CHFR expression and sensitivity of breast cancer cells to antimitotic agents in vitro and in the I-SPY trial

CHFR, which encodes an E3 ubiquitin ligase previously implicated in regulating the premitotic checkpoint and response to taxanes, is silenced in a subset of breast cancers. Here we assessed the impact of differences in CHFR expression on sensitivity to various antimitotic agents in vitro and on response to neoadjuvant taxane treatment in the clinical setting. Colony forming assays as well as live cell imaging in human breast cancer cell lines indicated that CHFR downregulation is associated with increased sensitivity to PLK1 inhibitors as well as paclitaxel in vitro that reflects premature mitotic exit and increased multinucleation. To assess the relationship between CHFR expression and neoadjuvant taxane response, we utilized immunohistochemistry to examine CHFR expression in the inter-regimen biopsy from 81 patients on the I-SPY neoadjuvant breast cancer trial (NCT01042379) who had dynamic contrast-enhanced breast MRIs before and after paclitaxel monotherapy. CHFR^Low cancers had indistinguishable volumes before taxane therapy but smaller MRI tumor volumes after paclitaxel [median 0.07 cm³ (interquartile range 0-1.1) in CHFR^Low versus 1.1 cm³ (0.02-5.0) in CHFR^High cancers, p = 0.03 by rank sum test]. Moreover, there was a strong association between higher CHFR expression and lower relapse-free survival in estrogen receptor (ER) positive, HER2 negative cancers (HR 7.8, p = 0.024). These observations identify CHFR as a potential predictive marker of sensitivity in ER positive breast cancer that warrants further investigation and suggest that CHFR might also be associated with response to certain other mitotic inhibitors.