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Originally published as JCO Early Release 10.1200/JCO.2008.18.3137 on September 2 2008 © 2008 American Society of Clinical Oncology.
Anthracyclines: The First Generation of Cytotoxic Targeted Agents? A Possible DreamSandro Pitigliani Medical Oncology Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy
In this issue of Journal of Clinical Oncology, Bartlett et al1 report the results of a retrospective study evaluating human epidermal growth factor receptor (HER) family membrane receptors and topoisomerase II- The study has, in our opinion, two interesting features. It investigates, for the first time to our knowledge, the interaction between the HER family membrane receptors and anthracycline activity in the context of a randomized trial for early-stage breast cancer patients. Furthermore, this is the first study (of five) suggesting that TOP2A gene amplification is not a helpful marker in predicting sensitivity to anthracyclines.2-5 Interestingly enough, the authors report that, in contradiction with the a priori study hypothesis, patients with normal HER1, HER2, and HER3 levels derive the largest benefit from the anthracycline-based therapy. Conversely and surprisingly, no superiority for anthracyclines over CMF is seen in the cohort of patients who have tumors with overexpression of at least one of the three HER family membrane receptors. On the basis of previously reported literature, the cohort of patients with HER1 to HER3 normal tumors is expected to be characterized by a high level of expression of hormone receptors (estrogen and progesterone receptors) and low proliferation rates.6-9 Why should an anthracycline-based therapy be more active than CMF in this specific subgroup of patients with endocrine-sensitive tumors? A possible explanation is that, in this cohort of patients, the level of ovarian suppression achieved with a full-dose, anthracycline-based regimen is expected to be more pronounced than with all intravenous CMF administered every 3 weeks. Supporting this explanation is the fact that almost 55% of the study population had a pre- or perimenopausal status.10 The present article1 and the clinical trial report10 do not provide details on the percentage of pre- and perimenopausal women with endocrine-sensitive tumors who actually received adjuvant tamoxifen for 5 years sequentially after adjuvant chemotherapy. The clinical trial report specifies that adjuvant hormonal treatment was not restricted and that 46% of those patients who were candidates for adjuvant tamoxifen were to receive this treatment concomitantly with chemotherapy.10 Accordingly, we speculate that a relevant proportion of the HER1 to HER3 normal population was pre- or perimenopausal, had endocrine-sensitive tumors, and did not receive adjuvant tamoxifen for 5 years sequentially after chemotherapy. Under these conditions, a full-dose, anthracycline-based therapy might produce a clinical benefit over a nonintensive CMF regimen that is independent of a cytotoxic mechanism and that is mediated by endocrine effects (ie, interference with ovarian function). Arguing against this hypothesis is the fact that rates of chemotherapy-related amenorrhea reported in the clinical trial report are 73% and 74% for the anthracycline-based and CMF regimens, respectively.10 It is meaningful to emphasize that rates of chemotherapy-related amenorrhea can vary over time and that differences in amenorrhea rates between two treatment groups can emerge and become clinically relevant several months after the end of adjuvant chemotherapy. Unfortunately, the limited study sample size (146 patients with HER1 to HER3 normal tumors) makes any reliable conclusion impossible in subgroup analysis according to hormone receptors and menopausal status. Hence, the conclusion that the suggested superiority of anthracyclines over CMF in the cohort of HER1 to HER3 normal tumors is mediated by endocrine effects has to remain hypothetical. Differently from the HER1 to HER3 normal cohort, the group of tumors carrying overexpression of at least one of the three markers is biologically heterogeneous, potentially represented by HER2-positive, triple-negative, and moderately hormone-sensitive tumors.7 Accordingly, it is difficult to formulate any hypothesis to explain the observed results in this specific cohort (ie, lack of superiority of anthracyclines over CMF). It is relevant to emphasize that, in the cohort of HER1- to HER3-positive tumors, the hazard ratio for the comparison of anthracyclines with CMF has a wide 95% CI. This makes the results unstable and, at the same time, highlights two different problems encountered in the vast majority of studies looking at molecular predictive markers—lack of adequate statistical power and biologic heterogeneity of the study population. As alluded to earlier, this is the first time that a retrospective analysis from a randomized trial suggests that TOP2A gene amplification does not define a population of early-stage breast cancer patients deriving increased benefit from an anthracycline-based adjuvant therapy. In the last 6 years, four different retrospective studies based on randomized phase III adjuvant therapy trials have shown that TOP2A gene amplification might indicate enhanced sensitivity to anthracyclines.2-5 This finding is in line with the notion that anthracyclines are selective inhibitors of TOP2A.11 The present study is characterized by a limited number of patients carrying TOP2A-amplified tumors (only 26 TOP2A-amplified tumors). The 95% CI of the hazard ratio between anthracyclines and CMF is extremely wide in this specific group, suggesting that the study results have to be interpreted with caution. The same degree of caution is needed when the results from the other four previously reported studies are analyzed. A modest sample size2-4 or a limited study follow-up5 makes the subgroup analysis results of these studies unstable and certainly not conclusive. The field of research on TOP2A as a marker predicting sensitivity to anthracyclines has an additional level of complexity related to the multifactorial regulation of the TOP2A protein (Fig 1). Increased gene transcription can be enhanced by proliferation signals independently of gene aberrations, and wide fluctuations of TOP2A mRNA levels are seen during the different phases of the cellular cycle.12-15 TOP2A mRNA half-life seems to be regulated by some redox-sensitive protein complexes that bind to the 3'-untranslated TOP2A mRNA region.14 Last, but not least, TOP2A mRNA splicing leads to different protein isoforms.16,17 Cytoplasmic isoforms, as opposed to nuclear isoforms, seem to be functionally inactive.17 Nuclear receptors mediate the transportation of the protein between the cytoplasmic and the nuclear compartments.18-21 This complex mechanism of TOP2A regulation underlines the concept that enhanced TOP2A protein activity can be achieved in hyperproliferating tumors independently of TOP2A gene status, although it seems reasonable to hypothesize that tumors carrying both gene amplification and hyperproliferation might be the most responsive to anthracyclines. In addition, the multifactorial regulation of TOP2A activity strongly supports the implementation of a diagnostic test measuring protein concentration and providing spatial localization of TOP2A within the different cellular compartments. Immunohistochemistry is suboptimal to quantify and localize the target. New technologies based on immunofluorescence and automated image analyses are under clinical validation and could be instrumental in improving our current knowledge on TOP2A as a marker predicting sensitivity to anthracyclines.22,23 Results from a new generation of trials, focusing on adequate numbers of breast cancer patients, in which topoisomerase II activity will reliably be measured could open a new scenario and could eventually lead to the conclusion that anthracyclines are a first example of cytotoxic targeted therapy.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Angelo Di Leo, Dako (C), Abbott Laboratories (C), Monogram Biosciences (C), Pfizer Inc (C), Schering-Plough (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Angelo Di Leo Collection and assembly of data: Erica Moretti Data analysis and interpretation: Angelo Di Leo, Erica Moretti Manuscript writing: Angelo Di Leo Final approval of manuscript: Angelo Di Leo
ACKNOWLEDGMENTS We acknowledge the research funding received by the Associazione Italiana Ricerca Cancro to support the fellowship of Erica Moretti, MD. REFERENCES
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O'Malley FP, Chia S, Tu D, et al: Prognostic and predictive value of topoisomerase II alpha in randomized trial comparing CMF to CEF in premenopausal women with node positive breast cancer (NCIC CTG MA. 5). J Clin Oncol 24:11s, 2006 (suppl, abstr 533) 5. Slamon D, Eiermann W, Robert N, et al: Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (ACT) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACTH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Breast Cancer Res Treat 94:S5, 2005 (abstr 1) 6. Konecny G, Pauletti G, Pegram M, et al: Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst 95:142-153, 2003 7. Arpino G, Weiss H, Lee AV, et al: Estrogen receptor-positive, progesterone receptor-negative breast cancer: Association with growth factor receptor expression and tamoxifen resistance. J Natl Cancer Inst 97:1254-1261, 2005 8. Witton CJ, Reeves JR, Going JJ, et al: Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. J Pathol 200:290-297, 2003[CrossRef][Medline] 9. Tovey SM, Witton CJ, Bartlett JM, et al: Outcome and human epidermal growth factor receptor (HER) 1-4 status in invasive breast carcinomas with proliferation indices evaluated by bromodeoxyuridine labelling. Breast Cancer Res 6:R246-R251, 2004[CrossRef][Medline] 10. Poole CJ, Earl HM, Hiller L, et al: Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med 355:1851-1862, 2006 11. Burden DA, Osheroff N: Mechanism of action of eukaryotic topoisomerase II and drugs targeted to the enzyme. 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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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(TOP2A) as markers predicting sensitivity to anthracycline-based therapy in early breast cancer patients. In the original phase III clinical trial, patients were randomly allocated to one of two study arms, either an all intravenous cyclophosphamide, methotrexate, and fluorouracil (CMF) regimen administered every 3 weeks or a sequential regimen consisting of full-dose, single-agent epirubicin followed by the same type of CMF regimen. Treatment duration was 24 weeks in both study arms. Archival primary tumor samples were collected and made available for a centralized biomarker analysis in 322 of 374 patients who participated in the clinical trial. Protein expression was evaluated by immunohistochemistry. HER2 and TOP2A gene aberrations were investigated by fluorescent in situ hybridization. 
