New Approaches in the Management of Breast Cancer

The 3^rd Investigators’ Workshop, sponsored by The Universityof Texas M. D. Anderson CancerCenter, included five separate scientific sessions. The topics covered werecolorectal carcinoma,lung carcinoma, breast carcinoma, miscellaneous tumors including lymphomas, andnovel uses of topoisomerases, including enhancement of radiation-inducedcytotoxicity.

Three publications are intended as a result of the workshop,held on July 13-16, 2000, in St. Croix, US Virgin Islands. This volume isdevoted to breast malignancies, and includes discussions of chemotherapeuticregimens, hormonal therapy, and novel delivery of therapeutic agents. The firstvolume that was published in March 2001 was devoted to gastrointestinalmalignancies. Volume 3 will be published in summer 2001, and it will cover novelagents in lung and other malignancies.

The purpose of these annual workshops is to review the latestdata on new agents, with a particular focus on the broadly used agent irinotecan(CPT-11, Camptosar). Investigators from around the world are invited to presentcurrent research. The forums are highly interactive and frank, thus allowingexchange of new ideas and directions. In addition to stimulating research,another purpose of these workshops is to develop enduring material for widerdistribution to those who did not attend this workshop. This and the othervolumes described above are intended to fulfill that mission.

Trials and Trends Reviewed

In this volume, Maureen Trudeau discusses the design andrationale of the soon-to-be-initiated MA.21 phase III, randomized study ofadjuvant chemotherapy. The study compares two standard therapies: CEF(cyclophosphamide [Cytoxan, Neosar], epirubicin [Ellence], fluorouracil [5-FU])and AC ® T (doxorubicin [Adriamycin], cyclophosphamide, followed by paclitaxel[Taxol]). A third arm of the study tests dose-dense, dose-intense EC ®Tregimen (epirubicin, cyclophosphamide, followed by paclitaxel). Dr. Trudeaureviews the data from previous clinical trials, and offers a perspective onidentifying optimal chemotherapeutic regimens based on these data and thoseexpected from the MA.21 study.

Michael Untch and colleagues discuss new chemotherapeutic agentsand strategies designed to increase survival following adjuvant therapy (ie,dose intensification and sequential therapy). Results of a multicenter Germantrial comparing a dose-intense EC regimen with sequential EC andcyclophosphamide/methotrexate/5-FU (CMF) showed increased disease-free survivalin the dose-intense arm, but no significant improvement in overall survival atthe 2-year mark. Longer follow-up may be required. Other related trials ofneoadjuvant therapy with dose-dense and dose-intense chemotherapeutic regimens,plus the addition of new agents such as the humanized monoclonal antibodytrastuzumab (Herceptin) are discussed.

Two updates on chemotherapy regimens that incorporate epirubicinare provided by PierFranco Conte and colleagues. In the first paper, the resultsof their phase I/II study in first-line therapy of the combination of docetaxel(Taxotere) and epirubicin are presented. The authors also discuss an ongoingphase III trial of epirubicin plus paclitaxel in the adjuvant setting, andpresent preliminary toxicity data. In their second paper, Dr. Conte et alpresent data from studies of new combinations of anthracyclines and taxanesdeveloped to improve responses to first-line therapy by such means as addingagents with nonoverlapping toxicity and diverse mechanisms of action. Theauthors’ GET study with gemcitabine (Gemzar)/epirubicin/paclitaxel achieved arelatively high response rate of 92%.

Hormonal strategies are also integral parts of the management ofbreast carcinoma in both the adjuvant and metastatic settings. James Inglediscusses how new agents, such as aromatase inactivators/inhibitors, are beingevaluated in sequence, in lieu of, or in combination with tamoxifen (Nolvadex),the present hormonal agent of choice, to improve the therapeutic index in thesesettings. His article discusses chemoprevention of breast cancer with tamoxifenand anti-aromatase agents, and provides numerous references. He hypothesizesthat estrogen genotoxicity plays a role in breast cancer development, andaromatase inactivators could be employed as chemopreventive agents in patientswith high-risk genotypes.

Reviewing the numerous clinical trials of tamoxifen inearly-stage breast cancer, Eleftherios Mamounas notes that the majority of dataindicate that by 5 years of tamoxifen hormonal therapy, greater proportions ofpatients may harbor tamoxifen-resistant residual or micrometastatic tumor cells;further hormone treatment might stimulate growth. Dr. Mamounas describes aNational Surgical Adjuvant Breast and Bowel Project (NSABP) trial among patientstreated for 5 years with tamoxifen. Patients were then randomized to receiveeither 2 years of exemestane (Aromasin) or placebo to determine whether additionof an aromatase inhibitor (to decrease estrogen stimulation) prolongs survivaland time to treatment failure.

Anne Hamilton and Franco Muggia present a discussion of the useof estramustine (Emcyt), a non-nitrogen mustard linked to estradiol, intaxane-refractory breast (and hormone-resistant prostate) cancers. Phase IIstudies suggest that the combination of estramustine and the taxanes resulted insynergistic activity; however, thromboembolic events occurred in 10% ofpatients. New approaches to improve the tolerability of estramustine are alsodiscussed.

Joseph Treat and colleagues conclude the volume by discussingliposomal encapsulation of chemotherapeutic agents as a strategy to alter notonly the pharmacokinetic profile and attenuate toxicity, but to overcomemultidrug resistance. In an amply referenced review, Dr. Treat looks at therationale and extensive data for liposomal-encapsulated doxorubicin in breastcancer (and other cancers). He also summarizes data for liposomal paclitaxel,and provides an update on his group’s phase I clinical trial with this agentin advanced malignancies.

In conclusion, I believe that the data presented at TheUniversity of Texas M. D. Anderson Cancer Center Investigators’ Workshopprovide new insights about the trends and practices in various areas ofoncology. I hope you, the reader, will find this information stimulating anduseful in designing new trials.