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Several recent publications have re-opened the question of whether HER2 status should be determined for all patients with newly diagnosed breast cancer. The barrier in the past to the use of HER2 has been the nonstandardization of HER2 status determination, which is the major caveat to its use today. Two test kits have been recently approved by the Food and Drug Administration for HER2 testing, one for determining HER2 amplification by fluorescence in situ hybridization and the other for measuring HER2 overexpression by immunohistochemistry. Neither of these tests, nor any of the other myriad tests used for HER2 determinations, has been validated in all the potential arenas for the use of HER2: refinement of estimates of prognosis of untreated low-risk patients, selection among treatment options for adjuvant therapy, and selection of patients for treatment with trastuzumab (Herceptin; Genentech, San Francisco, CA). The nonstandardization of testing has led to conflicting results and controversy as to the value of HER2 in evaluating breast cancer patient prognosis and the selection among therapeutic options. Thus, testing for HER2 is not yet routine for patients with newly diagnosed breast cancer, although it is of value for patients who develop metastatic disease and who need to know if they are candidates for trastuzumab.

The need for improved adjuvant chemotherapy programs for breast cancer patients is emphasized by the 1998 overview analysis of adjuvant trials, which demonstrates that although there has been substantial incremental advances in adjuvant therapy, relapse and death are prevented in less than half of women with micrometastatic disease. Because both docetaxel (Taxotere; Rhône-Pouleuc Rorer, Collegeville, PA) and paclitaxel have substantial non-cross-resistance with anthracyclines and therefore activity in anthracycline-resistant breast cancer, defining their roles in the adjuvant therapy of breast cancer is an area of great interest and active clinical investigation. The results of the adjuvant trials using docetaxel assume a particular importance because of the two taxanes in clinical use at this time, docetaxel may be the more active agent in the treatment of metastatic breast cancer, as demonstrated in the results from phase II and III randomized trials. Ongoing or soon-to-open adjuvant trials are evaluating the impact of docetaxel added to conventional adjuvant anthracyclines regimens, substituted for anthracyclines, used in combination with anthracyclines, and in direct comparison to paclitaxel. The results of these ongoing adjuvant trials will define the role of docetaxel in adjuvant chemotherapy programs for the management of patients with breast cancer and are eagerly awaited.

Until the introduction of the taxoids, docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) and paclitaxel (Taxol; Bristol-Myers Squibb Oncology, Princeton, NJ), in the 1990s, anthracyclines were widely recognized as the best single agents for the treatment of breast cancer. However, even when anthracyclines are used in combination regimens with response rates of over 50%, including complete responses in 17% of patients, few women (3%) with metastatic disease remain disease free at 5 years after treatment. The low level of sustained responses is largely due to the phenomenon of drug resistance. Anthracycline resistance often involves multidrug resistance efflux mechanisms, but also can involve factors affecting topoisomerase II and apoptosis. When combining other cytotoxic agents with anthracyclines, it is of value to use non-cross-resistant drugs so that the induction of anthracycline-resistance mechanisms does not also affect the efficacy of other agents in the combination therapy. Clinical studies have shown that docetaxel, which is highly active against metastatic breast cancer as a single agent, has a high level of non-cross-resistance with anthracyclines. The overall response rate to docetaxel monotherapy in patients with anthracycline-resistant or refractory metastatic disease has been shown to be 41%. The response rate to first-line docetaxel monotherapy for metastatic breast cancer has been shown to be 61%, suggesting that two thirds of the activity of docetaxel is retained in anthracycline-resistant disease. Treatment with a simultaneous combination of docetaxel and doxorubicin has been found to be very active, with a response rate of 89%, and trials to exploit the lack of cross-resistance between these agents, in sequential regimens and adjuvant therapies, are under way.

This report describes a computer program designed to assist health care professionals in making projections of the average benefit of systemic adjuvant therapy for individual breast cancer patients. It requires as input patient age (used to make projections of natural mortality), an estimate of breast cancer-related mortality at 5 years (used to make projections of breast cancer-specific mortality), and the proportional risk reduction for breast cancer mortality expected for the adjuvant therapy (with included tables from the Early Breast Cancer Trialist's 1992 meta-analysis). The program uses life table analytical techniques to make projections of outcome in three scenarios: that the breast cancer never occurred, that the breast cancer patient received definitive local therapy but no adjuvant systemic therapy, and that the patient received adjuvant therapy. The outcome projections are given for total, natural (non-breast cancer-related), and breast cancer-related mortality at several time points and also of total remaining life expectancy. These estimates are currently widely made by clinicians by nonnumerical techniques. Computer-based tools can serve as valuable aids in physician and patient education and in the process of informed decision making.

The results of recent clinical trials have shown that docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France), like paclitaxel (Taxol; Bristol-Myers Squibb Oncology, Princeton, NJ), has high levels of activity in patients with anthracycline-resistant breast cancer. Agents that are at least partially non-cross-resistant with anthracyclines are especially promising for the treatment of breast cancer; the taxoids (docetaxel and paclitaxel) are such agents. Although preclinical evaluations shows clear instances of strong cross-resistance (particularly in cells lines expressing the P-glycoprotein, multidrug resistance), high response rates have been reported in patients with prior anthracycline exposure and/or anthracycline resistance. Phase I studies of anthracycline and taxoid combinations have been conducted. Excellent response rates have been noted in some of these studies. In some studies using regimens combining doxorubicin and paclitaxel, unanticipated toxicities have occurred, such as typhlitis, as well as congestive heart failure at lower than expected cumulative doses of doxorubicin. Phase II and III studies of regimens including both anthracyclines and taxoids have been initiated. Docetaxel and paclitaxel appear to be valuable agents for use in anthracycline-resistant breast cancer patients, and may find a place in anthracycline-containing combination regimens.

Phase II studies have demonstrated that docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) is one of the most active single agents in the treatment of metastatic breast cancer. The overall response rate as front-line therapy for metastatic disease was 59% (95% confidence interval, 51% to 67%) in five phase II trials (four of which were multicenter) when 100 mg/m2 docetaxel was infused over 1 hour every 3 weeks. In the three phase II trials reported to date of patients with metastatic cancer who had failed previous frontline therapy, 100 mg/m2 docetaxel infused over 1 hour every 3 weeks produced an objective response rate of 49% (95% confidence interval, 40% to 58%). Two of these trials specifically included patients who had progressed while receiving either an anthracycline or an anthracenedione; the overall response rate in this subset of 83 patients was 48%. The most significant acute toxicity noted in these trials was neutropenia. Grade 4 neutropenia occurred in the majority of patients but rarely resulted in treatment delays. Hypersensitivity reactions also were common in nonpremedicated patients, but were rare after the institution of premedication with antihistamines and/or glucocorticoids. A novel toxicity observed in many patients was fluid retention syndrome, with onset at a median of four to five cycles. The fluid retention was of noncardiac or renal origin, was slowly progressive with additional cycles of therapy, was reversible after cessation of the drug, and could be largely ameliorated by oral diuretics and glucocorticoid premedication. Phase III studies to further define docetaxel's role in the treatment of breast cancer are now under way.