Carbonic anhydrase IX is a predictive marker of doxorubicin resistance in early-stage breast cancer independent of HER2 and TOP2A amplification

Abstract

Background:In early-stage breast cancer, adjuvant chemotherapy is associated with significant systemic toxicity with only a modest survival benefit. Therefore, there is considerable interest in identifying predictive markers of response to therapy. Doxorubicin, one of the most common drugs used to treat breast cancer, is an anthracycline chemotherapeutic agent, a class of drugs known to be affected by hypoxia. Accordingly, we examined whether expression of the endogenous hypoxia marker carbonic anhydrase IX (CA IX) is predictive of outcome in early-stage breast cancer patients treated with doxorubicin.Methods:We obtained 209 early-stage pre-treatment surgically-resected breast tumours from patients, who received doxorubicin in their chemotherapeutic regimen and had >10 years of follow-up. Immunohistochemistry was used to detect CA IX, and we used fluorescence in situ hybridisation to detect both human epidermal growth factor receptor (HER2) and DNA topoisomerase II-alpha (TOP2A) gene amplification.Results:Carbonic anhydrase IX intensity was significantly correlated with progression-free survival (PFS) and overall survival (OS) in patients receiving 300 mg m−2 of doxorubicin (HR=1.82 and 3.77; P=0.0014 and 0.010, respectively). There was a significant, inverse correlation between CA IX score and oestrogen receptor expression, but no significant correlations were seen with either HER2 or TOP2A ratio.Conclusion:We demonstrate that CA IX expression is correlated with worse PFS and OS for breast cancer patients treated with doxorubicin, independent of HER2 or TOP2A gene amplification. This study provides evidence that using CA IX to detect hypoxia in surgically-resected breast tumours may be of clinical use in choosing an appropriate chemotherapy regimen.

Dual Targeting of Hypoxia and Homologous Recombination Repair Dysfunction in Triple-Negative Breast Cancer

“…This approach builds on a strong mechanistic rationale; accumulating evidence supports the view that hypoxia is prevalent in, and contributes to, progression in TNBC (16)(17)(18)(19)(20)(21)(22)(23)(24), whereas exploiting HR dysfunction has been extensively studied in the context of cross-linking agents and synthetic lethal interactions with pharmacologic inhibition of PARP1/2 (45). Furthermore, simultaneously drugging hypoxia and HR dysfunction is made doubly attractive by the observation that ), and mean þ SEM of tumor volume is shown.…”

“…Although early definitive characterization of tumor hypoxia preceded molecular classification of breast cancer (15), recent compelling evidence across multiple technology platforms links hypoxia specifically with TN/BL subtypes, where it may negatively influence treatment outcome (16)(17)(18)(19)(20)(21)(22)(23)(24), raising the possibility that drugs targeted to tumor hypoxia may be an effective strategy for TNBC. Several classes of hypoxia-activated prodrugs (HAP) have been rationally developed to exploit tumor hypoxia (14).…”

Tumor metabolism, cancer cell transporters, and microenvironmental resistance

“…CA9 is correlated with tumor cell invasion/migration 90,92 ; it is associated with poor prognosis of the tumor 93,94 . Also, CA9 is associated with resistance to chemotherapy [95][96][97][98][99] .…”

The Clinical Importance of Assessing Tumor Hypoxia: Relationship of Tumor Hypoxia to Prognosis and Therapeutic Opportunities

“…Consistent with its function as a modulator of tissue pH, CA-IX plays an integral role in tumor acidity, especially under hypoxic conditions, which can impede the effectiveness of ionizable drugs. For example, CA-IX expression was found to significantly correlate with poor progression-free survival (PFS) (P = 0.014) and OS (P = 0.01) in breast cancer patients undergoing doxorubicin therapy (16). However, CA-IX expression does not significantly correlate with either pO 2 measurements or pimonidazole (PIMO) staining (136) in patients with H&NC (137,161), suggesting that its expression is linked to other causative factors besides pO 2 levels.…”