Abstract
IntroductionThe molecular biology involving neoadjuvant chemotherapy (NAC) response is poorly understood. To elucidate the impact of NAC on the breast cancer transcriptome and its association with clinical outcome, we analyzed gene expression data derived from serial tumor samples of patients with breast cancer who received NAC in the I-SPY 1 TRIAL.MethodsExpression data were collected before treatment (T1), 24–96 hours after initiation of chemotherapy (T2) and at surgery (TS). Expression levels between T1 and T2 (T1 vs. T2; n = 36) and between T1 and TS (T1 vs. TS; n = 39) were compared. Subtype was assigned using the PAM50 gene signature. Differences in early gene expression changes (T2 − T1) between responders and nonresponders, as defined by residual cancer burden, were evaluated. Cox proportional hazards modeling was used to identify genes in residual tumors associated with recurrence-free survival (RFS). Pathway analysis was performed with Ingenuity software.ResultsWhen we compared expression profiles at T1 vs. T2 and at T1 vs. TS, we detected significantly altered expression of 150 and 59 transcripts, respectively. We observed notable downregulation of proliferation and immune-related genes at T2. Lower concordance in subtype assignment was observed between T1 and TS (62 %) than between T1 and T2 (75 %). Analysis of early gene expression changes (T2 − T1) revealed that decreased expression of cell cycle inhibitors was associated with poor response. Increased interferon signaling (TS − T1) and high expression of cell proliferation genes in residual tumors (TS) were associated with reduced RFS.ConclusionsSerial gene expression analysis revealed candidate immune and proliferation pathways associated with response and recurrence. Larger studies incorporating the approach described here are warranted to identify predictive and prognostic biomarkers in the NAC setting for specific targeted therapies.Clinical trial registrationClinicalTrials.gov identifier: NCT00033397. Registered 9 Apr 2002.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0582-3) contains supplementary material, which is available to authorized users.
Highlights
The molecular biology involving neoadjuvant chemotherapy (NAC) response is poorly understood
Transcriptomic analysis of breast tumor samples before, during and after NAC revealed changes in molecular subtypes as well as genes and pathways associated with response and recurrence
CONSORT flowchart of patients and data and Venn diagrams of results for association analyses. (A) Gene expression analysis was performed on breast cancer tumors collected before treatment (T1), between 24 and 96 hours after initiation of anthracycline-based neoadjuvant chemotherapy (T2) and at the time of surgery (TS). (B) Venn diagram showing overlap of genes associated with chemotherapy response as defined by residual cancer burden (RCB)
Summary
The molecular biology involving neoadjuvant chemotherapy (NAC) response is poorly understood. Recent clinical studies involving NAC have provided an opportunity to evaluate prognosis based on the presence of residual disease and to elucidate predictors of response to different types of chemotherapeutics [7,8,9,10,11]. These studies have consistently shown that cancers in women who respond to NAC with a pathological complete response (pCR) are much less likely to recur than those in women with residual disease [5]. There are no genomic markers that can predict response to NAC [16, 17]
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