Data from GRP78 as a Novel Predictor of Responsiveness to Chemotherapy in Breast Cancer

Abstract

Listen

Translate article

<div>Abstract<p>The discovery of predictive factors for chemoresistance is critical for improving adjuvant therapy for cancer patients. The 78-kDa glucose-regulated protein (GRP78), widely used as an indicator of the unfolded protein response (UPR), is induced in the tumor microenvironment. <i>In vitro</i> studies suggest that GRP78 confers chemoresistance to topoisomerase inhibitors, such as Adriamycin (doxorubicin). Here, we report on a retrospective cohort study of 127 stage II and III breast cancer patients who were treated with Adriamycin-based chemotherapy. Archival tumor specimens were available for analysis and the relationship of GRP78 expression level to “time to recurrence” (TTR), used as a surrogate marker for drug resistance, was examined. Our data show that 67% of the study subjects expressed high level of GRP78 in their tumors before the initiation of chemotherapy and suggest an association between GRP78 positivity and shorter TTR [hazard ratio (HR), 1.78; <i>P</i> = 0.16]. Interestingly, subgroup analysis reveals that the HR for the GRP78-positive group increased significantly among patients who did not receive further taxane treatment (HR, 3.00; <i>P</i> = 0.022) and among mastectomy patients (HR, 3.33; <i>P</i> = 0.027). The HR was even stronger among mastectomy patients who did not receive further taxane treatment (HR, 4.82; <i>P</i> = 0.010). The use of GRP78 as a predictor for chemoresponsiveness and the potential interaction of GRP78 and/or the UPR pathways with taxanes warrant larger studies. (Cancer Res 2006; 66(16): 7849-53)</p></div>