Abstract
One of the hallmarks of cancer is sustained angiogenesis. Favorable results have been reported in some breast cancer (BC) patients receiving antiangiogenic therapy with bevacizumab (Bev) in combination with chemotherapy, and further knowledge on how Bev can be optimally combined with conventional treatment to increase efficacy is strongly needed. In this randomized, neoadjuvant phase II clinical trial, 132 patients with HER2‐negative, nonmetastatic BC were treated with Bev in combination with sequential chemotherapy. Biopsies were sampled before treatment, after 12 weeks with anthracycline and after taxane therapy at week 25. MicroRNA (miRNA) expression profiling was performed on biopsies from each time point. Altogether, 241 biopsies were analyzed with the aim of identifying miRNA‐based biomarkers of response to therapy. Results from the miRNA analyses were reported for the ER‐positive cohort, which were previously demonstrated to benefit from antiangiogenic therapy in this study. For both treatment arms of this cohort, significantly different expression was observed for 217 miRNAs between objective responding and nonresponding patients before treatment initiation. These miRNAs have been linked to regulation of epithelial–mesenchymal transition, metastasis, and tumor growth, among other processes. Bev in combination with chemotherapy resulted in similar miRNA changes to chemotherapy alone. However, the deregulation of miRNA expression occurred earlier in the Bev arm. In both arms, tumor suppressor miRNAs were found upregulated after treatment, while oncogenic miRNAs were downregulated in the Bev arm. Patients responding to Bev showed a strong correlation between deregulated miRNAs and decreased proliferation score during the course of treatment, with downregulation of miR‐4465 as the strongest indicator of reduced proliferation. Integrative analyses at miRNA‐, gene‐, and protein expression further indicated a longitudinal decrease in proliferation. Altogether, the results indicate that proliferation might represent a predictive factor for increased Bev sensitivity, which may aid in the identification of patients who could potentially benefit from Bev.
Highlights
Among women, breast cancer (BC) is the most common cancer type worldwide and the leading cause of cancer death (Bray et al, 2018)
We show that neoadjuvant addition of Bev to chemotherapy in HER2-negative, estrogen receptor (ER)-positive BC tumors elicits many of the same molecular changes as chemotherapy alone
We have demonstrated a difference in miRNA expression between objective response (OR) and nonresponders at diagnosis (Fisher’s exact test, P = 0.0096)
Summary
Breast cancer (BC) is the most common cancer type worldwide and the leading cause of cancer death (Bray et al, 2018). The mechanisms underlying BC development are diverse and complex, with the different molecular subtypes responding differentially to chemotherapy and targeted agents (Rouzier et al, 2005). The anti-VEGF antibody bevacizumab (Bev) has shown increased overall survival (OS) and progression-free survival (PFS) in patients with colorectal cancer when combined with first-line chemotherapy (Hurwitz et al, 2013). One potential explanation for the variation in outcome may be due to differential response in different BC subtypes, as shown in two neoadjuvant clinical trials with Bev; one reported increased response rates in the triple negative BC subset (von Minckwitz et al, 2012), whereas the other reported most responding patients in the estrogen receptor (ER)-positive BC patients (Bear et al, 2012). In addition to the heterogeneity of BC defined by the different transcriptomic subtypes, microRNAs (miRNAs) have been shown to increase this complexity through their posttranscriptional regulation of gene expression (Aure et al, 2015; Aure et al, 2017)
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