Low EC-pY397-FAK May Improve Survival in Neoadjuvant-Treated Locally Advanced Breast Cancer

Findings from a study published in JAMA Network Open suggest that low endothelial cell phosphorylated–focal adhesion kinase (EC-pY397-FAK) expression levels are associated with chemotherapy sensitivity and improved 5-year relapse-free survival after systemic therapy in patients with neoadjuvant-treated locally advanced breast cancer.

Overall, researchers indicated that this study highlights the potential clinical utility of EC-pY397-FAK expression levels in combination with blood vessel density (BVD) to guide therapeutic decision-making and testing of novel therapeutics in this high-risk group of patients.

“Our findings suggest that EC expression of activated FAK (EC-pY397-FAK) may be an independent prognostic biomarker for chemotherapy response in patients with advanced breast cancer who received neoadjuvant chemotherapy followed by adjuvant therapy,” the authors wrote. “Combining biomarkers for EC-pY397-FAK, TC-pY397-FAK, and BVD may provide an improved relapse risk stratification over individual features alone. These data have potential therapeutic implications for high-risk populations that could benefit from additional novel therapy.”

In this prognostic study, researchers used 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 to determine expression levels of EC-pY397-FAK and tumor cell (TC)-pY397-FA. Median follow-up time was 67 months.

Of note, all of the women included in the study underwent surgery followed by adjuvant radiotherapy and, if tumors were estrogen receptor (ER)-positive, 5-year treatment with tamoxifen.

In total, 82 women (age, 29-76 years) with locally advanced breast cancer (stage IIA-IIIC) were included in the study. Of these, 21 women (26%) had high EC-pY397-FAK expression that was associated with ER 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).

Among the 21 patients with high EC-pY397-FAK expression levels, none demonstrated pathologic complete response, compared with 11 of the remaining 61 patients with low EC-pY397-FAK expression levels who did demonstrate pathologic complete response (OR, 0.70; 95% CI, 0.61-0.82; P = .04).

High EC-pY397-FAK expression levels and high blood vessel BVD were associated with shorter 5-year relapse-free survival compared with those with low EC-pY397-FAK expression levels (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). However, 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.

After controlling for other validated prognostic factors, a multivariable Cox regression model for 5-year relapse-free survival suggested that high EC-pY397-FAK expression levels was an independent poor prognostic factor (HR, 3.91; 95% CI, 1.42-10.74; P = .01).

“Given that high EC-pY397-FAK expression levels were associated not only with lymph node stage but also with relapse and that the main cause of relapse is metastatic spread, it is plausible that EC-pY397-FAK also contributes to breast cancer metastasis,” the authors noted.

Ultimately, combined analysis of EC-pY397-FAK expression levels, TC-pY397-FAK expression levels, and BVD improved prognostic significance over individually tested features.

“Our findings have the potential to introduce an accurate predictive biomarker for identifying patients with ER-positive breast cancer who would or would not benefit from endocrine therapy and chemotherapy, and could also be used to monitor tumor response during treatment, thereby sparing patients with nonresponsive tumors the burden of adverse effects that would affect their quality of life,” explained the authors. “The next phase of our work is to develop this protocol into a diagnostic assay, which may prove to be cost-effective, and it will be validated in retrospective and prospective clinical studies and trials. This assay will help to deliver precision medicine for patient benefit.”

In addition, the investigators indicated that further work will also be required to streamline and accelerate the immunohistochemistry (IHC) and analysis processes for large numbers of patients. Moreover, given that protein expression is a dynamic and highly regulated process, FAK may potentially have different roles at later stages of the disease. Therefore, in future studies, it would also be of interest to determine the clinical relevance of EC-pY397-FAK in tumors taken at surgery.

Reference:

Roy-Luzzarraga M, Abdel-Fatah T, Reynolds LE, et al. Association of Low Tumor Endothelial Cell pY397–Focal Adhesion Kinase Expression With Survival in Patients With Neoadjuvant-Treated Locally Advanced Breast Cancer. JAMA Network Open. doi: 10.1001/jamanetworkopen.2020.19304