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Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

Elevated serum RAS p21 is an independent prognostic factor in metastatic breast cancer

Authors: Malgorzata Banys-Paluchowski, Tanja Fehm, Wolfgang Janni, Bahriye Aktas, Peter A. Fasching, Sabine Kasimir-Bauer, Karin Milde-Langosch, Klaus Pantel, Brigitte Rack, Sabine Riethdorf, Erich-Franz Solomayer, Isabell Witzel, Volkmar Müller

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

An important component of the RAS signalling pathway, the RAS p21 oncogene, is frequently hyperactivated in breast cancer. Its expression in tumor tissue has been linked to poor clinical outcome. This study was designed to evaluate the clinical relevance of RAS p21 levels in peripheral blood in a large cohort of metastatic breast cancer patients.

Methods

Two hundred fifty-one patients with metastatic breast cancer were enrolled in this prospective, multicentre, open-label, non-randomized study. Blood samples were collected before start of first-line or later-line treatment. RAS p21 was determined using a sandwich-type ELISA immunoassay. For the determination of the cutoff, blood samples from age-matched healthy controls were analyzed. A value above 452 pg/ml was regarded as elevated (mean + 2 x SD). In the univariate survival analysis, two other cutoffs were considered as well (50th and 75th percentile of patients, i.e. 229 pg/ml and 320 pg/ml). Circulating tumor cells (CTCs) were detected using the CellSearch system.

Results

29 of 251 (12%) patients had RAS p21 levels above the cut-off level of 452 pg/ml. Clinical-pathological parameters, such as hormone receptor and HER2 status, line of therapy and CTC status, did not correlate with RAS p21 levels. Elevated RAS p21 was significantly associated with shorter progression-free and overall survival in the univariate analysis (median PFS: 3.9 months [95%-CI: 1.8–6.0] for patients with elevated RAS p21 levels versus 8.5 months [95%-CI: 7.4–9.5] with non-elevated levels [p = 0.01]; median OS: 7.1 months [95%-CI: 0.3–14.2] versus not reached [p = 0.002], respectively). When RAS p21 cutoffs other than 452 pg/ml were considered, elevated RAS p21 was significantly associated with OS but not with PFS. Classical clinical-pathological factors were included into a multivariate Cox regression analysis. In addition, factors previously shown to influence survival in a univariate analysis, such as serum HER2, CAIX and TIMP1, were included as well. In the multivariate analysis, RAS p21, presence of ≥5 CTCs per 7.5 ml blood, higher grading and higher line of therapy remained independent predictors of shorter OS.

Conclusions

Metastatic breast cancer patients with elevated levels of circulating RAS p21 have significantly worse clinical outcome. Hypothetically, these patients might benefit from therapeutic strategies targeting RAS pathway.

Trial registration

Current Controlled Trials ISRCTN59722891 (DETECT); trial registration date: April, 17th 2010; the trial was registered retrospectively.
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Metadata
Title
Elevated serum RAS p21 is an independent prognostic factor in metastatic breast cancer
Authors
Malgorzata Banys-Paluchowski
Tanja Fehm
Wolfgang Janni
Bahriye Aktas
Peter A. Fasching
Sabine Kasimir-Bauer
Karin Milde-Langosch
Klaus Pantel
Brigitte Rack
Sabine Riethdorf
Erich-Franz Solomayer
Isabell Witzel
Volkmar Müller
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4282-0

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