158/1078-0432.CCR-24-2939}},
  volume       = {{31}},
  year         = {{2025}},
}