Hormone receptor status is an important predictor not only of long-term prognosis but also of response to endocrine therapy. Several studies demonstrated that patients with positive estrogen and progesterone receptor status have improved overall survival (84,85). Receptor status should be known when determining the need for and choice of adjuvant therapy. Histologic grade appears to predict overall survival. Patients with well-differentiated tumors tend to have more favorable outcomes than those with poorly differentiated ones (Table 40.5). In a British study of 1,168 women, histologic grade, along with tumor size and lymph node status, was an independent predictor of overall survival at 10 years (86).
Two multigene assays were rapidly developed and are commercially available including the 21-gene assay (Oncotype DX) and the 70-gene signature (Mammaprint). Oncotype DX was developed for identifying patients who have a high risk of recurrence distantly and for patients with node negative ER+ breast cancer. Large-scale phase III trials are under way in the United States and in Europe to test the clinical utility of these multigene assays, which will assist in determining the use of adjuvant systemic therapy.
The possible roles of specific tumor markers in predicting which patients will respond to chemotherapy regimens were investigated. The most thoroughly researched of these markers is HER-2/neu. In an NSABP study, patients with HER-2/neu overexpression who were not treated with anthracycline-based regimens fared worse (87). Another study showed that the addition of trastuzumab (Herceptin), an antibody directed against the HER-2/neu receptor, significantly increased the response rate to therapy over standard chemotherapy alone in the presence of metastatic disease (88). Reports from trials investigating the adjuvant use of trastuzumab for women with early-stage Her-2/neu breast cancers show significant improvements in disease-free survival for women receiving trastuzumab; trastuzumab is used as systemic adjuvant therapy for patients with Her-2/neu positive breast cancer, and the standard length of treatment is one full year (89–91).
description of the more commonly used regimens. Initially, trials involved a single perioperative course of chemotherapy aimed at eradicating circulating tumor cells. The Nissen-Meyer study from Norway showed that a single course of cyclophosphamide improved overall survival rates (92). Numerous trials demonstrated the benefit of adjuvant chemotherapy for certain subgroups of patients (93). In the initial NSABP adjuvant trial, a 2-year course of melphalan was superior to no treatment, and further trials demonstrated enhanced beneficial effect with the use of multiple drugs as well as with the combination of hormonal manipulation with chemotherapy (94,95).
Historically, the most frequently used adjuvant combination chemotherapy was CMF: cyclophosphamide (C), methotrexate (M), and 5-ﬂuorouracil (5-FU). In the original study by Bonadonna et al., patients with positive axillary lymph nodes were randomized to receive either 12 monthly cycles of CMF or no therapy after radical mastectomy (96). A statistically significant benefit was found with CMF treatment for premenopausal patients, especially those with one to three positive nodes. A subsequent study showed six cycles of CMF to be as effective as 12 cycles (97). No significant effect was seen for postmenopausal women, which may result from the fact that these women were less likely to tolerate the full course of therapy (98). After 20 years of follow-up, this trial demonstrated a persistent survival advantage for premenopausal women receiving CMF adjuvant therapy (99). In a later study involving node-negative, estrogen receptor–negative breast cancer patients, after 12 years of follow-up, 71% of patients treated with adjuvant CMF remained disease free compared with 48% in the control group, regardless of menopausal status (100).