Topoisomerase IIα expression rather than gene amplification predicts responsiveness of adjuvant anthracycline-based chemotherapy in women with primary breast cancer

Scheffold, Christian; Mayr, Doris; Olivier, Camille; Rack, Brigitte; Engelstaedter, Verena; Jueckstock, J; Jenderek, C; Andergassen, Ulrich; Jeschke, Udo; Friese, Klaus

doi:10.1007/s00432-009-0748-4

Cited by 29 publications

(35 citation statements)

References 30 publications

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“…Expression levels of top1 and top2a are also high in cancer cells, and these expression levels correlate with the chemotherapeutic outcome from topoisomerase-targeting agents (17,20,33,183,196,226). Levels of top1 in the NCI-60 cancer cell line panel correlate with sensitivity to the top1 poisons indenoisoquinoline and camptothecin (196,198,201).…”

Section: Raomentioning

confidence: 97%

“…Levels of top1 in the NCI-60 cancer cell line panel correlate with sensitivity to the top1 poisons indenoisoquinoline and camptothecin (196,198,201). top2a expression is elevated in solid tumors and predicts responsiveness to anthracycline-based chemotherapy in women with primary breast cancer (33,183,226). Similarly, top2b levels in hematological cells correlates with sensitivity to and apoptosis by doxorubicin (117).…”

Section: Raomentioning

confidence: 99%

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Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

Rao

2013

Antioxidants & Redox Signaling

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Significance: Iron and topoisomerases are abundant and essential cellular components. Iron is required for several key processes such as DNA synthesis, mitochondrial electron transport, synthesis of heme, and as a co-factor for many redox enzymes. Topoisomerases serve as critical enzymes that resolve topological problems during DNA synthesis, transcription, and repair. Neoplastic cells have higher uptake and utilization of iron, as well as elevated levels of topoisomerase family members. Separately, the chelation of iron and the cytotoxic inhibition of topoisomerase have yielded potent anticancer agents. Recent Advances: The chemotherapeutic drugs doxorubicin and dexrazoxane both chelate iron and target topoisomerase 2 alpha (top2a). Newer chelators such as di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone and thiosemicarbazone -24 have recently been identified as top2a inhibitors. The growing list of agents that appear to chelate iron and inhibit topoisomerases prompts the question of whether and how these two distinct mechanisms might interplay for a cytotoxic chemotherapeutic outcome. Critical Issues: While iron chelation and topoisomerase inhibition each represent mechanistically advantageous anticancer therapeutic strategies, dual targeting agents present an attractive multi-modal opportunity for enhanced anticancer tumor killing and overcoming drug resistance. The commonalities and caveats of dual inhibition are presented in this review. Future Directions: Gaps in knowledge, relevant biomarkers, and strategies for future in vivo studies with dual inhibitors are discussed. Antioxid. Redox Signal. 18, 930-955.

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Section: Raomentioning

confidence: 97%

Section: Raomentioning

confidence: 99%

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

Rao

2013

Antioxidants & Redox Signaling

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“…The amplification of the TOP2A gene is a rare abnormality, and is restricted to HER2-positive tumors [6,7,10,11,12,13,16,24,25]. The deletion of the gene is less frequent, and its role in anthracycline sensitivity is controversial [6,7,9,10,13,14,15,16,26].…”

Section: Discussionmentioning

confidence: 99%

“…TOP2A gene abnormalities such as amplification or deletion have been related to chemosensitivity in many studies [6,7,8,9,10,11,13,14,15,16]. The expression of TOP2A has been less extensively studied than its gene abnormalities, but tumors with high TOP2A expression have been found to be more responsive to anthracycline-based chemotherapy in the adjuvant [12], neoadjuvant [16,17] and metastatic settings [18]. Amplification [19,20] or increased expression [21] of the TOP2A gene have been shown to be a predictor of a poor prognosis among patients with estrogen receptor (ER)-positive breast cancer, and of a good prognosis in HER2-positive cases [11].…”

Section: Introductionmentioning

confidence: 99%

“…TOP2A is located on chromosome 17 q12–q21, next to the human epidermal growth factor receptor 2 (HER2) gene, and its aberrations (amplification or deletion) have been demonstrated mostly in HER2-positive breast cancers [3,4]. Around one third of all HER2-positive breast tumors, and at least one tenth of all breast cancers present with TOP2A gene amplifications, and 4–13% with deletion of the gene [4,6,7,8,9,10,11,12,13,14]. TOP2A gene abnormalities such as amplification or deletion have been related to chemosensitivity in many studies [6,7,8,9,10,11,13,14,15,16].…”

Section: Introductionmentioning

confidence: 99%

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Tumor Topoisomerase II Alpha Status and Response to Anthracycline-Based Neoadjuvant Chemotherapy in Breast Cancer

Nikolényi¹,

Sükösd²,

Kaizer³

et al. 2011

Oncology

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Objectives: Individualized chemotherapy for breast cancer improves the outcome. Anthracyclines target the enzyme topoisomerase IIα (TOP2A). We set out to perform a retrospective study of the presence of gene abnormalities and the expression of TOP2A in a cohort of breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. Methods: Forty-three patients with 45 breast cancers were treated with neoadjuvant docetaxel-epirubicin with/without capecitabine chemotherapy. The TOP2A status of the cancers, determined retrospectively by fluorescent in situ hybridization and immunohistochemistry, was analyzed in relation to the standard clinical and pathological data. Results: Clinically and pathologically complete remission (pCR) was achieved in 15 (33.3%) and 9 (20%) cases, respectively. The TOP2A gene was amplified in 2 human epidermal growth factor receptor 2 (HER2)-positive cancers (8%), and 32 (84.2%) overall exhibited TOP2A expression in >15% of the cells. The expression of TOP2A exhibited a strong correlation with the expression of Ki67 (R = 0.743, p < 0.001), and was negatively correlated with estrogen receptors (ER; R = 0.404, p = 0.012) and progesterone receptors (R = 0.430, p = 0.007). The expression of TOP2A was not related to the amplification of the TOP2A gene or the HER2 status of the tumor. The proportions of Ki67- and TOP2A-positive tumor cells were significantly reduced after chemotherapy (56.1 ± 23.6 vs. 19.0 ± 27.7%, p = 0.004, and 41.0 ± 27.9 vs. 12.7 ± 24.8%, p < 0.001, respectively). The development of pCR was related to a high grade (p = 0.054), ER negativity (p = 0.027) and high TOP2A expression (p = 0.037). The expression of TOP2A was an independent predictor of pCR (OR = 1.460, for every 10% increase, 95% CI: 1.016–2.096, p = 0.041). After a median follow-up time of 31.0 months, neither relapse-free survival nor overall survival was related to the tumor response. Conclusions: TOP2A expression is a marker of the tumor’s proliferation rate and sensitivity to anthracycline-based chemotherapy, and does not depend on the amplification of its gene.

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Dual-colour CISH is a reliable alternative to FISH for assessment of topoisomerase 2-alpha amplification in breast carcinomas

García‐Caballero

Prieto

Vázquez-Boquete

et al. 2013

Breast Cancer Res Treat

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Anthracyclines are among the most powerful antineoplastic drugs available for breast cancer treatment. Although HER2 amplification has been postulated to predict anthracycline benefit, numerous reports have demonstrated that HER2/TOP2A co-amplification is the clinically useful predictive marker of response to anthracyclines. The standard technique to evaluate gene status for target therapy selection is fluorescence in situ hybridization (FISH), but this technique has some disadvantages. Dual-colour chromogenic in situ hybridization (CISH) is an extension of the FISH protocol that allows bright-field microscopy and thus represents a user-friendly alternative to FISH. In order to evaluate whether dual-colour CISH is a reliable alternative to FISH in determining TOP2A gene amplification and to determine the frequency with which TOP2A and HER2 were co-amplified, we analysed 100 invasive breast cancer specimens (70 consecutive and 30 HER2-amplified samples) using tissue microarrays. Thus, a 99 % agreement was found between TOP2A status determined by dual-colour CISH and FISH, as well as a high degree of correlation in TOP2A ratios using both techniques. TOP2A gene amplification was present in 8.6 % of the 70 consecutive samples studied, all of which were HER2-amplified. Co-amplification of TOP2A was observed in 46.5 % of the additional 30 HER2-amplified samples (no TOP2A amplification was seen in non-amplified HER2 samples). We conclude that dual-colour CISH represents an excellent alternative to FISH for determination of TOP2A gene status in invasive breast cancer. Our results showing TOP2A amplification only in HER2-amplified cases also add to the evidence that TOP2A determination should be restricted to those cases.

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Topoisomerase IIα expression rather than gene amplification predicts responsiveness of adjuvant anthracycline-based chemotherapy in women with primary breast cancer

Cited by 29 publications

References 30 publications

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

Tumor Topoisomerase II Alpha Status and Response to Anthracycline-Based Neoadjuvant Chemotherapy in Breast Cancer

Dual-colour CISH is a reliable alternative to FISH for assessment of topoisomerase 2-alpha amplification in breast carcinomas

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