Clinical relevance of H-RAS, K-RAS, and N-RAS mRNA expression in primary breast cancer patients

Abstract

Purpose The RAS family comprises three proto-oncogenes (H-RAS, K-RAS, and N-RAS) and is among the most widely studied of oncogenes. The present study aimed at investigating the clinical relevance of mRNA levels of the three isoforms in a large group of breast cancer patients with a long-term follow-up. Methods 198 previously untreated patients were enrolled in the study. mRNA levels of K-RAS, H-RAS, and N-RAS were measured using microarray (Affymetrix HG-U133A). Results Elevated H-RAS levels were found significantly more frequently in patients with larger ( p \u2009=\u20090.021) and ER-positive tumors ( p \u2009=\u20090.048), while elevated K-RAS levels were associated with nodal positivity ( p \u2009=\u20090.001) and HER2-positivity ( p \u2009=\u20090.010). Patients with high N-RAS mRNA levels were more likely to be diagnosed with triple-negativity ( p \u2009<\u20090.001) and higher grading ( p \u2009=\u20090.001). Patients with high K-RAS levels were more likely to show an elevated H-RAS ( p \u2009=\u20090.003). After a median follow-up of 183\xa0months, patients with high N-RAS expression had significantly reduced overall survival (OS) compared with patients with low N-RAS (mean: 146.9 vs. 211.0\xa0months; median 169.3 vs. not reached; p \u2009=\u20090.009). In patients with non-metastatic disease at the time of tissue sampling, mean disease-free survival (DFS) was 150.1\xa0months for patients with high N-RAS versus 227.7\xa0months with low N-RAS; median DFS was not reached ( p \u2009=\u20090.004). The expression of H-RAS and K-RAS was not associated with DFS/OS. In the multivariable analysis, distant metastasis, HER2 positivity, and elevated N-RAS mRNA levels independently predicted reduced OS, while nodal status, HER2 status, and N-RAS predicted reduced DFS. Conclusions Elevated N-RAS mRNA levels predict impaired clinical outcome; hypothetically, further exploration of the RAS signaling pathway might enable identifying potential targeted treatment strategies. The association between high N-RAS levels and the most aggressive among breast cancer subtypes, the triple-negative phenotype, for which targeted approaches are still lacking, underlines the need to further investigate the RAS family.