Following surgery and radiation therapy, chemotherapy or hormonal therapy is advocated for most patients with curable breast cancer. The objective of adjuvant systemic therapy is to eliminate the occult metastases responsible for late recurrences while they are microscopic and most vulnerable to anticancer agents. In addition, adjuvant chemotherapy may decrease local recurrence in patients treated with breast conservation, whereas adjuvant hormonal manipulation decreases contralateral breast cancer occurrence.

Even the earliest studies comparing placebo with chemotherapy drugs having minimal activity, such as L-phenylalanine mustard, showed an improvement in both disease-free and overall survival for women who were disease free postoperatively. The landmark study from Milan evaluating the effect of 1 year of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) given on days 1 and 8 of each month for 12 months showed a significant improvement in survival for premenopausal women with node-positive disease. After 20 years of follow-up, significant improvement in survival persisted among those receiving chemotherapy. CMF rapidly became the standard management for premenopausal women with node-positive breast cancer. Subsequently, the use of chemotherapy for postmenopausal women and those at less risk than node-positive women was evaluated. Systemic chemotherapy improved survival in all groups of women treated. The improvement in survival for patients treated appears to be about 30% of the patients’ risk of death; that is, a woman with a 30% chance of recurrence and death derives about a 10% overall improvement in survival. This risk-reduction analysis has been confirmed in numerous studies and meta-analyses.

On the basis of the superiority of anthracycline-containing regimens in metastatic breast cancer, both doxorubicin and epirubicin have been studied extensively in the adjuvant setting and have been compared to CMF regimens. Studies comparing Adriamycin (doxorubicin) and cyclophosphamide (AC) or epirubicin and cyclophosphamide (EC) with CMF have shown that treatment with anthracycline-containing regimens are at least as effective, and perhaps more effective, as treatment with CMF. The NSABP B-23 compared four cycles of AC with six cycles of CMF and demonstrated the equivalence of these two regimens in node-negative, estrogen receptor (ER)-negative disease. Whereas four cycles of AC or EC have not demonstrated improved survival compared to CMF, the use of six cycles of fluorouracil plus AC (FAC) or fluorouracil plus EC (FEC) has shown improved survival compared to CMF alone. For node-negative patients, most oncologists offer four cycles of AC or six cycles of CMF in the adjuvant setting.

For node-positive patients, taxanes are now frequently combined with anthracycline-based regimens. The Cancer and Leukemia Group B (CALGB) study comparing four cycles of AC to four cycles of AC followed by four cycles of paclitaxel showed about a 20% proportional reduction in recurrence and a 4% absolute improvement in disease-free survival with the use of paclitaxel. Paclitaxel is now approved for and increasingly employed as adjuvant therapy in node-positive breast cancer.

Unfortunately, a subsequent study by the NSABP failed to show any benefits of the use of paclitaxel except in ER-negative patients with positive nodes. A 2002 National Institutes of Health (NIH) consensus panel felt that firm conclusions about the use of taxanes could not be drawn and recommended that patients receive adjuvant taxanes only in the context of a clinical trial. However, based on trends in improved survival, many oncologists add a taxane to AC for node-positive women. A trial comparing six cycles of FAC to six cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC) showed an improvement in disease-free survival for patients receiving the addition of paclitaxel. This benefit was most marked for patients with positive nodes and was seen in both ER-negative and ER-positive tumors. Until more information is obtained, the role of taxanes in the adjuvant setting remains unclear.

Controversy exists as to whether patients whose tumors overexpress the HER-2/neu oncogene benefit more from anthracycline regimens than from CMF regimens. Retrospective analysis of randomized trials suggests that patients with HER-2/neu overexpression may benefit more from doxorubicin than patients with HER-2/neu-negative disease. These retrospective studies have numerous problems, including the analysis of HER-2/neu on paraffin tissue blocks.

The overall duration of adjuvant chemotherapy still remains uncertain. However, based on the meta-analysis performed in the Oxford Overview (Early Breast Cancer Trialists’ Collaborative Group), the current recommendation is for 3-6 months of the commonly used regimens. The addition of taxanes required an additional duration of therapy of up to 6 months. Recently, increasing the frequency of chemotherapy administration (dose-dense chemotherapy) has been shown to be superior to standard dosing.

Adjuvant hormonal therapy is also highly effective in decreasing recurrence and mortality in women with ER-positive tumors. The standard regimen has been tamoxifen for 5 years. Hormonal therapy decreases the risk of mortality by approximately 25%. This appears to be effective regardless of age and may be used in both premenopausal and postmenopausal women. More recently, the aromatase inhibitors have been shown to be effective in the adjuvant setting. The large Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial in postmenopausal women with ER-positive disease showed improved disease-free survival in patients treated with anastrozole compared to those treated with tamoxifen alone or even with the combination of tamoxifen and anastrozole. In addition, anastrozole showed a decrease of over 50% in the recurrence of contralateral breast tumors and fewer side effects such as endometrial cancers, hot flushes, and thromboembolic events. Anastrozole is increasingly being used in the adjuvant setting in postmenopausal women. The American Society of Clinical Oncology, however, has recommended the use of tamoxifen for adjuvant hormonal therapy in the absence of significant contraindications; anastrozole is recommended when there are contraindications to tamoxifen.

Use of high-dose chemotherapy with stem cell support has not demonstrated a consistent, favorable impact on survival and should not be used outside of clinical trials. Although it is clear that dose intensity to a specific threshold is essential, there is no clear benefit to high-dose therapy with stem cell support.

An NIH consensus conference has reexamined the standards for adjuvant therapy of breast cancer. Since the last conference on this topic in 1990, the long-term advantage of systemic therapy has been further established. In the past 10 years, no new prognostic factors have been validated to aid in the selection of patients for adjuvant treatment. Its use should be based on the patient’s age; on the size, histopathologic grade, and hormone receptor status of the breast tumor; and on the status of the regional lymph nodes. The value of HER-2/neu, p53, angiogenesis factors, and vascular invasion is being investigated, but as yet they are not proven prognostic factors. Studies are being conducted evaluating trastuzumab in the adjuvant setting in a group of patients whose tumors overexpress HER-2/neu. The panel concluded that regardless of other factors, adjuvant systemic chemotherapy with drug combinations improves survival and should be used for most women who have potentially curable breast cancer. The use of anthracyclines is superior to combinations without anthracyclines. Tamoxifen should be used as a systemic agent in all women whose tumors are hormone receptor positive - regardless of age, menopausal status, or other prognostic factors. HER-2/neu status should not affect the choice of agents or the use of hormone therapy. Ovarian ablation in premenopausal patients with estrogen receptor-positive tumors may produce a benefit similar to that of adjuvant systemic chemotherapy. Taxanes have demonstrated benefit in patients with metastatic cancer and are being used in node-negative patients. Adjuvant systemic therapy should not be given to women who have small node-negative breast cancers with favorable histologic subtypes, such as mucinous or tubular carcinoma.

In practice, most medical oncologists are currently using systemic adjuvant therapy for patients with either node-negative or node-positive breast cancer. Prognostic factors other than nodal status being used to determine the patient’s risks are tumor size, estrogen and progesterone receptor status, nuclear grade, histologic type, proliferative rate, and oncogene expression (

Table 17-4). The assumption is made that all patients with node-negative aggressive tumors should receive adjuvant therapy except those who have serious coexistent medical problems. In general, systemic chemotherapy decreases the chance of recurrence by about 30%. Most patients tolerate at least tamoxifen. The use of chemotherapy prior to resection of the primary tumor (neoadjuvant) is gaining popularity. This enables the assessment of in vivo chemosensitivity. A complete tumor response in vivo prior to operation appears to be associated with improvement in survival. Neoadjuvant chemotherapy also permits breast conservation by shrinking the primary tumor in women who would otherwise need mastectomy for local control.

Important questions remaining to be answered are the timing and duration of adjuvant and neoadjuvant chemotherapy, which chemotherapeutic agents should be applied for which subgroups of patients, the use of combinations of hormonal therapy and chemotherapy, and the value of prognostic factors other than hormone receptors in predicting response to adjuvant therapy. Adjuvant systemic therapy is not generally used in patients with small tumors and those with negative lymph nodes who have favorable tumor markers. However, a small disease-free survival benefit, even in patients with small favorable tumors, has been suggested. It appears that adjuvant systemic therapy benefits all breast cancer patients, but the clinician must decide if the benefits outweigh the risks, complications, and expense.

_{Adjuvant Therapy for Breast Cancer. NIH Consensus Statement 2000. November 1-3;17(4):1-35.}

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