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Breast Cancer Research
Published in: Breast Cancer Research 1/2020

Open Access 01-12-2020 | Breast Cancer | Research article

TBCRC 002: a phase II, randomized, open-label trial of preoperative letrozole with or without bevacizumab in postmenopausal women with newly diagnosed stage 2/3 hormone receptor-positive and HER2-negative breast cancer

Authors: Christos Vaklavas, Brian S. Roberts, Katherine E. Varley, Nancy U. Lin, Minetta C. Liu, Hope S. Rugo, Shannon Puhalla, Rita Nanda, Anna Maria Storniolo, Lisa A. Carey, Mansoor N. Saleh, Yufeng Li, Jennifer F. Delossantos, William E. Grizzle, Albert F. LoBuglio, Richard M. Myers, Andres Forero-Torres, on behalf of the Translational Breast Cancer Research Consortium (TBCRC)

Published in: Breast Cancer Research | Issue 1/2020

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Abstract

Background

In preclinical studies, the expression of vascular endothelial growth factor (VEGF) in hormone receptor-positive breast cancer is associated with estrogen-independent tumor growth and resistance to endocrine therapies. This study investigated whether the addition of bevacizumab, a monoclonal antibody against VEGF, to letrozole enhanced the antitumor activity of the letrozole in the preoperative setting.

Methods

Postmenopausal women with newly diagnosed stage 2 or 3 estrogen and/or progesterone receptor-positive, HER2-negative breast cancer were randomly assigned (2:1) between letrozole 2.5 mg PO daily plus bevacizumab 15 mg/kg IV every 3 weeks (Let/Bev) and letrozole 2.5 mg PO daily (Let) for 24 weeks prior to definitive surgery. Primary objective was within-arm pathologic complete remission (pCR) rate. Secondary objectives were safety, objective response, and downstaging rate.

Results

Seventy-five patients were randomized (Let/Bev n = 50, Let n = 25). Of the 45 patients evaluable for pathological response in the Let/Bev arm, 5 (11%; 95% CI, 3.7–24.1%) achieved pCR and 4 (9%; 95% CI, 2.5–21.2%) had microscopic residual disease; no pCRs or microscopic residual disease was seen in the Let arm (0%; 95% CI, 0–14.2%). The rates of downstaging were 44.4% (95% CI, 29.6–60.0%) and 37.5% (95% CI, 18.8–59.4%) in the Let/Bev and Let arms, respectively. Adverse events typically associated with letrozole (hot flashes, arthralgias, fatigue, myalgias) occurred in similar frequencies in the two arms. Hypertension, headache, and proteinuria were seen exclusively in the Let/Bev arm. The rates of grade 3 and 4 adverse events and discontinuation due to adverse events were 18% vs 8% and 16% vs none in the Let/Bev and Let arms, respectively. A small RNA-based classifier predictive of response to preoperative Let/Bev was developed and confirmed on an independent cohort.

Conclusion

In the preoperative setting, the addition of bevacizumab to letrozole was associated with a pCR rate of 11%; no pCR was seen with letrozole alone. There was additive toxicity with the incorporation of bevacizumab. Responses to Let/Bev can be predicted from the levels of 5 small RNAs in a pretreatment biopsy.

Trial registration

This trial is registered with ClinicalTrials.gov (Identifier: NCT00161291), first posted on September 12, 2005, and is completed.
Appendix
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Metadata
Title
TBCRC 002: a phase II, randomized, open-label trial of preoperative letrozole with or without bevacizumab in postmenopausal women with newly diagnosed stage 2/3 hormone receptor-positive and HER2-negative breast cancer
Authors
Christos Vaklavas
Brian S. Roberts
Katherine E. Varley
Nancy U. Lin
Minetta C. Liu
Hope S. Rugo
Shannon Puhalla
Rita Nanda
Anna Maria Storniolo
Lisa A. Carey
Mansoor N. Saleh
Yufeng Li
Jennifer F. Delossantos
William E. Grizzle
Albert F. LoBuglio
Richard M. Myers
Andres Forero-Torres
on behalf of the Translational Breast Cancer Research Consortium (TBCRC)
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2020
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-020-01258-x

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