title: 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.
authors.affiliation: 333 Cedar St, WWW 213, Yale University, New Haven, CT 06850, USA. lyndsay.harris@yale.edu
authors.forename: Lyndsay N
authors.initials: LN
authors.lastname: Harris
authors.forename: Gloria
authors.initials: G
authors.lastname: Broadwater
authors.forename: Maysa
authors.initials: M
authors.lastname: Abu-Khalaf
authors.forename: David
authors.initials: D
authors.lastname: Cowan
authors.forename: Ann D
authors.initials: AD
authors.lastname: Thor
authors.forename: Daniel
authors.initials: D
authors.lastname: Budman
authors.forename: Constance T
authors.initials: CT
authors.lastname: Cirrincione
authors.forename: Donald A
authors.initials: DA
authors.lastname: Berry
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Hudis
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
authors.forename: Paula
authors.initials: P
authors.lastname: Friedman
authors.forename: Matthew
authors.initials: M
authors.lastname: Ellis
authors.forename: Lynn
authors.initials: L
authors.lastname: Dressler
mesh_terms: D018943:Anthracyclines / Q000627:therapeutic use*; D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000502:physiology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D003520:Cyclophosphamide / Q000494:pharmacology; D004250:DNA Topoisomerases, Type II / Q000235:genetics* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D005472:Fluorouracil / Q000494:pharmacology; D005784:Gene Amplification / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D003520:Cyclophosphamide; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D004317:Doxorubicin; D005472:Fluorouracil; D018719:Erb-b2 Receptor Tyrosine Kinases