Response rates and pathologic complete response by breast cancer molecular subtype following neoadjuvant chemotherapy

Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS. We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response--ypT0 ypN0, ypT0/is ypN0, and ypT0/is--for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS. We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0·44, 95% CI 0·39-0·51; ypT0/is ypN0: 0·48, 0·43-0·54) and OS (0·36, 0·30-0·44; 0·36, 0·31-0·42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0·60, 95% CI 0·55-0·66; OS 0·51, 0·45-0·58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0·24, 95% CI 0·18-0·33; OS: 0·16, 0·11-0·25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0·15, 0·09-0·27; OS: 0·08, 0·03, 0·22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R(2)=0·03, 95% CI 0·00-0·25) and OS (R(2)=0·24, 0·00-0·70). Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS. US Food and Drug Administration. Copyright © 2014 Elsevier Ltd. All rights reserved.

The limited information on predictors of locoregional recurrence (LRR) after neoadjuvant chemotherapy (NC) has resulted in controversy about the optimal use of adjuvant radiotherapy and the timing of sentinel lymph node biopsy. We examined patterns and predictors of LRR as first event in combined analysis of two National Surgical Adjuvant Breast and Bowel Project (NSABP) neoadjuvant trials. NC was either doxorubicin/cyclophosphamide (AC) alone or AC followed by neoadjuvant/adjuvant docetaxel. Lumpectomy patients received breast radiotherapy alone; mastectomy patients received no radiotherapy. Pathologic complete response was defined as the absence of invasive tumor in the breast. Multivariate analyses were used to identify independent predictors of LRR. The primary end point was time to LRR as first event. In 3,088 patients, 335 LRR events had occurred after 10 years of follow-up. The 10-year cumulative incidence of LRR was 12.3% for mastectomy patients (8.9% local; 3.4% regional) and 10.3% for lumpectomy plus breast radiotherapy patients (8.1% local; 2.2% regional). Independent predictors of LRR in lumpectomy patients were age, clinical nodal status (before NC), and pathologic nodal status/breast tumor response; in mastectomy patients, they were clinical tumor size (before NC), clinical nodal status (before NC), and pathologic nodal status/breast tumor response. By using these independent predictors, groups at low, intermediate, and high risk of LRR could be identified. Nomograms that incorporate these independent predictors were created. In patients treated with NC, age, clinical tumor characteristics before NC, and pathologic nodal status/breast tumor response after NC can be used to predict risk for LRR and to optimize the use of adjuvant radiotherapy.

To determine whether residual ductal carcinoma in situ (DCIS) after completion of preoperative chemotherapy affects the outcome of patients with histologically defined complete eradication of invasive cancer. Retrospective analysis of a database including 2,302 breast cancer patients treated with neoadjuvant chemotherapy at The University of Texas M.D. Anderson Cancer Center between 1980 and 2004 was performed. The overall survival (OS), disease-free survival (DFS), and local recurrence-free survival were compared for patients with no residual invasive or in situ cancer (pathologic complete response [pCR]) and patients with no residual invasive cancer but persistent in situ disease (pCR+DCIS). The mean follow-up time was 250 months. Of the 2,302 treated patients, 78 (3.4%) had pCR, 199 (8.6%) had pCR+DCIS, and 2,025 (88%) had residual invasive cancer. For patients with pCR and pCR+DCIS, the 5-year DFS rates (87.1% in both groups) and 10-year DFS rates (81.3% v 81.7%, respectively) were similar; the 5-year OS rates (91.9% v 92.5%, respectively) and 10-year OS rates (91.8% v 92.5%, respectively) were also similar and significantly better than the rate of patients with residual invasive cancer (74.4%; P < .001). The 5-year locoregional recurrence-free survival rates were also not different between patients with pCR (92.8%; 95% CI, 86.1% to 96.4%) and patients with pCR+DCIS (90.9%; 95% CI, 77.3% to 96.5%; P = .63). Residual DCIS in patients who experience complete eradication of the invasive cancer in the breast and lymph nodes does not adversely affect survival or local recurrence rate. Inclusion of patients with residual DCIS in the definition of pCR is justified when this outcome is used as an early surrogate for long-term survival.