9505 Background: We have demonstrated that patients with HER2 amplified tumors derive more benefit from higher doses of doxorubicin-containing chemotherapy (CAF). As topo II is a target for doxorubicin and is coamplified in 20-50% of HER2 amplified tumors, we postulated that Topo II gene copy number might be a more accurate predictive factor for CAF dose escalation. To address this hypothesis we examined Topo II and HER2 copy number, CAF dose and clinical outcomes in CALGB 8541 (a Phase III trial of CAF at 3 dose levels).
METHODS
Topo II and HER2 copy number was measured by fluorescent in-situ hybridization (FISH) using a triple probe system, which includes Topo II, HER2, and Chromosome 17 (Cep17) probes (Tricolor probe, Vysis). For the purposes of this study, Topo II and/or HER2 were considered amplified when >2 copies/Cep17 were detected and deleted when ≤ .67 copies /Cep17 were detected.
RESULTS
Topo II/HER2/Cep17 measurement was successful in 624/992 cases. HER2 was amplified in 117 cases (19%) and deleted in 40 cases (6%). Topo II was amplified in 41 cases (7%) and deleted in 69 (11%) cases. Topo II amplification was highly correlated with HER2 amplification (39/41), P<0.0001. Topo II was deleted in both the HER2 amplified (30/69; 43%), normal (15/69; 22%) and HER2 deleted tumors (17/69; 25%). Topo II amplification was associated with ER and/or PR negativity, HER2 by IHC (CB11) and by dual probe FISH. Although HER2 amplified tumors treated with higher dose CAF had an improved outcome, this was not observed in the Topo II amplified group. No interaction with dose was observed in the HER2 normal/deleted group or Topo II normal/deleted groups.
CONCLUSIONS
In CALGB 8541, Topo II was co-amplified in 33% of HER2 amplified tumors. Contrary to our hypothesis there was no relationship between Topo II amplification and benefit from CAF dose escalation. Interestingly Topo II deletion was more common than amplification. The clinical consequences and cellular phenotypes associated with Topo II deletion deserve further investigation. [Table: see text].