Are multiple copies of the centromeric enumeration probe (cep) 17 a true reflection of chromosome 17 copy number in the determination of HER2 status?

The human epidermal growth factor receptor 2 (HER2) is overxpressed in approximately 15% of breast cancers in the UK (NEQAS data). The HER2 protein is a therapeutic target for an increasing number of drugs, with Trastuzumab (Herceptin) probably the best known.

The HER2 status is determined by a two stage approach, initially through the evaluation of protein expression using immunohistochemistry and in equivocal cases by in situ hybridization to determine the gene status. The recommendations in the UK are to determine the ratio of the number of copies of the HER2 gene to the number of copies of chromosome 17 with a ratio greater than 2 being classed as amplified. Evaluation of HER2 status by FISH also reveals other genetic anomalies most frequently relating to copy number with many cases being classed as "polysomy" i.e. an increase in copy number of chromosome 17 with a comparable increase in the gene copy number. Polysomic cases have a ratio approaching 1 and are classed as not amplified and are therefore not eligible for treatment.

Recent evidence from studies using array CGH and multiple probes spanning chromosome 17 have bought the finding of "polysomy" into question, results indicating that the presence of additional copies of cep 17 are in fact indicative of gains and losses of regions of chromosome 17 with very few cases actually showing true polysomy i.e. replication of the whole of chromosome 17.

The aim of this study is to look at the centromere of chromosome 17 and telomeres 17p and 17q to look at the extremes of the chromosome to determine the extent of the gains and losses and to determine the level of true polysomy in the patient population.

FISH for cep 17, telomere 17p and telomere 17q by combining the probes in a triple reaction will be performed and the ratios of 17p and 17q to cep 17 determined.