y Association of Low Tumor Endothelial Cell pY397-Focal Adhesion Kinase Expression With Survival in Patients With Neoadjuvant-Treated Locally Advanced Breast Cancer

This prognostic study examines the use of endothelial cell phosphorylated-focal adhesion kinase as a biomarker for chemotherapy sensitivity in women with breast cancer. Question Are phosphorylated-focal adhesion kinase (pY397-FAK) expression levels in endothelial or tumor cells and tumor blood vessel density associated with response to chemotherapy and relapse-free survival after neoadjuvant chemotherapy in patients with locally advanced breast cancer? Findings In this prognostic study of 82 women with stage IIA to IIIC locally advanced breast cancer, low endothelial cell pY397-FAK expression levels in prechemotherapy core biopsies were associated with sensitivity to neoadjuvant chemotherapy and improved 5-year relapse-free survival. Combined analysis of high endothelial cell pY397-FAK, high tumor cell pY397-FAK, and high blood vessel density appeared to identify a high-risk population. Meaning The findings of this study suggest that endothelial cell pY397-FAK levels could be used as a clinical tool for indicating response to neoadjuvant chemotherapy. Importance Determining the risk of relapse after neoadjuvant chemotherapy in patients with locally advanced breast cancer is required to offer alternative therapeutic strategies. Objective To examine whether endothelial cell phosphorylated-focal adhesion kinase (EC-pY397-FAK) expression in patients with treatment-naive locally advanced breast cancer is a biomarker for chemotherapy sensitivity and is associated with survival after neoadjuvant chemotherapy. Design, Setting, and Participants In this prognostic study, expression levels of EC-pY397-FAK and tumor cell (TC)-pY397-FAK were determined by immunohistochemistry in prechemotherapy core biopsies from 82 female patients with locally advanced breast cancer treated with anthracycline-based combination neoadjuvant chemotherapy at Nottingham City Hospital in Nottingham, UK. Median follow-up time was 67 months. The study was conducted from December 1, 2010, to September 28, 2019, and data analysis was performed from October 2, 2019, to March 31, 2020. Exposures All women underwent surgery followed by adjuvant radiotherapy and, if tumors were estrogen receptor-positive, 5-year tamoxifen treatment. Main Outcomes and Measures Outcomes were pathologic complete response and 5-year relapse-free survival examined using Kaplan-Meier, univariable logistic, multivariable logistic, and Cox proportional hazards models. Results A total of 82 women (age, 29-76 years) with locally advanced breast cancer (stage IIA-IIIC) were included. Of these, 21 women (26%) had high EC-pY397-FAK expression that was associated with estrogen receptor positivity (71% vs 46%; P = .04), progesterone receptor positivity (67% vs 39%; P = .03), high Ki67 (86% vs 41%; P < .001), 4-immunohistochemically stained luminal-B (52% vs 8%; P < .001), higher tumor category (T3/T4 category: 90% vs 59%; P = .01), high lymph node category (N2-3 category: 43% vs 5%; P < .001), and high tumor node metastasis stage (IIIA-IIIC: 90% vs 66%; P = .03). Of 21 patients with high EC-pY397-FAK expression levels, none showed pathologic complete response, compared with 11 of 61 patients with low EC-pY397-FAK expression levels who showed pathologic complete response (odds ratio, 0.70; 95% CI, 0.61-0.82; P = .04). High EC-pY397-FAK expression levels and high blood vessel density (BVD) were associated with shorter 5-year relapse-free survival compared with those with low EC-pY397-FAK expression levels (hazard ratio [HR], 2.21; 95% CI, 1.17-4.20; P = .01) and low BVD (HR, 2.2; 95% CI, 1.15-4.35; P = .02). High TC-pY397-FAK expression levels in 15 of 82 women (18%) were not associated significantly with pathologic complete response or 5-year relapse-free survival. A multivariable Cox regression model for 5-year relapse-free survival indicated that high EC-pY397-FAK expression levels was an independent poor prognostic factor after controlling for other validated prognostic factors (HR, 3.91; 95% CI, 1.42-10.74; P = .01). Combined analysis of EC-pY397-FAK expression levels, TC-pY397-FAK expression levels, and BVD improved prognostic significance over individually tested features. Conclusions and Relevance The findings of this study suggest that low EC-pY397-FAK expression levels are associated with chemotherapy sensitivity and improved 5-year relapse-free survival after systemic therapy. Combined analysis of high EC-pY397-FAK expression levels, high TC-pY397-FAK expression levels, and high BVD appeared to identify a high-risk population.