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Originally published as JCO Early Release 10.1200/JCO.2008.20.1640 on February 9 2009 © 2009 American Society of Clinical Oncology.
Anthracyclines and Early Breast Cancer: The End of an Era?Division of Medical Oncology, Istituto dei Tumori di Milano, Milan, Italy
Fondazione Michelangelo, Milan, Italy For the last 25 years, anthracyclines have been unchallenged as the backbone of all the most popular chemotherapy regimens for women with operable breast cancer. Over such a long period, there have been many improvements in adjuvant chemotherapy, as a result of incorporation of anthracyclines into sequential non–cross-resistant regimens with cyclophosphamide, methotrexate, fluorouracil (CMF)1 or with the taxanes,2–5 new combinations with docetaxel,6 or novel scheduling approaches such as dose-dense administration.7 In this issue of Journal of Clinical Oncology, Jones et al8 update the results of the US Oncology 9735 (USO-9735) study that compared four cycles of docetaxel and cyclophosphamide (TC) with four cycles of doxorubicin and cyclophosphamide (AC).8,9 At 7 years, the report confirms superior disease-free survival with TC (81% TC v 75% AC, P = .033; hazard ratio [HR] = 0.74; 95% CI, 0.56 to 0.98).8 It also shows for the first time a significant survival benefit (87% TC v 82% AC, P = .032; HR = 0.69; 95% CI, 0.50 to 0.97).8 In many ways, the findings of USO-9735 question some tenets related to the popularity of the AC regimen in the United States and other regions of the world. In particular, the results are an integral part of the recent debate on the possibility that oncologists might undergo a radical departure from established practice by ending the era of anthracyclines in early breast cancer.10 Such a debate is one more reason to place the findings from USO-9735 into context. The simple design of USO-9735 allows for a straightforward interpretation of the main results and undoubtedly establishes TC as more effective than AC. In addition, the study shows that tolerability was qualitatively different (more nausea and vomiting and one cardiac death from congestive heart failure with AC, and more febrile neutropenia leading to one toxic death with TC), but TC was as feasible as AC, overall and in all subgroups of patients.8,9 These features prompted the investigators to propose that TC might be a preferred regimen for many patients, including older women and node-negative women.8 Overall, the data of USO-9735 support the role of TC as a new treatment option for early breast cancer, fully justifying its incorporation as the only nonanthracycline regimen in the long list of regimens supported by level I evidence in the guidelines of the National Comprehensive Cancer Network [Clinical Practice Guidelines in Oncology, v1.2008]. When proposing the use of the TC regimen, the USO-9735 investigators make much of unplanned and exploratory subset analyses.8,9 Exploratory analyses are now common and perceived as relevant in giving new insights and in generating new hypotheses. This method of eliciting new ideas might justify a departure from statistical purity, but it warrants great caution.11 In USO-9735, none of the unplanned subset analyses according to age, estrogen/progesterone receptor status, and human epidermal growth factor receptor 2 (HER-2) status shows anything but trends favoring TC, as illustrated by the fact that confidence limits cross the unity line of the forest plot.8 Therefore, the conclusion that TC performs equally well or better than AC in these subsets is not proven. This consideration is pertinent to implications for practice based on the results of USO-9735. Similarly pertinent is whether the superiority of TC over AC is enough to conclude that anthracyclines are not required for superior antitumor efficacy in early breast cancer. AC was originally tested in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-15 study, in which it performed as well as classical oral CMF12 and was perceived as a better option mostly because of its shorter treatment duration (2 v 6 months), better acute tolerability, and lower logistical burden on patients and hospitals. Therefore, AC was selected on the basis of convenience, not superior efficacy. Indeed, however popular it is, AC is far from being one of the most effective anthracycline-based regimens. Several studies have demonstrated the superiority of fluorouracil, epirubicin, and cyclophosphamide (FEC) or cyclophosphamide, doxorubicin, and fluorouracil (CAF) regimens over CMF,13–15 leading to the reasonable inference that such anthracycline regimens are better than AC. A large body of evidence also supports the concept that anthracyclines perform best in adjuvant sequential regimens, and that using the taxanes in sequence with anthracyclines, rather than in their substitution, can be very effective. Stemming from the seminal work of Bonadonna et al,1 a recent trial showed the superiority of sequential epirubicin and CMF over CMF.16 The BIG98-02 trial and the European Cooperative Trial in Operative Breast Cancer (ECTO) study showed that incorporation of taxanes improved the benefit of sequential doxorubicin followed by CMF.4,5 Sequential addition of taxanes also resulted in superiority over AC in Cancer and Leukemia Group B (CALGB) 9344,2 over FEC in Grupo Español de Investigación del Cáncer de Mama (GEICAM) 9906,17 and over FEC in PACS-01.18 In three of the referenced trials, the addition of a taxane into the sequential treatment occurred in regimens of identical duration.4,17,18 In brief, there is a formidable array of available anthracycline- and anthacycline/taxane-containing regimens that are superior to AC. The better efficacy of TC over AC does not justify discarding any of them. A more general argument against anthracycline-containing regimens proposed in the first and in the present report of USO-97358,9 is based on a wider set of considerations than the results of the trial itself.10 Jones et al argue that in their study TC performed equally well in HER-2–positive and HER-2–negative disease.8 This is based on an exploratory subset analysis in 170 of the 1,016 patients enrolled onto the study. Scouting for new leads in such a small backyard can hardly be considered representative of the much larger and unexplored surrounding forest. Yet, this is a central topic when the authors shape the scenarios of applicability of TC in patients with HER-2–negative tumors.8 As indicated by the original report of Muss19 and in a recent pooled analysis of the literature,20 anthracyclines should be preferentially active in tumors with HER2 overexpression/amplification. The appraisal of that pooled analysis should not dismiss the fact that the literature is hardly representative with regard to the association between a biomarker and a treatment. Results of a lack of association seldom, if ever, find their way to the literature, if they are ever submitted for publication by the investigators themselves. Interestingly, after the appearance of the overview implying that anthracyclines should be restricted to HER-2–positive cases, a study published in the Journal showed an interaction between anthracyclines and HER-2 in the opposite direction, on the basis of a trial that compared epirubicin followed by CMF with CMF alone.21
The concept of an association between HER-2 and anthracycline sensitivity has been redefined by the report of the Breast Cancer International Research Group (BCIRG) 006 study that tested adjuvant trastuzumab combined with docetaxel following AC (ACTH) or combined with docetaxel and carboplatin (TCH) in women with HER2-amplified tumors.22 Thirty-five percent of the tumors also carried amplification of the gene that encodes for topoisomerase II The space of an editorial does not allow for a comprehensive discussion of this controversial issue. Furthermore, at the time of this writing, the results of BCIRG-006 were not as yet published in a full report, thus preventing discussion of their full impact. Cardiotoxicity has been a cause of concern for the past 25 years, but all past and recent studies show that the benefit associated with anthracyclines largely overcomes the impact of the toxicity.25 In addition, the mechanisms of the antitumor effects of anthracyclines are not restricted to the targeting of top2A, and the activity of the enzyme increases during cell growth independently of amplification.22,25 It is therefore unclear why sensitivity to anthracyclines should be restricted to tumors that carry top2A gene amplification. Finally, the sequential administration of anthracyclines and taxanes appears to provide improved therapeutic effects that are largely consistent with these drugs' lack of cross-resistance and does not support the concept of substituting anthracyclines with taxanes. On the basis of all the above, anthracycline regimens should remain as a solid reference for the adjuvant treatment of breast cancer and should not be disposed of until more stringent data become available that corroborate their limited or even negligible role in any subset of breast cancer patients. The US Oncology investigators appear to be aware of the drawbacks and limitations of proposing TC as the new standard adjuvant chemotherapy instead of anthracycline-based regimens, and have launched a new study in women with HER-2–negative tumors that compares six cycles of adjuvant TC with six cycles of docetaxel, doxorubicin, and cyclophosphamide.6 It is unfortunate that they did not consider including an anthracyline/taxane sequential regimen for comparison. As in most modern trials, the researchers are giving the highest priority to the collection of a bio-bank with which to conduct molecular studies.8 This is a key feature of the study that will contribute to the ongoing effort to define predictive markers of efficacy.26 Indeed, it is our opinion that the real challenge and innovation in adjuvant therapy for breast cancer will not be based on the end of the anthracycline era, but on the end of the current era of "one-size-fits-all" treatment, a time when treatments and drugs, including anthracyclines, will be tailored to the individual characteristics of the tumor and the patient.26 We are not yet there. 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: Luca Gianni, Sanofi-aventis (C), Pfizer (C), Roche (C), Genentech (C), Wyeth (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Luca Gianni, Pinuccia Valagussa Collection and assembly of data: Luca Gianni, Pinuccia Valagussa Data analysis and interpretation: Luca Gianni, Pinuccia Valagussa Manuscript writing: Luca Gianni Final approval of manuscript: Pinuccia Valagussa REFERENCES
1. Bonadonna G, Zambetti M, Valagussa P: Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes: Ten-year results. JAMA 273:542–547, 1995. 2. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976–983, 2003. 3. Sparano JA, Wang M, Martino S, et al: Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358:1663–1671, 2008. 4. Francis P, Crown J, Di Leo A, et al: Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial. J Natl Cancer Inst 100:121–133, 2008. 5. 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J Natl Cancer Inst 100:805–814, 2008. 18. Roché H, Fumoleau P, Spielmann M, et al: Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: The FNCLCC PACS 01 Trial. J Clin Oncol 24:5664–5671, 2006. 19. Muss HB, Thor AD, Berry DA, et al: C-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 330:1260–1266, 1994. 20. Gennari A, Sormani MP, Pronzato P, et al: HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: A pooled analysis of randomized trials. J Natl Cancer Inst 100:14–20, 2008. 21. Bartlett JM, Munro A, Cameron DA, et al: Type 1 receptor tyrosine kinase profiles identify patients with enhanced benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial. J Clin Oncol 26:5027–5035, 2008. 22. Slamon D, Eiermann W, Robert N, et al. 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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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(top2A), the enzyme mechanistically linked to tumor kill by anthracyclines.
