Gabriel N. Hortobagyi, MD, FACP

This effort has already brought important contributions to countries of low and middle incomes: the basic guidelines, which not only indicate how patients with breast cancer can be treated even with modest resources, but also provide a minimum level of care below which countries, governments and health care systems cannot even pretend that they provide care for women with breast cancer.

Carcinomas arising from the breast represent a heterogeneous group of tumors of distinct biologic subtypes that have been shown to be diverse in terms of response to therapy and prognostic outcomes.

Twenty years ago, antiestrogen therapy with tamoxifen played only a secondary role in breast cancer care. All hopes to cure metastatic breast cancer were still pinned on either the discovery of new cytotoxic drugs or a dose-dense combination of available cytotoxic drugs with bone marrow transplantation. A similar strategy with combination chemotherapy was employed as an adjuvant for primary breast cancer. Simply stated, the goal was to kill the cancer with nonspecific cytotoxic drugs while keeping the patient alive with supportive care. However, medical research does not travel in straight lines, and an alternative approach emerged to solve the problem of controlling tumor growth with minimal side effects: targeted therapy. The approach of using long-term antihormone therapy to control early-stage breast cancer growth would revolutionize cancer care by targeting the tumor estrogen receptor (ER). The success of the strategy would contribute to a decrease in the national mortality figures for breast cancer. More importantly, translational research that targeted the tumor ER with a range of new antiestrogenic drugs would presage the current fashion of blocking survival pathways for the tumor by developing novel targeted treatments. But a surprise was in store when the pharmacology of "antiestrogens" was studied in detail: The nonsteroidal "antiestrogens" are selective ER modulators—ie, they are antiestrogens in the breast, estrogens in the bone—and they lower circulating cholesterol levels. This knowledge would establish a practical approach to breast cancer chemoprevention for women at high risk (tamoxifen) and low risk (raloxifene).

Drs. Ramaswamy and Shapiropresent a timely and comprehensivereview of the potentialuses of bisphosphonates and theirindications in the prevention and treatmentof bone metastasis. The reviewprovides a concise summary of thepathophysiology of skeletal metastasesand describes emerging biologicprinciples that open the door for novel,highly targeted therapeutic interventions.It is generally accepted thatrelative osteoclast hyperactivity resultsin excess bone resorption, which isthe basic process behind bone metastasis,osteoporosis, and hypercalcemiaof malignancy. Osteoprotegerin,the receptor activator of nuclear factor–kappa B (RANK), and the kappa Bligand (RANK-L) have critical rolesin osteoclastogenesis. In addition,parathyroid hormone–related proteinalso plays a major role in osteoblastactivation and production of RANKLas well as terminal osteoclast differentiationand activation.

Adjuvant systemic chemotherapy has been shown to prolong survival in all subsets of patients with breast cancer. In addition, among patients with locally advanced breast cancer, neoadjuvant or preoperative chemotherapy has

Adjuvant chemotherapy is an integral component of the multidisciplinary curative treatment of primary breast cancers. The experience of the last 3 decades indicates that anthracycline-containing regimens provide the most effective cytotoxic treatment for this purpose.

Breast cancer is sensitive to several cytotoxic drugs. Combination cytotoxic regimens are associated with higher response rates and longer durations of response and, occasionally, survival, than are single-agent regimens.

The book Progress in Anti-Cancer Chemotherapy, Volume II is the second of a series of three books edited by Drs. Hortobagyi and Khayat, and published by different publishing houses between 1998 and 1999. Volume II is a collection of

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

HER2 is a member of the type I tyrosine kinase growth factor receptor family and participates in normal growth control mechanisms. It is overexpressed or amplified in 20% to 30% of breast cancers, as well as other carcinomas. HER2 overexpression is associated with adverse prognostic indicators in primary breast cancer, and a number of reports have shown that HER2-overexpressing breast cancer is linked to an increased rate of recurrence/metastases, and therefore, decreased disease-free and overall survival rates.

Ever since the first phase II study of paclitaxel (Taxol) began, there has been ongoing controversy about the optimal dose and schedule of administration of this drug. The initial reports of marked antitumor activity against metastatic breast cancer were obtained using 250 mg/m² administered by 24-hour continuous IV infusion. This schedule was originally developed in an attempt to reduce the incidence and severity of anaphylactic reactions. Subsequent to the determination that this dose and schedule was effective and safe, there were multiple attempts to develop more convenient schedules, and dose/schedules associated with an improved side-effect profile.

Gómez-Bernal et al (abstract #341) report the results of a docetaxel (Taxotere)/vinorelbine (Navelbine) combination as second-line therapy for metastatic breast cancer. Both agents were administered on the same day and repeated every 14 days. The 52% objective response rate is impressive, since vinorelbine alone would be expected to produce a 20%–30% response rate in this setting, with docetaxel projected to achieve a 40% complete and partial remission rate. Therefore, the results suggest an additive interaction between the two agents.

Over the past 5 years it has become evident that the administration of taxanes on a weekly schedule dramatically changes their toxicity profile, compared to the standard 3-weekly schedule. Weekly docetaxel (Taxotere) is markedly less

Evidence generated by controlled clinical trials over the past 4 decades indicated that combination chemotherapy produced superior results to single-agent cytotoxic therapy. Response rates and times to progression were superior with combination chemotherapy, and survival was also favorably altered by this approach. This paradigm has been recently challenged on the basis of the Norton-Simon hypothesis and by the development of more effective, new cytotoxic agents, specifically the taxanes.

Abstracts #317 and #322 attest to the high degree of antitumor activity of docetaxel (Taxotere) in the management of locally advanced breast cancer. In abstract #317 the authors tested two hypotheses: first, that the administration of a non–cross-resistant cytotoxic regimen after induction or neoadjuvant chemotherapy improved the outcome of combined-modality treatment for both responders and nonresponders to neoadjuvant chemotherapy; and second, that the addition of docetaxel to a standard, anthracycline-containing regimen improved both clinical and pathologic response rates in locally advanced breast cancer.

Before the introduction of the taxanes into the management of breast cancer, the anthracyclines (and doxorubicin and epirubicin [Ellence] in particular) were considered the most active agents against this malignancy. The marked activity of single-agent taxanes suggested that their antitumor efficacy might match and perhaps exceed that of the anthracyclines. Several prospective randomized trials have confirmed these initial impressions. At intermediate doses (60 mg/m²), the activity of doxorubicin and paclitaxel (Taxol) was similar; at higher doses (75 mg/m²), doxorubicin appeared more effective. Conversely, docetaxel (Taxotere) was reported to be more active than doxorubicin in one trial.

Gemcitabine (Gemzar) has emerged from its initial clinical evaluation in patients with metastatic breast cancer as an effective antitumor agent. Its usual schedule of administration is weekly, and it is a very well-tolerated regimen. In combination with anthracyclines, the activity matches that of other commonly used multidrug regimens, including CMF (cyclophosphamide [Cytoxan, Neosar]/methotrexate/fluorouracil) or FAC (fluorouracil/doxorubicin [Adriamycin]/cyclophosphamide). When the taxanes became the most effective agents against breast cancer, two-drug and three-drug combinations with gemcitabine were initiated. This development was stimulated by the need to discover effective, non–cross-resistant regimens for patients previously exposed to anthracyclines and classical alkylating agents.

In abstract #403 the combination of docetaxel (Taxotere) and doxorubicin was tested in a prospective, multicenter, phase II trial, by one of the foremost breast cancer research cooperative groups-the National Surgical Adjuvant Breast and Bowel

The development of a new drug is not only complex but also requiresa major investment in time, resources, patients, and most important, a

Since the emergence of paclitaxel (Taxol) in 1983, clinical developmentof the taxoids has progressed at a rapid pace, with the introduction ofdocetaxel (Taxotere) into clinical trials in 1990, and international phaseII studies in 1992. Although these two taxoids are related, increasingclinical experience indicates that paclitaxel and docetaxel should notbe considered interchangeable.

Development of the taxoids has progressedrapidly in the 1990s. In vitro studies have demonstrated that docetaxel(Taxotere) has a longer residence time and higher accumulation within tumorcells than paclitaxel (Taxol), possibly accounting for its greater cytotoxicity.

Clinical trials to develop paclitaxel (Taxol)-containing combinations started in 1992 with several approaches to combine doxorubicin and paclitaxel. Schedule-dependent toxicity limited doses in the initial trials, although antitumor activity was high. More recently, a well-tolerated, highly effective doxorubicin/paclitaxel regimen was developed with the use of bolus anthracycline administration and a 3-hour infusion of paclitaxel. Combinations of paclitaxel with cisplatin have provided mixed results. Paclitaxel combined with fluorouracil (5-FU) and folinic acid proved effective in patients with extensive prior chemotherapy; the addition of mitoxantrone (Novantrone) to this combination was feasible, well tolerated, and possibly enhanced the efficacy of paclitaxel and 5-FU. Combinations of paclitaxel with cyclophosphamide (Cytoxan, Neosar), vinorelbine (Navelbine), edatrexate, and radiation continue in clinical development. [ONCOLOGY 11(Suppl):29-37, 1997]

Several new agents undergoing clinical development appear to be effective and tolerable in the management of metastatic breast cancer. In recent years, a number of new and exciting combinations have been described, with an efficacy similar or, in some cases, apparently superior to that of standard chemotherapeutic regimens, such as FAC and CMF. The next several years will witness a large number of comparative clinical trials, the major purpose of which will be to establish the role of these new drugs and combinations in the management of metastatic breast cancer. Almost simultaneously, similar strategies will be pursued for adjuvant therapy for primary breast cancer, with the goal of improving the curative efficacy of current regimens. These prospects are exciting; however, enthusiasm must be tempered with the knowledge that long-term toxicity is always a distinct possibility. Therefore, the development of new combinations, especially in the setting of adjuvant chemotherapy, should follow a systematic, conservative strategy. [ONCOLOGY 10(Suppl):30-36, 1996]

Over the past 5 years, many new cytotoxic agents with activity against metastatic cancer have been discovered, and several are currently undergoing clinical trials. Whether their marked degree of activity represents a real