new perspectives with antimetabolites in the management of breast cancer

Clinical Breast Cancer Supplement January 2004 • S99

Introduction

Joyce A. O’Shaughnessy, MDSupplement Editor

One of the most important hypotheses under study re-garding adjuvant breast cancer chemotherapy is whetheradministering sequential, non–cross-resistant chemother-apy agents or combinations will improve patients’ overalloutcomes. Support for this hypothesis has come from clin-ical trials demonstrating that epirubicin followed by CMF(cyclophosphamide/methotrexate/5-fluorouracil) is moreeffective than CMF alone and that AC (doxorubicin/cyclophosphamide) followed by paclitaxel is superior toAC alone. The next generation of phase III trials investi-gates AC followed by docetaxel versus AC followed by do-cetaxel plus capecitabine, posing the question of whethera 4-drug regimen containing agents that are at least par-tially non–cross-resistant with each other is more effec-tive than a 3-drug regimen. Into this investigational arenaenter gemcitabine combination therapies. Although sin-gle-agent gemcitabine clearly has activity in untreatedpatients with metastatic breast cancer and those pre-treated with an anthracyline and a taxane, in my opinion,the promise of gemcitabine rests with its synergistic anti-tumor activity with other agents. For example, gemcita-bine combinations with an anthracycline or a taxane haveshown impressive levels of preclinical antitumor activityas well as high objective response rates as first- or second-line therapy for metastatic breast cancer. These phase IIstudies have led to the development of gemcitabine/dox-orubicin/paclitaxel and gemcitabine/epirubicin/paclitaxelregimens, which have very high levels of antitumor ac-tivity in metastatic breast cancer and are currentlybeing evaluated as neoadjuvant and adjuvant therapies.The results of the pivotal phase III trial of gemcitabineplus paclitaxel in metastatic breast cancer have clearlydemonstrated statistically superior response rates andtime to disease progression with this combination com-pared with paclitaxel alone, with little in the way of addi-tional toxicities. As few phase III trials in metastaticbreast cancer have shown significant improvement in

time to disease progression, the gemcitabine/paclitaxelcombination is being considered for rapid evaluation bythe National Surgical Adjuvant Breast and Bowel Projecton an every-2-week schedule following dose-dense ACcompared with dose-dense AC followed by paclitaxel.Again, the question at hand is whether 4 agents that areat least partially non–cross-resistant, given on a dose-dense schedule in this case, can improve the outcome forpatients with early-stage breast cancer compared with aneffective 3-drug regimen.

Gemcitabine/platinum combinations are also of greatinterest for breast cancer. At least 6 phase II trials of gem-citabine plus cisplatin in patients with metastatic breastcancer who were untreated or heavily pretreated havedemonstrated the remarkable activity of this highlysynergistic combination. This regimen is of potential im-portance because it may target subclones of metastaticand micrometastatic breast cancer that retain DNA re-pair capacity and may be inadequately treated with exist-ing regimens. In order for there to be synergistic cytotox-icity with gemcitabine and a platinum agent, cancer cellsmust repair platinated DNA, and, in so doing, incorporategemcitabine triphosphate into the mended DNA. The USOncology Research Network will soon begin a phase IItrial of gemcitabine plus carboplatin on an every-2-weekschedule in separate cohorts of patients with taxane-naiveand taxane-pretreated disease, adding trastuzumab forpatients whose breast cancer is HER2-positive. We hy-pothesize that this regimen will be associated with a highdegree of antitumor activity based on the promising gem-citabine and cisplatin data, but with less toxicity, includ-ing alopecia. The ultimate hope for this regimen is thatits safety and efficacy profile will warrant testing it as an-other partially non–cross-resistant regimen in the adju-vant setting, following an anthracycline and a taxane.Another gemcitabine combination deserving of our at-tention is the GTX regimen of gemcitabine, docetaxel,and capecitabine, which has been developed in patientswith pancreatic cancer. The elegant preclinical work byFine and colleagues presented at the 2003 Annual Meet-ing of the American Society of Clinical Oncology remindsus that it may be possible to optimize synergy between

Address for correspondence: Joyce A. O’Shaughnessy, MD, Baylor Charles A. Sammons Cancer Center, Collins Bldg, 5th Floor, 3535 Worth St, Dallas, TX 75246

New Perspectives with Antimetabolitesin the Management of Breast Cancer

Baylor Charles A. Sammons Cancer Center, Dallas, TX

S100 • Clinical Breast Cancer Supplement January 2004

agents by separating in time the administration of agentsthat inhibit the G1/S transition (gemcitabine andcapecitabine) from those that act in G2/M (docetaxel).1

This highly active new regimen shows intriguing promisein the treatment of unresectable and metastatic pancre-atic cancer and warrants evaluation as neoadjuvant andmetastatic breast cancer therapy.

While there is reason to postulate that gemcitabinecombinations may further improve the natural history ofearly breast cancer, there is no doubt that gemcitabine incombination with an anthracycline, taxane, vinorelbine,or a platinum agent provides excellent palliation ofmetastatic breast cancer. Numerous phase II studies haveshown high levels of antitumor activity with these combi-nations, with acceptable toxicity profiles. Although theappropriate choice of sequential single agents versus com-bination chemotherapy for metastatic disease depends on

specific patient and disease characteristics, I am con-vinced that well-tolerated combinations provide excellentpalliation for patients with late-stage metastatic breastcancer who are symptomatic and for whom single agentsoffer little chance of benefit. Gemcitabine is an agent Ifrequently use in combination with a taxane or carbo-platin in patients with pretreated metastatic diseasewhose disease tempo and/or symptoms warrant combina-tion therapy. Gemcitabine, whose contribution to thetherapy of pancreatic, bladder, and lung cancers has beenestablished, is finally under intensive development to de-termine where its greatest impact will lie in breast cancer.

1. Fine RL, Fogelman DR, Sherman W, et al. The GTX regimen:a biochemically synergistic combination for advanced pancre-atic cancer (PC). Proc Am Soc Clin Oncol 2003; 22:281 (Ab-stract #1129).