Clinical relevance of H-RAS, K-RAS and N-RAS in a large cohort of primary breast cancer patients

Background:

Since the first description of the Ras proteins over three decades ago, the Ras family has become one of the most extensively studied oncogenes. The name 'Ras' is an abbreviation of 'Rat sarcoma', reflecting how the genes were initially discovered. The aim of the present study was to evaluate the clinical significance of H-Ras/K-Ras/N-ras in a well-characterized cohort of primary breast cancer patients.

Methods:

198 previously untreated breast cancer patients were enrolled. Tumor tissue was collected at primary surgery. H-Ras/K-Ras/N-Ras mRNA levels were analysed using microarray data (Affymetrix).

Results:

Elevated H-RAS was associated with larger tumors and positive ER-status, while patients with lymph node metastasis and HER2-positivity were more likely to overexpress K-RAS. Elevated N-RAS was highly associated with triple-negative subtype and higher grading. No correlation was found between N-RAS and the other two genes, while elevated K-RAS was associated with elevated H-RAS (p = 0.003). After a median follow up of 183 months, patients with N-RAS expression ≥the 75^th percentile had significantly shorter OS than those with N-RAS< 75^th percentile (mean: 146.9 months vs. 211.0 months; median 169.3 months vs. not reached;p = 0.009). Mean DFS was 139.0 months for patients with N-RAS≥75^th percentile versus 194.2 months with N-RAS< 75^th percentile (median 128.5 months vs. not reached;p = 0.056). The expression of H-RAS/K-RAS was not associated with DFS/OS. In the multivariate analysis, N-RAS levels, distant metastasis and HER2-status remained independent predictors of shorter OS.

Conclusions:

Elevated N-RAS expression in primary breast cancer independently predicts shorter survival while the expression of K-RAS/H-RAS is not associated with clinical outcome.