PURPOSE We have demonstrated that patients with HER2-amplified
tumors derive more benefit from higher doses of
doxorubicin-containing
chemotherapy (
cyclophosphamide,
doxorubicin, and
fluorouracil [CAF]). Because topoisomerase IIalpha (
Topo-IIalpha) is a target for
doxorubicin and is coamplified in 20% to 50% of HER2-amplified
tumors, we postulated that
Topo-IIalpha copy number might account for the benefit from CAF dose escalation in HER2-positive
tumors. To address this hypothesis, we examined
Topo-IIalpha and HER2 copy number, CAF dose, and clinical outcomes in
Cancer and
Leukemia Group B (CALGB) 8541. PATIENTS AND METHODS
Topo-IIalpha and HER2 copy number were measured by fluorescent in situ hybridization (FISH) using a triple-probe system, which includes
Topo-IIalpha, HER2, and chromosome 17 (CEP17).
Topo-IIalpha and/or HER2 were classified as amplified (> or = two copies/CEP17, deleted (< or = 0.67 copies/CEP17) and normal copy number (> .67 to < 2.0 copies/CEP17). Results
Topo-IIalpha/HER2/CEP17 measurement was successful in 624 of 687 cases. HER2 was amplified in 117 cases (19%).
Topo-IIalpha was amplified in 41 cases (7%) and deleted in 69 cases (11%).
Topo-IIalpha amplification was highly correlated with HER2 amplification (39 of 41; P < .0001), HER2 by immunohistochemistry, and by dual-probe FISH.
Topo-IIalpha was deleted in both the HER2-amplified (30 of 69; 43%), normal (22 of 69; 32%) and HER2-deleted
tumors (17 of 69; 25%). Although
Topo-IIalpha-amplified
tumors were nearly always HER2 amplified, these
tumors did not receive benefit from increasing the dose of CAF (P = .15). CONCLUSION The correlative companion study CALGB 8541-150013 does not support the hypothesis that
Topo-IIalpha amplification is the mechanism behind benefit from increased dose of
anthracyclines in HER2-positive
breast cancer.