High Expression of Brachyury Associated With Poor Prognosis in Breast Cancer Patients Receiving Adjuvant Tamoxifen
Epithelial-mesenchymal transition plays a key role in tumor cell invasion, metastasis, and drug resistance and the transcription factor brachyury has recently been identified as a driver of this process. In a study reported in the Journal of the National Cancer Institute, Palena et al found that a high level of brachyury mRNA expression in breast tumors was associated with markedly increased risks of recurrence and distant metastasis in patients who had received adjuvant tamoxifen.
In initial studies, the investigators found that 27 of 30 primary breast tumors were positive for brachyury expression, whereas 16 benign breast tissue samples were negative, except for two cases of focal expression in the setting of fibroadenoma. In studies in vitro, a higher level of brachyury expression in breast cancer cells was associated with invasiveness of the extracellular matrix, efficient formation of mammospheres, and resistance to docetaxel.
Values for high (highest quartile), intermediate, and low (lowest quartile) levels of brachyury mRNA were derived from analysis of 4,010 breast tumor samples. In a Cox proportional hazards regression analysis among 357 patients who received adjuvant tamoxifen for 5 years, brachyury expression in the three subgroups was significantly associated with risk of recurrence (P = .003) and distant metastasis (P = .003).
For the high vs low group, the hazard ratio for recurrence was 7.5 (P = 5.14 × 10-4) and the hazard ratio for distant metastasis was 15.2 (P = 3.01 × 10-4). Among 609 patients who did not receive systemic neoadjuvant or adjuvant treatment, brachyury mRNA expression was not associated with risk of recurrence, suggesting that brachyury expression might be associated with tamoxifen resistance.
In evaluation of the potential for an immunotherapeutic approach in brachyury-positive tumors, expanded brachyury-specific cytotoxic T cells were found to lyse breast cancer cells that were both brachyury and HLA-A2–positive but not cells that were brachyury-positive and HLA-A2–negative.
The investigators concluded, “The studies reported here provide the rationale for the use of a vaccine targeting brachyury for the therapy of human breast cancer, either as a monotherapy or in combination therapies.”
Jeffrey Schlom, PhD, of the National Cancer Institute, is the corresponding author for the Journal of the National Cancer Institute article.
The research was supported by the National Cancer Institute, Italian Ministry of Instruction, University and Research, and Department of Defense Breast Cancer Research Program. The study authors reported no potential conflicts of interest.
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