Association of Pathologic Complete Response to Neoadjuvant Therapy in HER2-Positive Breast Cancer With Long-Term Outcomes: A Meta-Analysis
- Additional Document Info
- View All
IMPORTANCE: The expense and lengthy follow-up periods for randomized clinical trials (RCTs) of adjuvant systemic therapy in breast cancer make them impractical and even impossible to conduct. Randomized clinical trials of neoadjuvant systemic therapy for breast cancer may help resolve this dilemma. OBJECTIVE: To assess the utility of pathologic complete response (pCR) for neoadjuvant drug development in human epidermal growth factor receptor 2 (HER2 [also referred to as ERBB2])-positive breast cancer. DATA SOURCES: We searched MEDLINE (Ovid), Embase (Ovid), CENTRAL (Wiley), and Northern Light Life Sciences Conference Abstracts (Ovid) in December 2014. Searches combined terms for "breast cancer" and "neoadjuvant therapy," with no limit on publication date. STUDY SELECTION: Cohort studies and RCTs were selected that met following criteria: stages I to III HER2-positive breast cancer, neoadjuvant therapy, and reports of both pCR and an event-free survival (EFS)-type outcome. The initial search identified 2614 publications, of which 38 studies met the selection criteria. DATA EXTRACTION AND SYNTHESIS: Two authors independently screened each study for inclusion and extracted the data. Data were analyzed using Bayesian hierarchical models. MAIN OUTCOMES AND MEASURES: Event-free survival and overall survival (OS) hazard ratios (HRs) for pCR vs non-pCR. For RCTs, main outcome measures were treatment benefits in pCR and the corresponding treatment HRs for EFS and OS. RESULTS: A total of 36 studies with EFS by pCR status representing 5768 patients with HER2-positive breast cancer were included in the patient-level analysis. Overall, the improvement in EFS for pCR vs non-pCR was substantial: HR, 0.37 (95% probability interval [PI], 0.32-0.43). This association was greater for patients with hormone receptor-negative disease (HR, 0.29 [95% PI, 0.24-0.36]) than hormone receptor-positive disease (HR, 0.52 [95% PI, 0.40-0.66]). In RCTs, the R2 correlations between odds ratios for pCR and HRs were 0.63 for EFS and 0.29 for OS. Based on absolute treatment improvements in pCR rate, predicted HRs for EFS for RCTs were concordant with observed HRs. CONCLUSIONS AND RELEVANCE: Pathologic complete response in HER2-positive breast cancer is associated with substantially longer times to recurrence and death. This relationship is maintained in RCTs. For any particular new therapy the relationship between pCR and survival may differ. Quantifying the importance of pCR is necessary for designing efficient clinical trials, which should adapt to the relationship between pCR and survival for the therapy under investigation.
author list (cited authors)
Broglio, K. R., Quintana, M., Foster, M., Olinger, M., McGlothlin, A., Berry, S. M., ... Berry, D. A.