Implications of Anthracycline-Resistant and Taxane-Resistant Metastatic Breast Cancer and New Therapeutic Options

Abstract

Patients with advanced or metastatic breast cancer commonly develop disease resistant to chemotherapy (typically anthracyclines and taxanes), which presents a major obstacle to therapy and leaves few effective treatment options. Drug resistance can occur due to various mechanisms including modification of drug efflux membrane transporters such as P-glycoprotein, as well as alterations in beta-tubulin. The novel epothilone B analog, ixabepilone, which has low susceptibility to various drug-resistance mechanisms, has demonstrated preclinical activity in drug-resistant breast cancer. The clinical activity of ixabepilone was evaluated in metastatic breast cancer patients with highly pretreated and/or resistant/refractory disease. Results were reviewed from three phase II trials in which ixabepilone was administered as monotherapy and one phase III trial that evaluated ixabepilone in combination with capecitabine. As a single agent, ixabepilone demonstrated activity in women who were heavily pretreated and resistant to an anthracycline, a taxane, and/or capecitabine. The combination of ixabepilone and capecitabine was significantly more active than capecitabine alone in patients with prior treatment or resistance to anthracyclines and taxanes. Treatment-related adverse events were generally low grade except for grade 3/4 toxicities, including neutropenia (53-54%) and reversible peripheral sensory neuropathy (14-16%). Ixabepilone has significant activity in patients with heavily pretreated metastatic breast cancer who are disease resistant or refractory to anthracyclines and taxanes. Further clinical evaluation of this agent in patients with drug-resistant breast cancer and in specific patient subsets is warranted.

Gemcitabine and cisplatin combination regimen in patients with anthracycline- and taxane-pretreated metastatic breast cancer

“…The commonly used agents include capecitabine, vinorelbine, gemcitabine, pegylated liposomal doxorubicin, irinotecan, and ixabepilone [17]. The current study confirms the previous reports that combination chemotherapy with gemcitabine and cisplatin [13,[18][19][20][21][22].…”

Multiple mechanisms underlying acquired resistance to taxanes in selected docetaxel-resistant MCF-7 breast cancer cells

“…Typical taxanes used in current treatment regimens for breast cancer include paclitaxel (Taxol) and docetaxel (Taxotere), while typical anthracyclines include doxorubicin (Adriamycin) and epirubicin (Pharmorubicin) [4,5]. Docetaxel belongs to the group of taxanes that were first introduced into clinical use during the 1990’s.…”

“…Chemoresistance presents a major obstacle to therapy and leaves few effective treatment options [5]. Both innate and acquired resistance to taxanes and doxorubicin are common as more breast cancer patients receive these drugs [1,14].…”

“…Some other studies show that no correlation between ABCB expression level and response to either paclitaxel or docetaxel treatment in breast cancer patients [18]. On the other hand, both ABCC1 and ABCG2 mediate resistance to doxorubicin, but not paclitaxel [5,19]. …”

Neoadjuvant Chemotherapy Induces Expression Levels of Breast Cancer Resistance Protein That Predict Disease-Free Survival in Breast Cancer

“…Many studies have investigated Pgp expression levels and their prognostic impact in breast cancer [3], but use of a variety of assay methods has lead to widely differing detection rates and therefore conflicting conclusions [4]; some find Pgp expression to be associated with poor prognoses [5], while others do not [6]. There is, however, broad consensus that Pgp expression can be induced by neoadjuvant chemotherapy [7], suggesting that Pgp may contribute to acquired chemotherapy resistance in some cases.…”