Abstract P2-02-15: Elevated serum RAS p21 is an independent prognostic factor in metastatic breast cancer
Authors: Banys-Paluchowski M , Fehm T , Janni W , Aktas B , Fasching PA , Kasimir-Bauer S , Milde-Langosch K , Pantel K , Rack B , Riethdorf S , Solomayer E-F , Witzel I , Müller V 
Published: February 2018

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
251 patients with metastatic breast cancer were enrolled in this prospective, multicentre, non-randomized study conducted on behalf of the DETECT Study Group (Current Controlled Trials ISRCTN59722891). 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.
Patients' characteristics. TotalRAS p21 elevated n (%)p-valueOverall25129 (12%) ER status 0.611Negative7610 (13%) Positive17419 (11%) PR status 0.358Negative10114 (14%) Positive14915 (10%) HER2 status 0.873Negative14318 (13%) Positive769 (12%) Metastatic site 0.482Visceral9813 (13%) Bone352 (6%) Both11814 (12%) Extent of metastatic disease 0.768One site849 (11%) Multiple sites16720 (12%) Therapeutic setting 0.2491st-line988 (8%) 2nd-line6611 (17%) 3rd-line or more8610 (12%) Grading 0.604G151 (20%) G212913 (10%) G310314 (14%) Circulating tumor cells 0.101&lt; 5 CTCs / 7.5 ml12217 (14%) ≥ 5 CTCs / 7.5 ml1219 (7%)
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 (p = 0.019 in case of 229 pg/ml; p = 0.003 in case of 320 pg/ml), 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
This is the first study to address the clinical relevance of circulating RAS p21 in a large group of metastatic breast cancer patients. Patients with elevated levels of circulating RAS p21 had significantly worse clinical outcome. Hypothetically, these patients might benefit from therapeutic strategies targeting RAS pathway.
Citation Format: Banys-Paluchowski M, Fehm T, Janni W, Aktas B, Fasching PA, Kasimir-Bauer S, Milde-Langosch K, Pantel K, Rack B, Riethdorf S, Solomayer E-F, Witzel I, Müller V. Elevated serum RAS p21 is an independent prognostic factor in metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-02-15.