Endothelial cell pY397-FAK expression predicts risk of breast cancer recurrences after radiotherapy in SweBCG91-RT cohort.

Abstract

Purpose: Identifying biomarkers of radiotherapy (RT) response is important for optimising the treatment of early breast cancer (BC). Here 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 randomised study. Preclinical data suggests an enhanced effect of RT with low EC_ pY397-FAK expression.

Methods: We analysed tissue microarrays (TMAs) from the SweBCG91-RT (stage I-II, lymph node-negative) BC cohort, consisting of 1,178 patients randomly assigned to receive either BCS alone or BCS plus adjuvant-RT. TMA sections were immunostained for pY397-FAK, CD31, α-smooth-muscle-actin (αSMA) and pan-cytokeratin (panCK). HALO analysis scored mean pY397-FAK intensity in CD31+ ECs, panCK+ tumour epithelial cells (TCs) and αSMA+ mural/stromal cells per core. For 822 patients, multivariable Cox regression analysis was performed for the primary and secondary 5-year endpoints, locoregional recurrence (LRR) 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, LRR (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 lower risk for all recurrence (HR 0.74 per SD, CI 95% 0.57-0.96, p=0.026).

Conclusion: Within the first 5-years post-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.