A Mainstay of Breast Cancer Treatment, Cytotoxics Class Must Grow

Joyce A. O’Shaughnessy, MD

Co-Director, Breast Cancer Research, Baylor Charles A. Sammons Cancer Center, Texas Oncology/US Oncology, Dallas, TX

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.”

New Agents Target Microtubule

“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.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.

Additional Approaches Evaluated

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.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.

The drug, in combination with carboplatin, was evaluated for the treatment of MBC in HER2-negative patients, following approximately two cycles of chemotherapy.⁴ The primary endpoint was the overall response rate (ORR) by hormone receptor (HR) status. The ORR was similar but slightly better for HR-positive versus TNBC patients (32.1% vs 29.8%), but median duration of response was longer for those with TNBC (10.2 months vs 6 months). Because the drug was active and well tolerated in both sets of patients, O’Shaughnessy said, it will have clinical utility in practice.

Halaven (eribulin mesylate) Injection is a synthetic analogue of the marine sponge Halichondria okadai, above.

A new oral taxane, tesetaxel, showed significant activity as first-line treatment in HER2-negative MBC in a phase II study, O’Shaughnessy reported. In 44 patients, she said, the ORR was 45%. A first-line, phase III trial in the same population is planned.

Standard Therapies Revisited

Meanwhile, two topoisomerase-1 inhibitors, one a pegylated active metabolite of irinotecan (PEG-SN38)⁵ and the other a polymer conjugate of irinotecan (NKTR- 102), showed significant activity and acceptable tolerability in phase II studies of pretreated patients, including those with TNBC, O’Shaughnessy said. NKTR-102 is currently being evaluated in a phase III trial.Amid the looks at new therapies, O’Shaughnessy said, one team considered the value of long-term continuation of standard treatments that have been effective in patients with MBC, and found evidence to support that practice.

KCSG-BR 0702 was a phase III trial of maintenance therapy versus observation in MBC patients who had experienced a clinical response to gemcitabine plus paclitaxel as first-line treatment.⁶ Patients were followed for a median of 33 months. The median progression-free survival (PFS) rate for maintenance therapy was superior as compared with the rate for observation, with a 27% improvement from 3.8 months to 7.5 months (P = 0.031), and OS rates were 35% better, with survival improved by about eight months in patients who continued treatment (P = .048). Toxicity was manageable and quality of life acceptable. The study’s authors recommended this course of treatment in patients with HR-negative, visceral MBC with a high tumor burden, and O’Shaughnessy agreed.

In another look at current uses for older MBC therapies, O’Shaughnessy discussed the results of the GeparTrio trial⁷, which showed that patients with highly proliferative estrogen receptor (ER)-positive, HER2-negative breast cancer who had stopped responding to TAC therapy (docetaxel, doxorubicin, and cyclophosphamide) benefited from a switch to combination vinorelbine and capecitabine.

An important message can be drawn from those results, O’Shaughnessy said.

“This is an example of patients with a very specific clinical phenotype getting a benefit, and it would be nice to know who those patients are up front,” she said. “In their very important Nature paper,⁸ Ellis, Mardis, and colleagues have given us a lovely blueprint of the key molecular changes in luminal breast cancer, and it will be very interesting to go into very well-defined clinical phenotypes and take a look, because I bet we’ll find genotypes that are fairly understandable and uniform. Then, we may be able to do prospective studies to select those patients up front and see whether or not, for example, a vinorelbine/capecitabine might be a better therapy for them.”

References

1. Nik-Zainal S, Van Loo P, Wedge DC, et al. The life history of 21 breast cancers [published online ahead of print May 17, 2012]. Cell. 2012;149(5):994- 1007. doi: 10.1016/j.cell.2012.04.023.
2. Jordan MA, Kamath K. How do microtubule-targeted drugs work? An overview. Curr Cancer Drug Targets. 2007;7(8):730-742.
3. Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study [published online ahead of print March 2, 2011]. Lancet. 2011;377(9769):914-923. doi:10.1016/S0140-6736(11)60070-6.
4. Osborne C, Challagalla JD, Fanning SR, et al. Phase II trial of ixabepilone plus carboplatin in patients with metastatic breast cancer: the ECLIPSE study. Cancer Res. 2011;71(24 suppl; abstr P5-19-09).
5. O’Shaughnessy JA, Osborne CRC, Steinberg MA, et al. Phase II, open-label study of of EZN-2208 (PEG-SN38) in patients with previously treated metastatic breast cancer. Cancer Res. 2011;71(24 suppl; abstr P3-16-18).
6. Im Y-H, Park YH, Jung KH, et al. A phase III, multicenter, randomized trial of maintenance versus observation after achieving clinical response in patients with metastatic breast cancer who received six cycles of gemcitabine plus paclitaxel as first-line chemotherapy (KCSG-BR 0702, NCT00561119). J Clin Oncol. 2012;30 (suppl; abstr 1003).
7. Von Minckwitz G, Kümmel S, Vogel P, et al. Intensified neoadjuvant chemotherapy in early-responding breast cancer: phase III randomized GeparTrio study [published online ahead of print April 8, 2008]. J Natl Cancer Inst. 2008;100(8):552-562. doi: 10.1093/jnci/djn089.
8. Ellis MJ, Ding L, Shen D, et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature. 2012;486:353-360.