Despite the trend toward targeted therapies, cytotoxic drugs remain a mainstay of metastatic breast cancer (MBC) treatment, and new therapies in that class are needed, according to Joyce A. O’Shaughnessy, MD.

While capecitabine, gemcitabine, carboplatin, and taxanes are widely used and proven agents, the anthracyclines, vinorelbine, and the cyclophosphamide-methotrexate- 5-fluorouracil combination are not supported by as much efficacy data, are associated with toxicity concerns, and may result in cross-resistance with previous treatments, said O’Shaughnessy.

She made her comments during a presentation at the 11th International Congress on the Future of Breast Cancer in Coronado, California, in July, where she served as program director. O’Shaughnessy is co-director of Breast Cancer Research at the Baylor Charles A. Sammons Cancer Center, Texas Oncology/US Oncology, in Dallas.

New cytotoxic agents are needed to treat patients whose tumors are resistant to existing therapies, whether cytotoxic or targeted, O’Shaughnessy said. There is a particular need for effective therapies for triple-negative breast cancer (TNBC), O’Shaughnessy pointed out, and for new cytotoxic agents that exhibit lower toxicity than existing drugs, yet have equivalent or superior efficacy.

O’Shaughnessy discussed the work of Nik-Zainal and colleagues, who examined the genomes of 21 breast tumors.¹ In this study, very large numbers of clonal mutations were mapped and several clusters of discrete subclones were revealed, each representing a fraction of tumor cells. O’Shaughnessy called the heterogeneity of MBC “sobering.”

“In the curative setting, it’s the rationale for using combination chemotherapy to kill off as many subclones as we can, and in the metastatic setting, we can see that we need sequential therapies because these subclones will grow out over time once they have become resistant to the current therapy the patient is receiving,” she said.

New Agents Target Microtubule

One approach to systemic therapy that has been a focus over the last decade targets the microtubule to impede proliferation, invasion, and metastasis. There are different binding sites for three types of antimitotics:² the vinca alkaloids (such as vinblastine), the taxanes (such as paclitaxel), and a new agent, eribulin mesylate, a synthetic analog of the naturally occurring compound halichondrin B.

Eribulin (Halaven) was approved in the United States in 2010 for the treatment of MBC after at least two treatment regimens including an anthracycline and a taxane, based on the results of an open-label, randomized, phase III study of eribulin monotherapy (the EMBRACE trial) in patients with locally recurrent or MBC.³

In that study, investigators sought to determine whether eribulin would be cross-resistant with taxanes, and so selected patients who had been heavily pretreated with an anthracycline and a taxane and, in 73% of participants, with capecitabine, O’Shaughnessy said. Eribulin was compared with the treatment of physician’s choice (TPC).

EMBRACE turned out to be the only single-agent trial in this population to show a survival advantage, O’Shaughnessy said. While there was only a modest improvement in overall survival (OS) with eribulin versus TPC (median 13.2 months vs 10.5 months; P = .014), the results were unusual in such late-stage patients, she said.

Another trial, Study 301, comparing eribulin with capecitabine in MBC refractory to recent chemotherapy, showed no statistically significant difference between the two treatments, although it did demonstrate a trend toward improved OS with eribulin, O’Shaughnessy said.

The doctor added that there are four ongoing, phase II, single-arm eribulin trials in early-line MBC, including a single-agent study, studies combining eribulin with capecitabine or trastuzumab, and a safety study. The aim of the trials, she said, is to determine whether eribulin looks promising enough in early-stage disease to warrant large adjuvant or neoadjuvant studies comparing it with current standard treatments, particularly taxanes.

Additional Approaches Evaluated

Also tested in MBC patients has been ixabepilone (Ixempra), which, according to the National Cancer Institute, binds to tubulin and promotes tubulin polymerization and microtubule stabilization.