Abstract | BACKGROUND: METHODS: RESULTS: In both treatment arms, good responders (GR) and non-responders (NR) displayed significant difference in genomic instability index (GII) at time of diagnosis. In the combination arm, copy number alterations at 25 loci at the time of diagnosis were significantly different between the GR and NR. An inverse aberration pattern was also observed between the two extreme response groups at 6p22-p12 for patients in the combination arm. Signs of subclonal reduction were observed, with some aberrations disappearing and others being retained during treatment. Increase in subclonal amplification was observed at 6p21.1, a locus which contains the VEGFA gene for the protein which are targeted by the study drug bevacizumab. Of the 13 pre-treatment samples that had a gain at VEGFA, 12 were responders. Significant decrease of frequency of subclones carrying gains at 17q21.32-q22 was observed at 12 weeks, with the peak occurring at TMEM100, an ALK1 receptor signaling-dependent gene essential for vasculogenesis. This implies that cells bearing amplifications of VEGFA and TMEM100 are particularly sensitive to this treatment regime. CONCLUSIONS: Taken together, these results suggest that heterogeneity and subclonal architecture influence the response to targeted treatment in combination with chemotherapy, with possible implications for clinical decision-making and monitoring of treatment efficacy. TRIAL REGISTRATION: NCT00773695 . Registered 15 October 2008.
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Authors | Elen Kristine Höglander, Silje Nord, David C Wedge, Ole Christian Lingjærde, Laxmi Silwal-Pandit, Hedda vdL Gythfeldt, Hans Kristian Moen Vollan, Thomas Fleischer, Marit Krohn, Ellen Schlitchting, Elin Borgen, Øystein Garred, Marit M Holmen, Erik Wist, Bjørn Naume, Peter Van Loo, Anne-Lise Børresen-Dale, Olav Engebraaten, Vessela Kristensen |
Journal | Genome medicine
(Genome Med)
Vol. 10
Issue 1
Pg. 92
(11 29 2018)
ISSN: 1756-994X [Electronic] England |
PMID | 30497530
(Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
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Chemical References |
- Angiogenesis Inhibitors
- VEGFA protein, human
- Vascular Endothelial Growth Factor A
- Bevacizumab
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Topics |
- Angiogenesis Inhibitors
(therapeutic use)
- Antineoplastic Combined Chemotherapy Protocols
(therapeutic use)
- Bevacizumab
(therapeutic use)
- Breast Neoplasms
(genetics, therapy)
- Cell Proliferation
- Female
- Genomic Instability
- Humans
- Neoadjuvant Therapy
- Vascular Endothelial Growth Factor A
(genetics)
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