Clifford A. Hudis, MD

We speak with Clifford Hudis, MD, Memorial Sloan-Kettering Cancer Center, about the recent advances in breast cancer treatment and the top news to come out of this year’s ASCO Breast Cancer Symposium.

The anthracyclines doxorubicin (A) and epirubicin (E) are among the most active agents for breast cancer.

E-Updates in the Adjuvant Treatment of Breast Cancer, Volume 2Updates on Chemotherapeutic Options and Targeted Therapies

The studies presented at SABCS 2008 regarding adjuvant taxane schedules are well designed and add to a growing body of data on how best to use these drugs, although they leave some questions unresolved. NSABP B-30 nicely controlled for number of cycles of treatment. All patients received four cycles of doxorubicin and four of docetaxel (Taxotere), and some got four cycles of cyclophosphamide, so there was some control over the duration of exposure and total number of doses for each drug.

In general, metastatic breast cancer (MBC) is treated systemically using chemotherapy, hormonal therapy, and newer targeted therapies when appropriate. About 75% of breast cancers test positive for estrogen receptors (ER) and progesterone receptors (PR), and estrogen stimulation of these receptors plays an important role in the proliferation of these tumors.

Breast cancer is the most commonly diagnosed cancer in women and is the second leading cause of cancer-related mortality, after lung cancer. The overall incidence of breast cancer was increasing until recently, but mortality has declined since 1990, presumably due to earlier detection and better treatments.

After peaking in 1990, the absolutenumber of deaths peryear attributed to breast cancerhas fallen steadily.[1] This declineoccurred despite trends thatwould seem to increase breast cancermortality (population growth, aging,increased obesity) and was mirroredeven in countries lacking routine supportfor mammography. Systemictherapy is at least partly responsiblefor this mortality decline, and in supportof this conclusion the predictedbenefits (based on trials and metaanalyses)have been seen in population-based studies.[2] In this issue ofONCOLOGY, Mina and Sledge providea timely and inspiring review of2 decades of progress in systemic therapyfor breast cancer. This leads toseveral questions, including: How didwe get here and what is next?

The improved survival associated with adding the anti-vascular endothelialgrowth factor (VEGF) monoclonal antibody bevacizumab(Avastin) to chemotherapy for the treatment of patients with metastaticcolorectal cancer demonstrates the importance of targeting collateralcells involved in tumor growth, progression, and metastatic spread.Based on the Gompertzian model of tumor growth, adding anti-VEGFagents to standard chemotherapy may be especially effective in earlystages of cancer. By improving chemotherapy delivery to the tumor andinhibiting regrowth between treatment cycles, anti-VEGF agents mayalter the growth pattern of a tumor such that it is more susceptible toeradication. These concepts also suggest that anti-VEGF agents couldenhance the effectiveness of chemotherapy given conventionally or ina dose-dense fashion. As such, it is possible that the effectiveness ofchemotherapy could be maintained or improved, even at lower cumulativedoses, which may improve its tolerability. Additionally, the effectsof anti-VEGF agents on metronomic chemotherapy, which is reportedto have antiangiogenic properties on its own, warrant further evaluation.Preclinical data demonstrate that cytostatic angiogenesis inhibitorsare potent complementary agents to metronomic chemotherapy,producing sustained complete regressions in some models of humancancer. Dose-dense and metronomic chemotherapy have in common ashortened dosing interval and resultant increased and/or prolongedexposure of tumor cells to chemotherapy in vivo. Optimizing the use ofanti-VEGF agents in the clinic demands further investigation of themost appropriate way to combine them with chemotherapy, particularlyregimens designed to exploit known tumor growth patterns andthose designed to target the endothelial cells involved inneovascularization with multiple agents.

Breast cancer is the most common noncutaneous malignancy inwomen in industrialized countries. Chemotherapy prolongs survival inpatients with early-stage breast cancer, and maintaining the chemotherapydose intensity is crucial for increasing overall survival. Manypatients are, however, treated with less than the standard dose intensitybecause of neutropenia and its complications. Prophylactic colonystimulatingfactor (CSF) reduces the incidence and duration of neutropenia,facilitating the delivery of the planned chemotherapy doses.Targeting CSF to only at-risk patients is cost-effective, and predictivemodels are being investigated and developed to make it possible forclinicians to identify patients who are at highest risk for neutropeniccomplications. Both conditional risk factors (eg, the depth of the firstcycleabsolute neutrophil count nadir) and unconditional risk factors(eg, patient age, treatment regimen, and pretreatment blood cell counts)are predictors of neutropenic complications in early-stage breast cancer.Colony-stimulating factor targeted toward high-risk patients startingin the first cycle of chemotherapy may make it possible for fulldoses of chemotherapy to be administered, thereby maximizing patientbenefit. Recent studies of dose-dense chemotherapy regimens with CSFsupport in early-stage breast cancer have shown improvements in disease-free and overall survival, with less hematologic toxicity than withconventional therapy. These findings could lead to changes in how earlystagebreast cancer is managed.

At first glance, high-dose chemotherapy for breast cancer makes sense. The disease is often sensitive to chemotherapy, potentially curable, and highly prevalent, which means that even a modest benefit would be tremendously important. Unfortunately, multiple clinical trials have failed to demonstrate that high-dose therapy is more effective than other chemotherapeutic approaches. Thus far, no prospective study has demonstrated a benefit based on its planned primary objective and planned analysis, and none has shown a survival advantage (see Table 1).[1-5]

This supplement to ONCOLOGY includes a collection of papers focusing on the clinical development and use of capecitabine (Xeloda), a novel agent with significant activity in patients suffering from metastatic breast cancer. It is now clear that this

Available data on the use of active chemotherapy agents in advanced breast cancer suggest that sequential single-agent therapy is associated with outcomes similar to those achieved with concurrent combination therapy. Since

Tumorigenesis is a complex process, and understanding the mechanisms behind tumorigenesis is key to identifying effective targeted therapies. Prostaglandins are signaling lipophilic molecules derived from phospholipids that are involved in normal physiologic functions.

Adjuvant chemotherapy represents a significant advance in the management of early-stage breast cancer and, as such, has saved many lives. Worldwide, adjuvant chemotherapy has benefitted all groups tested, including

The use of dose-dense therapy is one approach to overcoming the “resistance” of malignant cells to adjuvant therapy caused by inadequate drug exposure. In this approach, active drugs are delivered sequentially at their “ideal” dose level separated by short intertreatment intervals. Thus, dose intensification is achieved by means of rapidly recycled treatments rather than by dramatic dose escalation. To overcome absolute cellular resistance, the addition of new, active, non-cross-resistant drugs holds great promise and has specifically motivated the testing of the taxanes. This article describes the results of clinical trials of dose-dense therapy, with particular emphasis on attempts to incorporate one taxane, paclitaxel (Taxol), into the dose-dense regimen of sequential doxorubicin and cyclophosphamide-the so-called A ® T ® C regimen, and into more conventional regimens.[ONCOLOGY 12(Suppl 1)16-18, 1998]

The recognition of paclitaxel's (Taxol's) activity and non-cross-resistance with doxorubicin (Adriamycin) in the treatment of metastatic breast cancer has motivated study of the agent in the adjuvant setting. However, the ideal

The proven safety profile and antitumor activity of paclitaxel (Taxol) in the treatment of metastatic breast cancer led investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) to further examine the agent's potential in the treatment of advanced breast cancer. Efficacy and tolerability studies of paclitaxel as single-agent therapy were undertaken, along with parallel investigations of quality-of-life parameters. The studies examined the effects of 96-hour infusion schedules of paclitaxel and are currently assessing the feasibility of a weekly 1-hour infusion schedule. Researchers at MSKCC also compared the results of a variety of two- and three-drug paclitaxel-containing regimens to determine possible synergism and better define safety profiles. They examined the combination of paclitaxel and edatrexate, as well as a promising combination of paclitaxel and a monoclonal antibody directed at growth factor receptors. The latter ongoing trial will include both laboratory studies that examine possible cellular mechanisms for the combination's observed synergy and a clinical trial that combines paclitaxel with a monoclonal antibody directed against the epidermal growth factor. In conclusion, the investigators discuss the optimal integration of paclitaxel into doxorubicin/cyclophosphamide (Cytoxan, Neosar)-based adjuvant therapy for node-positive stage II-III resectable breast cancer. [ONCOLOGY 11(Suppl):20-28, 1997]