Novel biomarker of response to neoadjuvant breast cancer chemotherapy identified
medwireNews: The endothelial cell (EC) expression of phosphorylated–focal adhesion kinase (pY397-FAK) could serve as a prognostic biomarker in women who receive neoadjuvant chemotherapy for locally advanced breast cancer, research suggests.
These findings “open new opportunities for enriching recruitment studies of novel therapeutics for this population,” and also “have potential therapeutic implications for high-risk populations that could benefit from additional novel therapy,” say the study authors in JAMA Network Open.
Kairbaan Hodivala-Dilke (Barts Cancer Institute, London, UK) and collaborators explain that “developing biomarkers that will predict responses to chemotherapies” is a key unmet need in the field, and they therefore focused on FAK, which “is a ubiquitously expressed nonreceptor tyrosine kinase that is upregulated in many carcinomas, including breast cancer.”
The team adds: “Evidence suggests that [EC] FAK expression levels correlate with the molecular subtype of breast cancer, indicating that EC-FAK expression is potentially more clinically relevant than tumor cell (TC) FAK expression in breast cancer.”
The researchers performed immunohistochemical analysis of prechemotherapy biopsy samples from 82 women who received anthracycline-based neoadjuvant chemotherapy for locally advanced breast cancer (T2–T4, N0–N3, M0) at Nottingham City Hospital in the UK before undergoing surgery and adjuvant radiotherapy; individuals with estrogen receptor (ER)-positive tumors also received 5 years of adjuvant tamoxifen therapy.
None of the 21 participants with high EC-pY397-FAK expression, defined as levels equal to or above the median of 121.96, achieved a pathologic complete response (pCR) after neoadjuvant treatment. By contrast, 11 of the 61 women with low EC-pY397-FAK expression achieved a pCR, which equated to a significant 30% reduced likelihood of pCR for those with high levels.
Similarly, high EC-pY397-FAK expression levels were also significantly associated with worse 5-year relapse-free survival (RFS), at a hazard ratio (HR) of 2.21 relative to low expression levels. And the findings were similar in both the ER-positive and ER-negative subgroups, with respective HRs of 2.40 and 2.90 for high versus low levels.
And EC-pY397-FAK expression remained significantly associated with RFS after accounting for other validated prognostic factors, including ER, progesterone receptor, and HER2 status, Ki67 expression, lymph node stage, and T category (HR=3.91).
There were no such significant associations between TC-pY397-FAK expression levels and either pCR or 5-year RFS, which suggests that “TC-pY397-FAK expression is not as relevant as EC-pY397-FAK expression levels in assessing prognosis,” say Hodivala-Dilke and colleagues.
They note, however, that high tumor blood vessel density (BVD) was significantly associated with poor 5-year RFS (HR=2.2), and combined analysis of all three biomarkers – EC- and TC-pY397-FAK and BVD – “may provide an improved relapse risk stratification over individual features alone.”
Specifically, almost 90% of patients with low levels of all three biomarkers were relapse-free at the 5-year mark, compared with 51% of those with low levels of EC- and TC-pY397-FAK, but high tumor BVD.
Hodivala-Dilke et al say that the next phase of their work is “to develop this protocol into a diagnostic assay,” which “will be validated in retrospective and prospective clinical studies and trials.”
They continue: “Further work will be required to streamline and accelerate the [immunohistochemistry] and analysis processes for large numbers of patients.
“Given that protein expression is a dynamic and highly regulated process, it is possible that FAK has different roles at later stages of the disease. Thus, in future studies, it would also be of interest to determine the clinical relevance of EC-pY397-FAK in tumors taken at surgery.”
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