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Abstract
Purpose: This study examined the feasibility, efficacy (abscopal effect), and immune effects of TGFβ blockade during radiotherapy in metastatic breast cancer patients.Experimental Design: Prospective randomized trial comparing two doses of TGFβ blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 weeks for five cycles, with focal radiotherapy to a metastatic site at week 1 (three doses of 7.5 Gy), that could be repeated to a second lesion at week 7. Research bloods were drawn at baseline, week 2, 5, and 15 to isolate PBMCs, plasma, and serum.Results: Twenty-three patients were randomized, median age 57 (range 35-77). Seven grade 3/4 adverse events occurred in 5 of 11 patients in the 1 mg/kg arm and in 2 of 12 patients in the 10 mg/kg arm, respectively. Response was limited to three stable disease. At a median follow up of 12 months, 20 of 23 patients are deceased. Patients receiving the 10 mg/kg had a significantly higher median overall survival than those receiving 1 mg/kg fresolimumab dose [hazard ratio: 2.73 with 95% confidence interval (CI), 1.02-7.30; P = 0.039]. The higher dose correlated with improved peripheral blood mononuclear cell counts and a striking boost in the CD8 central memory pool.Conclusions: TGFβ blockade during radiotherapy was feasible and well tolerated. Patients receiving the higher fresolimumab dose had a favorable systemic immune response and experienced longer median overall survival than the lower dose group.

Author information

Formenti SC1, Lee P2,3, Adams S4, Goldberg JD5,6, Li X5,6, Xie MW2, Ratikan JA2, Felix C2, Hwang L3, Faull KF7, Sayre JW8, Hurvitz S3,9, Glaspy JA3,9, Comin-Anduix B3,9, Demaria S10,11, Schaue D#2,3, McBride WH#12,3.
1
Department of Radiation Oncology, Weill Cornell Medical College, New York, NY. wmcbride@mednet.ucla.edu formenti@med.cornell.edu.
2
Department of Radiation Oncology, University of California, Los Angeles, California.
3
Jonsson Compressive Cancer Center, University of California, Los Angeles, California.
4
Department of Medicine, New York University School of Medicine, New York, NY.
5
Department of Population Health, New York University School of Medicine, New York, NY.
6
Department of Environmental Medicine, New York University School of Medicine, New York, NY.
7
Pasarow Mass Spectrometry Laboratory at University of California, Los Angeles, California.
8
Public Health Biostatistics at University of California, Los Angeles, California.
9
Medicine, Hematology & Oncology at University of California, Los Angeles, California.
10
Department of Radiation Oncology, Weill Cornell Medical College, New York, NY.
11
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY.
12
Department of Radiation Oncology, University of California, Los Angeles, California. wmcbride@mednet.ucla.edu formenti@med.cornell.edu.
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Contributed equally