Drake Rebecca J G, Landén Amalia H, Holmberg Erik, Stenmark Tullberg Axel, Killander Fredrika, Niméus Emma, Jordan Alexander, McGuinness Jennifer, Karlsson Per, Hodivala-Dilke Kairbaan
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.
Clin Cancer Res. 2025 Apr 1;31(7):1323-1332. doi: 10.1158/1078-0432.CCR-24-2939.
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.
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.
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).
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.
识别放疗（RT）反应的生物标志物对于优化早期乳腺癌的治疗至关重要。在本研究中，我们在一项随机研究中测试了磷酸化酪氨酸397粘着斑激酶（pY397-FAK）的内皮细胞（EC）表达与辅助放疗对保乳手术（BCS）后临床结局的相互作用。临床前数据表明，放疗对低EC_pY397-FAK表达具有增强作用。
我们分析了来自瑞典乳腺癌研究组91放疗（I-II期，淋巴结阴性）乳腺癌队列的组织微阵列，该队列由1178例患者组成，这些患者被随机分配接受单纯BCS或BCS加辅助放疗。组织微阵列切片进行pY397-FAK、CD31、α平滑肌肌动蛋白和全细胞角蛋白免疫染色。HALO分析对每个核心中CD31+内皮细胞、全细胞角蛋白阳性肿瘤上皮细胞和α平滑肌肌动蛋白+壁/基质细胞中的平均pY397-FAK强度进行评分。对于822例患者，分别以局部区域复发和所有复发这两个5年主要和次要终点作为因变量，以放疗和EC_pY397-FAK作为自变量进行多变量Cox回归分析。
EC_pY397-FAK表达对主要终点局部区域复发无预测作用（P = 0.098），但放疗效果的方向与临床前研究结果一致。对于次要终点所有复发，EC_pY397-FAK与放疗之间存在显著相互作用（P = 0.026）。在未接受放疗的情况下，较高的EC_pY397-FAK表达导致所有复发风险较低（每标准差风险比=0.74；95%置信区间=0.57-0.96；P = 0.026）。
在BCS后的前5年内，低EC_pY397-FAK表达的患者比高EC_pY397-FAK表达的患者从放疗中获益更大。然而，在未接受放疗的情况下，低EC_pY397-FAK表达与更高的复发风险相关。
