Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2025 Apr 1;31(7):1323-1332.
doi: 10.1158/1078-0432.CCR-24-2939.

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

Rebecca J G Drake  1 , Amalia H Landén  2 , Erik Holmberg  2 , Axel Stenmark Tullberg  2 , Fredrika Killander  3 , Emma Niméus  4   5 , Alexander Jordan  1 , Jennifer McGuinness  6 , Per Karlsson  2 , Kairbaan Hodivala-Dilke  1
Affiliations
Randomized Controlled Trial

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

Rebecca J G Drake et al. Clin Cancer Res. .

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 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 = 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 = 0.026) between EC_pY397-FAK and RT. Without RT, higher EC_pY397-FAK expression resulted in a lower risk for all recurrence (HR = 0.74 per SD; 95% confidence interval = 0.57-0.96; P = 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.

PubMed Disclaimer

Conflict of interest statement

E. Holmberg reports a patent for Exact Sciences pending and a patent for PreludeDx pending. A. Stenmark Tullberg reports other support from PreludeDx during the conduct of the study, as well as a patent for PreludeDX pending. A. Jordan reports grants from Cancer Research UK during the conduct of the study. P. Karlsson reports other support from Novartis, AstraZeneca, and Seagen outside the submitted work, as well as a patent for Exact Sciences pending and a patent for PreludeDx pending. K. Hodivala-Dilke reports nonfinancial support from Ellipes Pharma, RGDscience-Indegra Therapeutics, and VasoDynamics during the conduct of the study, as well as a patent for 62/560,217 pending, a patent for WO2021032955A1 pending, and a patent for N421127GB pending. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
CONSORT diagram of the SweBCG91-RT study. The SweBCG91-RT randomized early-stage breast cancer (BC) trial was used for this analysis. (Created in BioRender. Drake, R. [2025] https://BioRender.com/j62v741).
Figure 2.
Figure 2.
Cumulative incidence of LRR stratified according to the receipt of radiation treatment or no-radiation treatment. Data are presented for lowest 25% EC_pY397-FAK expression in Q1 (A); 25%–50% EC_pY397-FAK expression in Q2 (B); 50%–75% EC-pY397-FAK expression in Q3 (C); and 75%–100% EC_pY397-FAK expression in Q4 (D). HRs were estimated by the use of cause-specific Cox proportional hazard regression. To meet the proportionality condition, the follow-up (FU) time is split into two periods: 0–5 years and 5–10 years. The Fine and Gray model for competing risk analysis is used to plot and compare the cumulative incidence curves and estimate PCIF for the difference between the curves.
Figure 3.
Figure 3.
Cumulative incidence of all recurrence stratified according to the receipt of radiation treatment or no-radiation treatment. Data are presented for lowest 25% EC_pY397-FAK expression in Q1 (A); 25%–50% EC_pY397-FAK expression in Q2 (B); 50%–75% EC_pY397-FAK expression in Q3 (C); and 75%–100% EC_pY397-FAK expression in Q4 (D). HRs were estimated by the use of cause-specific Cox proportional hazard regression. To meet the proportionality condition, the follow-up (FU) time is split into two periods: 0–5 years and 5–10 years. The Fine and Gray model for competing risk analysis is used to plot and compare the cumulative incidence curves and estimate PCIF for the difference between the curves.
See this image and copyright information in PMC

References

    1. Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, et al. ; Global Burden of Disease Cancer Collaboration . Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol 2017;3:524–48. - PMC - PubMed
    1. Siegel RL, Miller KD, Jemal A: Cancer statistics, 2020. CA Cancer J Clin 2020;70:7–30. - PubMed
    1. Iacoviello L, Bonaccio M, de Gaetano G, Donati MB. Epidemiology of breast cancer, a paradigm of the “common soil” hypothesis. Semin Cancer Biol 2021;72:4–10. - PubMed
    1. Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M, et al. ; Early Breast Cancer Trialists’ Collaborative Group EBCTCG . Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011;378:1707–16. - PMC - PubMed
    1. McGale P, Taylor C, Correa C, Cutter D, Duane F, Ewertz M, et al. ; EBCTCG Early Breast Cancer Trialists’ Collaborative Group . Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 2014;383:2127–35. - PMC - PubMed

Publication types

MeSH terms