Breast cancer biology: implications for local-regional therapy.

I-SPY 1 was an important multicenter trial conducted to identify indicators of response to neoadjuvant chemotherapy, recurrence-free survival, and the relationship between the two. The study enrolled patients with clinical and biologic high-risk features; all tumors measured C3 cm, 41 % were hormone receptor (HR) negative, 90 % were intermediate or high grade, and 91 % were characterized as high risk by the 70-gene profile. 1 Pathologic complete response (pCR) rates varied by constructed molecular subtypes, with the highest rates seen in patients with HRnegative/HER2-positive tumors and the lowest rates in patients with HR-positive/HER2-negative tumors. Achieving a pCR predicted for favorable recurrence-free survival. The investigators concluded that outcomes were dictated by tumor biology. In the current article from Cureton et al., they extend this observation to local recurrence. Specifically, they report that local recurrence is associated with aggressive biological features, including higher clinical stage and the presence of lymphovascular invasion. This article therefore adds to a growing body of literature demonstrating the importance of tumor biology in local-regional outcomes for breast cancer patients. One question that Cureton and colleagues sought to address with their study was whether breast conserving therapy (BCT) provides adequate local control after neoadjuvant chemotherapy. In the NSABP B-18 trial, the in-breast recurrence rate was 16 % for patients downsized to BCT versus 10 % in patients initially planned for breast conservation, a difference that was not significant when controlling for age and clinical tumor size. 2 Similarly, in the EORTC 10902 trial, 23 % of patients were downsized and underwent BCT, and there was no significant difference in localregional recurrence (LRR) rates when compared with patients who were BCT candidates at presentation. 3 In a meta-analysis of studies comparing neoadjuvant with adjuvant chemotherapy, Mieog et al. found that when patients were analyzed by type of surgery, LRR rates in patients undergoing BCT were not affected by the timing of chemotherapy. 4 These older studies demonstrated that tumors in a significant number of patients will decrease in size after neoadjuvant chemotherapy, facilitating breast preservation and overall providing good local control. The question remained, however, whether factors such as adverse biologic characteristics could be used to identify the subset of patients with higher rates of local regional failure and who may be better served by mastectomy. These data from the I-SPY 1 trial, which evaluated local recurrence rates according to clinical and pathologic factors in the context of BCT versus mastectomy, suggest that more aggressive surgery, i.e., mastectomy, will not overcome aggressive biology. As an example, for patients presenting with node-positive disease, the 5-year local recurrence risks were 36 and 29 %, respectively, for patients undergoing mastectomy and BCT. In contrast, for patients presenting with node-negative disease, the 5-year local recurrence risks were 11 and 6 %, respectively. It is also notable that very few patients experienced a local recurrence without also experiencing distant disease. This impact of ‘‘bad biology’’ is consistent with data recently published from our own institution evaluating local-regional control in patients undergoing BCT to include segmental mastectomy with whole-breast irradiation (WBI). 5 This study included 652 patients who received neoadjuvant chemotherapy, whom we compared with 2331 patients who underwent surgery as a first intervention. As would be anticipated, patients receiving neoadjuvant chemotherapy had more adverse clinicopathologic characteristics. The 10-year LRR-free survival rates were 94 % for surgery-first patients and 90 % for those receiving neoadjuvant chemotherapy. It is important to note that, when compared by presenting clinical stage, there were