In a paper in JAMA Network Open, they report that low expression of endothelial-cell phosphorylated-focal adhesion kinase was associated with chemotherapy sensitivity and improved relapse-free survival after systemic therapy.
Focal adhesion kinase (FAK) is upregulated in breast cancer, and some evidence has suggested that endothelial cell (EC) FAK expression levels correlate with the molecular subtype of breast cancer.
Dr. Kairbaan Hodivala-Dilke of Barts Cancer Institute, Queen Mary University of London, and colleagues examined whether phosphorylated Y397-FAK expression levels in the endothelium of breast cancer (EC-pY397-FAK) before treatment were associated with outcomes following anthracycline-based combination neoadjuvant chemotherapy in 82 women with locally advanced breast cancer (stage IIA-IIIC).
Overall, 21 women (26%) had high EC-pY397-FAK expression levels, and these high expression levels were associated with estrogen receptor (ER) positivity, progesterone receptor (PR) positivity, high Ki67, 4-IHC-luminal B, and higher T, lymph node and TNM stage.
None of the women with high EC-pY397-FAK expression levels had pathologic complete responses, whereas 11 of 61 women with low EC-pY397-FAK expression levels showed pathologic complete responses (odds ratio, 0.70; P=0.04).
High EC-pY397-FAK expression levels were associated with a significantly shorter five-year relapse-free survival overall and in both ER-positive and ER-negative subgroups (hazard ratio, 2.21; P=0.01).
High tumor-cell expression of pY397-FAK (TC-pY397-FAK), on the other hand, was not significantly associated with pathologic complete response or relapse-free survival.
High blood-vessel density (BVD) within tumors, present in 52% of patients, was also associated with shorter five-year relapse-free survival.
In combined analyses, women with low EC-pY397-FAK, low TC-pY397-FAK, and low BVD had significantly better clinical outcomes than other women.
In multivariable models, high EC-pY397-FAK expression levels independently predicted worse relapse-free survival after adjustment for other validated prognostic factors.
"Our findings suggest that 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 conclude. "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," they add.
Dr. Jun-Lin Guan of the University of Cincinnati College of Medicine, in Ohio, who recently examined the role of FAK signaling in breast-cancer cell migration and metastasis, told Reuters Health by email, "EC-pY397-FAK, and more broadly speaking, alterations in the tumor microenvironment, rather than only tumor cell per se, should be considered and examined."
"It will be interesting to study the outcomes for the low-EC-pY397-FAK, but high-TC-pY397-FAK group of patients," said Dr. Guan, who was not involved in the study. "This could mimic the clinical situation of using FAK inhibitor (that blocked its activity in EC, but TC developed other ways to become equivalent of high FAK activity despite the inhibitor, due to its higher mutation/adaptive ability) to treat patients."
The study had no commercial funding.
Dr. Hodivala-Dilke did not respond to a request for comments.
SOURCE: https://bit.ly/3nDO9af JAMA Network Open, online October 27, 2020.
By Will Boggs MD
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