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

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.

Keywords: Bevacizumab; Breast cancer; Hormone receptor-positive breast cancer; Letrozole; Luminal breast cancer; Postmenopausal; Preoperative therapy.

Conflict of interest statement

C.V. consulting or advisory board: Daiichi-Sankyo, Genentech (unpaid); research funding (paid to the University of Alabama at Birmingham): Roche, Pfizer, Incyte, Novartis, Pharmacyclics, Tracon, Innocrin, H3 Biomedicine, Zymeworks. A.F.T received support from Genentech to conduct clinical and laboratory research (paid to the University of Alabama at Birmingham). A.F.T. is currently an employee of Seattle Genetics. N.U.L.—consulting or advisory board: Puma, Daiichi-Sankyo, Seattle Genetics, Genentech; research funding (paid to institution): Genentech, Pfizer, Novartis, Seattle Genetics, Array Biopharma. The remaining authors declare that they have no competing interests.

Figures

Fig. 1

CONSORT diagram

Fig. 2

Waterfall plot of response by treatment arm. a Pathologic responses were assessed by comparing the maximum cumulative diameter of the target lesion(s) at the time of diagnosis as assessed by imaging studies with the size of the tumor in the final surgical pathology. b Radiological responses were assessed according to RECIST by breast ultrasound or breast MRI in selected cases (whichever modality was consistently obtained throughout the protocol therapy and most accurately assessed the status of the tumor)

Fig. 3

a Quantile-quantile plot of small RNA p values for association with letrozole/bevacizumab response. The observed p values from the association of small RNA expression values with letrozole/bevacizumab response (see the “Methods” section) are plotted against the null (uniform) distribution. Small RNAs selected by LASSO regression for an optimal classifier model (see the “Methods” section) are marked by black dots and labeled. b Classifier model performance on three cohorts. Classifier values calculated from qPCR data for each patient tumor sample (x-axis) across three cohorts are plotted on the y-axis (see the “Methods” section). Bar color indicates responder status. The dotted line indicates the common threshold used to calculate model accuracy. The “discovery cohort” is the cohort of patients who received letrozole/bevacizumab in the present study. The “validation cohort” is the cohort of patients who received the same treatment in a separate independent clinical trial [15]. The “letrozole cohort” consists of patients who received letrozole in the present study. The model was trained on sequencing data from the discovery cohort