Preoperative Chemotherapy for Breast Cancer: Pearls and Pitfalls: Benefits of Preoperative Chemotherapy

Benefits of Preoperative Chemotherapy

Improvement in Surgical Options and Pathologic Assessment

A well recognized role of PST is the ability to improve surgical options for patients by downsizing tumors and increasing the chances for breast conservation.^[2-6] In the landmark National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial,^[4] 1523 patients with primary operable breast cancer were randomized to either pre- or postoperative systemic therapy with 4 cycles of standard doxorubicin (60 mg/m²) plus cyclophosphamide (600 mg/m²) (AC) given every 3 weeks. The administration of preoperative therapy in this trial increased the proportion of patients able to receive breast conservation surgery by 12% (the breast conservation therapy rate increased from 60% to 68%). This result has been confirmed in other studies, suggesting that PST can enable downsizing of tumors and reduce mastectomy rates in favor of breast conservation therapy. Critical to the success and widespread adoption of this approach was the demonstration of comparable distant disease control with PST vs adjuvant chemotherapy. In the NSABP B-18 trial, at a mean of 9.5 years of follow-up, no significant differences were seen in disease-free and overall survival rates between the 2 randomized groups (69% vs 70%, P = .80; 55% vs 53%, P = .50, respectively).^[5] Similar results have been observed in other randomized studies, and a recent pooled meta-analysis demonstrated that both approaches provide equivalent survival outcomes for patients.^[7] Hence, PST is a safe alternative to adjuvant therapy, especially in patients in whom breast conservation therapy is desired.

A unique advantage of the PST approach is that it allows pathologic assessment of the breast and nodes after systemic treatments. The clinical and pathologic response rates are surrogates for the traditional long-term endpoint of disease-free survival typically obtained from adjuvant treatment trials. In the European Organisation for Research and Treatment of Cancer (EORTC) 10902 trial,^[6] 698 patients with operable breast cancer were randomized to receive either pre- or postoperative therapy with 4 cycles of 5-fluorouracil (600 mg/m²), epirubicin (60 mg/m²), and cyclophosphamide (600 mg/m²) (FEC) given every 3 weeks. At 56 months median follow-up, no significant difference was noted in the primary and secondary endpoints of disease-free and overall survival, confirming previously known benefits of both approaches. In the group that received preoperative therapy, 13 patients achieved a pathologic complete response (pCR), defined as the absence of malignant cells in the breast and axillary nodes. Compared with the group treated with PST that did not achieve a pCR, these 13 patients experienced a statistically improved overall survival with a hazard ratio (HR) of 0.86 (95% confidence interval [CI], 0.77-0.96; P = .008). Based on these and other data showing a similar correlation between pCR and disease-free and overall survival,^[5,8,9] it appears that pathologic results achieved with PST can be used as surrogate endpoints of the traditional long-term survival outcomes and allow more rapid evaluation of treatments for patients with early-stage breast cancer.

A follow-up study to NSABP B-18 was the NSABP B-27 trial,^[10] which enrolled 2411 patients with early-stage operable breast cancer who received PST with AC for 4 cycles every 3 weeks and were then randomized to 1 of 3 arms: surgery alone; further sequential PST with docetaxel (100 mg/m²) for 4 cycles every 3 weeks followed by surgery; or surgery followed by 4 cycles of docetaxel (100 mg/m²) every 3 weeks. Irrespective of the treatment group, pCR (defined specifically as no invasive cancer in the breast) did correlate with an improved overall survival (HR = 0.33; 95% CI, 0.23-0.27; P < .0001); however, this result did not hold when the type of chemotherapy was factored in. In spite of improved pCR rates with the addition of docetaxel to AC chemotherapy (from 13% to 26%), no survival advantage was apparent. The B-27 trial was underpowered for this analysis, but it may yet be premature to consider early improvements in pCR as a replacement for the traditional clinical disease-free and overall survival endpoints. In addition, hormone receptor-positive patients received tamoxifen concurrently with chemotherapy in the B-18 and B-27 studies, which also may have influenced pCR rates.

Investigators at the MD Anderson Cancer Center have developed a prognostic model that quantifies residual disease in the breast and nodes (called residual cancer burden) after PST to determine distant relapse rates at 5 years.^[11] This validated tool may ultimately evolve as the optimal surrogate marker for long-term survival endpoints.