Association of Low Tumor Endothelial Cell pY397–Focal Adhesion Kinase Expression With Survival in Patients With Neoadjuvant-Treated Locally Advanced Breast Cancer
Authors: Marina Roy-Luzarraga, Tarek Abdel-Fatah, Louise E. Reynolds, Andrew Clear, Joseph G. Taylor, John G. Gribben, Stephen Chan, Louise Jones, Kairbaan Hodivala-Dilke
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Determining the risk of relapse after neoadjuvant chemotherapy in patients with locally advanced breast cancer is required to offer alternative therapeutic strategies. <h3>Objective</h3> 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. <h3>Design, Setting, and Participants</h3> 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. <h3>Exposures</h3> All women underwent surgery followed by adjuvant radiotherapy and, if tumors were estrogen receptor–positive, 5-year tamoxifen treatment. <h3>Main Outcomes and Measures</h3> Outcomes were pathologic complete response and 5-year relapse-free survival examined using Kaplan-Meier, univariable logistic, multivariable logistic, and Cox proportional hazards models. <h3>Results</h3> 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%;<i>P</i> = .04), progesterone receptor positivity (67% vs 39%;<i>P</i> = .03), high Ki67 (86% vs 41%;<i>P</i> &lt; .001), 4-immunohistochemically stained luminal-B (52% vs 8%;<i>P</i> &lt; .001), higher tumor category (T3/T4 category: 90% vs 59%;<i>P</i> = .01), high lymph node category (N2-3 category: 43% vs 5%;<i>P</i> &lt; .001), and high tumor node metastasis stage (IIIA-IIIC: 90% vs 66%;<i>P</i> = .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;<i>P</i> = .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;<i>P</i> = .01) and low BVD (HR, 2.2; 95% CI, 1.15-4.35;<i>P</i> = .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;<i>P</i> = .01). Combined analysis of EC-pY397-FAK expression levels, TC-pY397-FAK expression levels, and BVD improved prognostic significance over individually tested features. <h3>Conclusions and Relevance</h3> 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.