Abstract
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. In vitro 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; P = 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; P = 0.022) and among mastectomy patients (HR, 3.33; P = 0.027). The HR was even stronger among mastectomy patients who did not receive further taxane treatment (HR, 4.82; P = 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.
Highlights
Adjuvant therapy of early breast cancer improves survival; standard treatment strategies result in unnecessary treatment and exposure to side effects of large numbers of women who do not benefit [1]
From 1989 to 1999, 432 female patients with stage II or III invasive breast cancer were treated in the University of Southern California (USC)/Norris Cancer Hospital (Los Angeles, CA), among whom 209 patients were treated with Adriamycin-based adjuvant chemotherapy
GRP78 has been implicated as a major player in cancer progression by its role in protecting cancer cells from apoptosis, promoting metastasis, and allowing dormant cancer cells to resist Adriamycin toxicity [9, 10, 17]
Summary
Adjuvant therapy of early breast cancer improves survival; standard treatment strategies result in unnecessary treatment and exposure to side effects of large numbers of women who do not benefit [1]. Because current adjuvant strategies are primarily based on grouped risk assessments mainly using tumor stage, histologic grade, and receptor status, there is a critical need for identification of additional, novel predictive factors for chemoresponsiveness. Adriamycin (doxorubicin), an anthracyclineinhibiting topoisomerase II, is a standard chemotherapeutic agent for adjuvant therapy of early-stage breast cancer. F50% of patients with stage II and III disease will recur. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Phone: 323-865-0507; Fax: 323-865-0094; E-mail: amylee@ usc.edu
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