Originally published as JCO Early Release 10.1200/JCO.2008.18.4085 on May 26 2009

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Topoisomerase II Amplification Does Not Predict Benefit From Dose-Intense Cyclophosphamide, Doxorubicin, and Fluorouracil Therapy in HER2-Amplified Early Breast Cancer: Results of CALGB 8541/150013

From the Yale Cancer Center, New Haven, CT; Duke University, Durham; University of North Carolina, Chapel Hill, NC; University of Colorado, Denver, CO; North Shore Hospital Center, Long Island; Memorial Sloane-Kettering Cancer Center, New York, NY; The University of Texas M. D. Anderson Cancer Center, Houston, TX; Dana-Farber Cancer Institute, Boston, MA; University of Michigan, Ann Arbor, MI; Cancer and Leukemia Group B Central Office, Chicago, IL; and Washington University, St Louis, MO.

Corresponding author: Lyndsay Harris, MD, 333 Cedar St, WWW 213, Yale University, New Haven, CT 06850; e-mail: lyndsay.harris{at}yale.edu.

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 II (Topo-II) is a target for doxorubicin and is coamplified in 20% to 50% of HER2-amplified tumors, we postulated that Topo-II copy number might account for the benefit from CAF dose escalation in HER2-positive tumors. To address this hypothesis, we examined Topo-II and HER2 copy number, CAF dose, and clinical outcomes in Cancer and Leukemia Group B (CALGB) 8541.

Patients and Methods Topo-II and HER2 copy number were measured by fluorescent in situ hybridization (FISH) using a triple-probe system, which includes Topo-II, HER2, and chromosome 17 (CEP17). Topo-II and/or HER2 were classified as amplified ( two copies/CEP17, deleted ( 0.67 copies/CEP17) and normal copy number (> .67 to < 2.0 copies/CEP17).

Results Topo-II/HER2/CEP17 measurement was successful in 624 of 687 cases. HER2 was amplified in 117 cases (19%). Topo-II was amplified in 41 cases (7%) and deleted in 69 cases (11%). Topo-II amplification was highly correlated with HER2 amplification (39 of 41; P < .0001), HER2 by immunohistochemistry, and by dual-probe FISH. Topo-II 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-II–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-II amplification is the mechanism behind benefit from increased dose of anthracyclines in HER2-positive breast cancer.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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