Brief-exposure to preoperative bevacizumab reveals a TGF-β signature predictive of response in HER2-negative breast cancers.
To best define biomarkers of response, and to shed insight on mechanism of action of certain clinically important agents for early breast cancer, we used a brief-exposure paradigm in the preoperative setting to study transcriptional changes in patient tumors that occur with one dose of therapy prior to combination chemotherapy. Tumor biopsies from breast cancer patients enrolled in two preoperative clinical trials were obtained at baseline and after one dose of bevacizumab (HER2-negative), trastuzumab (HER2-positive) or nab-paclitaxel, followed by treatment with combination chemo-biologic therapy. RNA-Sequencing based PAM50 subtyping at baseline of 46 HER2-negative patients revealed a strong association between the basal-like subtype and pathologic complete response (pCR) to chemotherapy plus bevacizumab (p ≤ 0.0027), but did not provide sufficient specificity to predict response. However, a single dose of bevacizumab resulted in down-regulation of a well-characterized TGF-β activity signature in every single breast tumor that achieved pCR (p ≤ 0.004). The TGF-β signature was confirmed to be a tumor-specific read-out of the canonical TGF-β pathway using pSMAD2 (p ≤ 0.04), with predictive power unique to brief-exposure to bevacizumab (p ≤ 0.016), but not trastuzumab or nab-paclitaxel. Down-regulation of TGF-β activity was associated with reduction in tumor hypoxia by transcription and protein levels, suggesting therapy-induced disruption of an autocrine-loop between tumor stroma and malignant cells. Modulation of the TGF-β pathway upon brief-exposure to bevacizumab may provide an early functional readout of pCR to preoperative anti-angiogenic therapy in HER2-negative breast cancer, thus providing additional avenues for exploration in both preclinical and clinical settings with these agents.
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH.
Vinay
V
Varadan
Philips Research North America, 345 Scarborough Road, Briarcliff Manor, NY.
Sitharthan
S
Kamalakaran
Department of Pathology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH.
Hannah
H
Gilmore
Philips Research North America, 345 Scarborough Road, Briarcliff Manor, NY.
Nilanjana
N
Banerjee
Philips Research North America, 345 Scarborough Road, Briarcliff Manor, NY.
Angel
A
Janevski
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH.
Kristy L S
KL
Miskimen
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH.
Nicole
N
Williams
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH.
Ajay
A
Basavanhalli
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH.
Anant
A
Madabhushi
Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT.
Kimberly
K
Lezon-Geyda
Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT.
Veerle
V
Bossuyt
Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT.
Donald R
DR
Lannin
Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT.
Maysa
M
Abu-Khalaf
Warren Alpert Medical School of Brown University, Providence, RI.
William
W
Sikov
Philips Research North America, 345 Scarborough Road, Briarcliff Manor, NY.
Nevenka
N
Dimitrova
Seidman Cancer Center, University Hospitals, Cleveland, OH.
Lyndsay N
LN
Harris
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D015687:Cell Hypoxia; D005260:Female; D006801:Humans; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*
D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D018719:Erb-b2 Receptor Tyrosine Kinases; D016212:Transforming Growth Factor beta; C508053:ERBB2 protein, human