ACE and CXCL10 as predictive biomarkers in the LEA study

Abstract

Background: LEA Study (GEICAM/2006‐11/GBG51), is a randomized clinical trial comparing bevacizumab in combination with endocrine therapy (ET + B) with endocrine therapy (ET) in postmenopausal women with advanced or metastatic HR‐positive/HER2‐negative breast cancer (BC) with indication of hormonotherapy as first‐line treatment. Patients with secondary hypertension had better progression‐free survival (PFS) and overall survival (OS).We have evaluated the role of two hypertension‐related biomarkers, Angiotensin‐Converting Enzyme (ACE) and Small‐Inducible Cytokine B10 (CXCL10) as prognostic and/or predictive biomarkers of benefit to bevacizumab in the first line metastatic disease. Methods: From 380 patients, 266 were included in 33 Spanish sites. Median age was 64 years, 63.5% had measurable disease, 97.4% were metastatic at randomization, 51.5% had visceral disease and 52.6% received previous chemotherapy. PFS was 14.3 months (range 0.8‐61.1), OS was 34 months (range 0.8‐71.6) and 93 patients had Objective Response (OR).We analyzed 124 plasma samples collected before treatment (52 from ET and 72 from ET + B arms). Circulating levels of ACE and CXCL10 were determined by ELISA. ACE levels of 115ng/ml and 135ng/ml were pre‐defined as cutoff values. CXCL10 was explored as a quantitative variable. Results: PFS was 15.1 months (range 1.4‐61.1), OS was 31.1 months (range 2.8‐61.1) and 40.3% had OR. OR was significantly different between treatment arms (p < 0.001) but not PFS or OS. Median ACE concentration was 130.9ng/ml (range 35.3‐315.4). Low ACE (<135ng/ml) had better PFS in the whole population (p = 0.048) and in the ET + B arm (p = 0.041). ACE cutoff of 115 ng/ml was not able to identify any subgroup with better prognosis. Median CXCL10 concentration was 230.3pg/ml (range 15.1‐4129.6). A higher expression of CXCL10 was significantly associated with worse OS in the whole population (p < 0.0001) and each treatment arm (p = 0.002 and p = 0.001 in ET and ET + B, respectively). No association with OR were identified neither for ACE nor for CXCL10. Conclusions: ACE levels could be considered a prognostic and a bevacizumab predictive biomarker of PFS. CXCL10 could be prognostic of OS. Confirmatory studies are warranted.