Abstract
TGFb signature at 2 weeks to predict response to preoperative therapy (PT) with bevacizumab (B) and chemotherapy (CT) in early breast cancer (EBC)
Journal of clinical oncology, Vol.31(15_suppl), pp.1046-1046
05/20/2013
DOI: 10.1200/jco.2013.31.15_suppl.1046
Abstract
1046
Background: Gene expression profiles from core biopsies taken during PT for EBC may identify markers associated with benefit. B was recently shown to improve pathologic complete response (pCR) to CT in two randomized trials, but is associated with increased toxicity. Predictive signatures are critical to optimizing benefit. We have shown that changes in TGF-β pathway activity after one dose of B are associated with pCR. To confirm these results and understand the mechanism of alteration of the TGFb pathway, we evaluated the 61-gene TGFb signature by RT-PCR, measured markers of TGFb pathway activation and assessed TGFb gene mutations. Methods: Real-time PCR was performed on paired (pre/post) core biopsy RNA samples from 21 patients (pts) who received B, trastuzumab (T) or nab-paclitaxel prior to combined CT and targeted therapy using Custom RT2 Profiler PCR Arrays (384-well plate, 64x6 format) containing 60 genes from our TGF-beta signature and 3 housekeeping genes, IPO8, ALAS1, and SDHA. RT- PCR reactions containing Qiagen RT
2
SYBR Green qPCR Mastermix and 5 ng of amplified cDNA were run on a Roche LightCycler480 machine. Cp values were determined using the Roche LightCycler480 software. Antibodies to p-Smad2, TGFBR1 and TGFBR2 were analyzed in FFPE IHC pre and post therapy. TGFb pathway genes with known mutations in TCGA were assessed using an Illumina Custom Amplicon and miSeq next generation sequencing. Results: The log 2 FPKM value of the 60 genes correlated well with the ΔC
P
values calculated normalized to ALAS1 housekeeping gene. The ΔΔC
P
values was determined by subtracting the 60 gene ΔC
P
values of baseline samples from post-exposure samples. Patients were clustered using the ΔΔC
P
. Pts exposed to B who achieved a pCR showed down-regulation of signatures genes, in contrast to a strong non-pCR cluster. Signature evaluation showed no association with response in the T arm. TGFb pathway protein expression and mutation frequency is under analysis. Conclusions: TGFb signature predicts response to B containing chemotherapy after one dose of B and is validated by RT- PCR as a potential predictive tool. TGFb pathway activation and gene mutation analysis will be presented. Clinical trial information: NCT00617942.
Details
- Title: Subtitle
- TGFb signature at 2 weeks to predict response to preoperative therapy (PT) with bevacizumab (B) and chemotherapy (CT) in early breast cancer (EBC)
- Creators
- Nicole Williams - University Hospitals Seidman Cancer CenterVinay Varadan - PhilipsAditi Vadodkar - Case Western Reserve UniversityKristy Miskimen - Case Western Reserve UniversityHannah L. Gilmore - Case Western Reserve UniversityNicholas Beckloff - Case Western Reserve UniversitySimone Edelheit - Case Western Reserve UniversityDhivya Prabhakar - Case Western Reserve UniversityAngel Janevski - PhilipsNila Banerjee - PhilipsSitharthan Kamalakaran - PhilipsMaysa M. Abu-Khalaf - Yale Cancer CenterWilliam M. Sikov - Brown UniversityNevenka Dimitrova - PhilipsLyndsay Harris - University Hospitals Seidman Cancer Center
- Resource Type
- Abstract
- Publication Details
- Journal of clinical oncology, Vol.31(15_suppl), pp.1046-1046
- DOI
- 10.1200/jco.2013.31.15_suppl.1046
- ISSN
- 0732-183X
- eISSN
- 1527-7755
- Language
- English
- Date published
- 05/20/2013
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984363298002771
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