Table 6. Standard Adjuvant Chemotherapy Regimens for Stage I, II, IIIA, and Operable IIICHER2/neuNon-Overexpressing Breast Cancer continued...
Docetaxel and cyclophosphamide
The regimen of docetaxel and cyclophosphamide (TC) compared with doxorubicin plus cyclophosphamide (AC) was studied in 1,016 women with stage I or stage II invasive breast cancer. Patients were randomly assigned to receive four cycles of either TC or AC as adjuvant postoperative therapy. At 5 years, DFS was statistically significantly superior for TC compared with AC (86% vs. 80%, HR, 0.67; 95% CI, 0.50–0.94; P = .015).[Level of evidence: 1iiA] At the time of the original report, OS was not statistically significantly improved. However, a 7-year update of results for DFS and OS demonstrated that four cycles of TC was superior to standard AC for both DFS and OS.[Level of evidence: 1iiA]. At 7 years, DFS was significantly superior for TC compared with AC (81% vs. 75%, HR, 0.74; 95% CI, 0.56–0.98; P = .033). At 7 years, OS was significantly superior for TC compared with AC (87% vs. 82%, HR, 0.69; 95% CI, 0.50–0.97; P = .032). With TC, patients had fewer cardiotoxic effects but other side effects included more myalgia, arthralgia, edema, and febrile neutropenia compared with AC.
The role of bisphosphonates as part of adjuvant therapy for early stage breast cancer is unclear. The ABCSG-12 (NCT00295646) trial was a 2 × 2 factorial-design randomized trial that assigned 1,803 premenopausal patients with ER+ breast cancer to receive ovarian function suppression with goserelin and tamoxifen versus goserelin and anastrozole. These patients then underwent a second randomization to receive zoledronic acid (4 mg intravenously every 6 months) versus no zoledronic acid.[Level of evidence: 1iiA] There was no significant difference in DFS between the anastrozole and tamoxifen groups. However, the addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy without zoledronic acid, resulted in a relative reduction of 36% in the risk of disease progression (HR, 0.64; P = .01) but did not significantly reduce the risk of death.
While bisphosphonates appear to improve DFS in a population with low-to-intermediate-risk breast cancer, this benefit does not appear to be seen in all patients with breast cancer. The AZURE trial was a randomized, phase III trial that assigned 3,660 patients with stage II or III breast cancer to receive chemotherapy and/or hormone therapy with or without zoledronic acid.[Level of evidence: 1iiA] At a median follow-up of 59 months, there was no significant benefit in the DFS in both groups (77% in each group; HR, 0.98; P = .79). OS was also similar, at 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted HR, 0.85; P = .07).
Based on the conflicting results of these trials, the exact role for bisphosphonates in adjuvant therapy for breast cancer is controversial. An ongoing phase III trial (NCT01077154) is examining the activity of the bone-modifying agent, denosumab, in stage II and III breast cancer.