There is data to suggest that this heterogeneity may be clinically important: 2–5% of women whose primary breast tumors lacked definite HER-2 amplification or HER-2 protein (3+) over-expression nevertheless had lymph node metastases that were amplified/over-expressed [70], suggesting that small HER-2-positive tumor subclones present in the primary tumor may evolve to give rise to metastatic tumor growths. This evidence concerns the gene ERBB2 and neoplasm.