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Topoisomerase II{alpha} amplification does not predict benefit from dose-intense cyclophosphamide, doxorubicin, and fluorouracil therapy in HER2-amplified early breast cancer: results of CALGB 8541/150013.

Abstract
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.
AuthorsLyndsay N Harris, Gloria Broadwater, Maysa Abu-Khalaf, David Cowan, Ann D Thor, Daniel Budman, Constance T Cirrincione, Donald A Berry, Eric P Winer, Clifford A Hudis, Daniel F Hayes, Paula Friedman, Matthew Ellis, Lynn Dressler
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 27 Issue 21 Pg. 3430-6 (Jul 20 2009) ISSN: 1527-7755 [Electronic] United States
PMID19470942 (Publication Type: Journal Article)
Chemical References
  • Anthracyclines
  • Antibiotics, Antineoplastic
  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Doxorubicin
  • Cyclophosphamide
  • Receptor, ErbB-2
  • DNA Topoisomerases, Type II
  • Fluorouracil
Topics
  • Anthracyclines (therapeutic use)
  • Antibiotics, Antineoplastic
  • Antigens, Neoplasm (genetics, physiology)
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Biomarkers, Tumor (analysis)
  • Breast Neoplasms (drug therapy, genetics)
  • Cyclophosphamide (pharmacology)
  • DNA Topoisomerases, Type II (genetics, physiology)
  • DNA-Binding Proteins (genetics, physiology)
  • Doxorubicin (pharmacology)
  • Drug Interactions
  • Fluorouracil (pharmacology)
  • Gene Amplification (drug effects)
  • Humans
  • Immunohistochemistry
  • Receptor, ErbB-2 (genetics, metabolism)

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