By William B. Ershler, MD, Editor
SYNOPSIS:In a Phase 3, randomized clinical trial of primary systemic therapy for patients with early, locally advanced breast cancer, the addition of capecitabine to each of six 3-weekly cycles of epirubicin-docetaxel resulted in a 1.64 fold increase in the possibility of primary tumor pathologic complete response. Small tumor size, hormone receptor negative disease, and high-grade cellular features were predictors of the greatest benefit of neoadjuvant treatment.
SOURCE:Steger GG, et al, on behalf of the Austrian Breast and Colorectal Study Group (ABCSG). Epirubicin and docetaxel with or without capecitabine as neoadjuvant treatment for early breast cancer: Final results of a randomized phase III study (ABSG-24). Ann Oncol 2014;25:366-371.
Neoadjuvant chemotherapy is now considered treatment of choice for locally advanced, newly diagnosed breast cancer, particularly when patients are not candidates for immediate breast-conserving surgery (BCS).1 Such is based on observations that primary systemic therapy (PST) downstages the primary tumor and lymph node metastases2,3 and increases opportunities for BCS. PST also provides the opportunity to assess chemosensitivity in vivo and to apply therapy early in a disease with a high distant failure rate. The Austrian Breast and Colorectal Study Group (ABCSG) previously demonstrated that duration of therapy impacts pathologic complete response (pCR) rate,4 and additional analyses have shown a correlation between pCR and extended disease-free survival (DFS) and overall survival (OS).5 This supports the conclusion that pCR of the primary tumor is a surrogate marker for eradication of micrometastases and improved survival. Published data show pCR rates of approximately 20% with anthracycline-taxane regimens.4,6 The question remains whether the addition of a third drug would improve this response without unacceptable toxicity. For this, capecitabine (C) seemed the logical choice as it has a favorable toxicity profile, is effective as monotherapy, and has been shown to improve response rates in patients with metastatic breast cancer when used with taxanes.7
In this light, the ABCSG conducted the current Phase 3 trial to compare pCR rates after PST of breast cancer following neoadjuvant epirubicin-docetaxel (ED) ± C, and evaluated the addition of trastuzumab in HER2-positive tumors.
Patients with invasive breast cancer (except T4d) were randomly assigned to receive six 3-weekly cycles of ED (both 75 mg/m2) ± C (1000 mg/m2, twice daily, days 1–14). Patients with HER2-positive disease were further randomized to receive trastuzumab (8 mg/kg, then 6 mg/kg every 3 weeks) or not. The study primary endpoint was tumor pCR rate at the time of surgery.
A total of 536 patients were randomized to ED (n = 266) or EDC (n = 270); 93 patients were further randomized to trastuzumab (n = 44) or not (n = 49). pCR rate was significantly increased with EDC (23.0% vs 15.4% ED; P = 0.027) and nonsignificantly further increased with trastuzumab (38.6% EDC vs 26.5% ED, P = 0.212). Rates of axillary node involvement at surgery and breast conservation were improved with EDC vs ED but not significantly; the addition of trastuzumab had no further impact. Hormone receptor status, tumor size, grade, and the addition of capecitabine were independent prognostic factors for pCR (all P ≤ 0.035).
These findings (an improved pCR rate from 15.4% to 23.0%) show that the integration of capecitabine into a neoadjuvant taxane-/anthracycline-based regimen is an effective treatment option for locally advanced breast cancer. Although the benefit observed is what might be expected from the incremental advantage of adding capecitabine to regimens in the treatment of metastatic breast cancer, two prior studies had indicated no added benefit in the neoadjuvant setting.8,9 However, as the authors point out, in both trials capecitabine was used at lower dose and only for four cycles. It is notable that in addition to capecitabine use, the hormone receptor status, tumor stage, and grade were independent prognostic factors for pCR. Hormone receptor-negative disease and undifferentiated (G3) tumors were associated with a significant increased chance of pCR after treatment with ED or EDC. In particular, triple-negative tumors (most of which are high grade) reached a pCR rate of 45.3% in this trial. Thus, further neoadjuvant studies might well focus on TNBC.
This was a large, carefully conducted multicenter prospective, randomized clinical trial and the findings are of value. U.S. oncologists are less familiar with the epirubicin-docetaxel regimen and the immediate applicability of the published report will more likely occur in Europe or elsewhere. However, it can be concluded that the integration of capecitabine into taxane/anthracycline-based neoadjuvant strategies is feasible, safe, and of demonstrable efficacy. The identification of greatest benefit in those with high-grade, triple-negative disease is of additional importance.