Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada

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1 The Oncologist Breast Cancer Anthracyclines in Early-Stage Breast Cancer: Is It the End of an Era? DANNY ROBSON,SUNIL VERMA Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada Key Words. Adjuvant chemotherapy Anthracyclines Breast neoplasm Cardiotoxicity Leukemogenicity Disclosures: Danny Robson: None; Sunil Verma: Honoraria: AstraZeneca, Sanofi-Aventis, Pfizer; Research funding/contracted research: AstraZeneca, Sanofi-Aventis. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors or independent peer reviewers. ABSTRACT Anthracycline regimens have been the mainstay of adjuvant care in breast cancer for >20 years. A growing body of clinical experience has uncovered an unacceptable rate of significant cardiac and leukomogenic toxicities. Asystematic review of the literature was performed highlighting anthracycline- and nonanthracycline-based adjuvant regimens. The published data suggest that nonanthracycline alternatives are less toxic INTRODUCTION The anthracycline antibiotics are among the most important anticancer agents in use today. First extracted from fungal Streptomyces species in 1958, daunorubicin [1] and subsequently doxorubicin [2] have found important roles in standard oncologic practice over the past 40 years. Biochemical modifications have produced epirubicin, idarubicin, and, more recently, liposomal preparations, further expanding their spectrum of activity and altering their toxicity profile. In the mid 1980s, a number of clinical trials in the adjuvant breast cancer setting evaluated anthracyclines in comparison with the standard cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) regimen, thus paving the way for what might be considered the anthracycline era of early than anthracycline-containing regimens and equally, if not more, efficacious. Molecular predictors, such as human epidermal growth factor receptor 2 and topoisomerase II, are further refining the optimal role of anthracyclines. With these new advances, the current role of anthracycline-based chemotherapy in earlystage breast cancer demands re-examination. The Oncologist 2009;14: breast cancer [3 6]. However, our growing understanding of the long-term anthracycline toxicities, the increasing use of adjuvant chemotherapy in the node-negative and elderly populations, the rapidly evolving understanding of the molecular determinants of anthracycline sensitivity, and the emergence of nonanthracycline chemotherapy alternatives are calling into question the role of anthracyclines in the modern adjuvant therapy of breast cancer. Herein, we review the literature reporting the efficacy and toxicity of adjuvant anthracycline therapy for earlystage invasive breast cancer. We limit our focus to the most common anthracyclines in clinical practice doxorubicin and epirubicin and summarize the progress toward molecular predictive markers of anthracycline efficacy. We Downloaded from by guest on November 28, 2018 Correspondence: Sunil Verma, B.Sc., M.D., M.S.Ed., F.R.C.P.C., T-Wing, 2nd Floor, Sunnybrook Odette Cancer Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada, M2N3E6. Telephone: ; Fax: ; sunil.verma@sunnybrook.ca Received March 24, 2008; accepted for publication May 23, 2009; first published online in The Oncologist Express on June 26, AlphaMed Press /2009/$30.00/0 doi: /theoncologist The Oncologist 2009;14:

2 Robson, Verma 951 then place in context the newer nonanthracycline regimens and their relative merits. TOXICITIES MATERIALIZE Cardiac Clinical experience with anthracyclines in the metastatic breast cancer setting has uncovered a significant and doserelated incidence of cardiac dysfunction [7, 8]. Anthracyclines are the most active drugs in the palliative setting of recurrent and metastatic breast cancer, with response rates higher than with nonanthracycline regimens, albeit without significant survival differences [9]. Nevertheless, because of the short survival duration of these women, the long-term risk for cardiotoxicity is less clinically important in the metastatic setting. However, in the adjuvant setting, potential life-threatening cardiac toxicities are of greater concern, given that many patients with early breast cancer can be rendered disease free following definitive surgery alone. The reported literature on the relationship between cardiotoxicity and adjuvant anthracycline exposure must be reviewed in full awareness that studies vary widely in dose and schedule of anthracycline, methodology (including population-based, retrospective, and prospective studies), populations treated, and the intensity, duration, and nature of cardiac monitoring (Table 1) [10 16]. Furthermore, the definitions of cardiac dysfunction and congestive heart failure (CHF) have not been formally standardized, and considerable variation exists among trials. Nonetheless, there is a consensus that the risk for cardiotoxicity is related to the cumulative anthracycline dose administered, pre-existing heart disease, a history of mediastinal irradiation, and the coadministration of desrazoxane, paclitaxel, and trastuzumab [17]. Furthermore, this risk is of particular concern in the elderly. Pinder et al. [18], in their review of the Surveillance, Epidemiology, and End Results Medicare database, found a statistically and clinically significant higher risk for CHF in women aged who received anthracycline-based chemotherapy compared with those who received nonanthracycline regimens (hazard ratio [HR], 1.26). Among the studies examining adjuvant cardiotoxicity issues, large series have consolidated individual trial results. Valagussa et al. [19] reported a 0.8% incidence of CHF with older adjuvant regimens incorporating doxorubicin. Fumoleau et al. [20] reviewed the French Adjuvant Study Group (FASG) s experience with adjuvant epirubicin and recorded a 1.3% incidence of clinical cardiac dysfunction. Other series have explored the influences of dose and length of follow-up. The Cancer and Leukemia Group B (CALGB) 9344 adjuvant breast cancer trial [11] found a Table 1. Cardiotoxicity of common adjuvant regimens Regimen Study Frequency of cardiotoxicity a FE 100 C-D [10] PACS % 5 AC-T [11] CALGB % 5 ddac-t [12] CALGB % 7 CE 120 F [13] MA % 5 TAC [14] BCIRG % 5 FE 100 C [15] FASG-5 1.7% 5 TC [16] USON % 7 Follow-up (yrs) a No uniform definition for cardiotoxicity was presented. Most trials, however, used standardized criteria (World Health Organization, National Cancer Institute Common Toxicity Criteria, CALGB expanded common toxicity criteria) and reported on the combined incidences of: decrease in cardiac ejection fraction, cardiac symptomatology (dysrhythmia, pericarditis, acute coronary syndrome), congestive heart failure, and cardiac death. Abbreviations: AC-T, doxorubicin, cyclophosphamide, and docetaxel; BCIRG, Breast Cancer International Research Group; CALGB, Cancer and Leukemia Group B; CE 120 F, cyclophosphamide, epirubicin (120 mg/m 2 ), 5-fluorouracil; ddac-t, dose-dense doxorubicin, cyclophosphamide, and paclitaxel; FASG, French Adjuvant Study Group; FE 100 C-D, 5-fluorouracil, epirubicin (100 mg/m 2 ), cyclophosphamide, and docetaxel; TAC, docetaxel, doxorubicin, and cyclophosphamide; TC, docetaxel and cyclophosphamide; USON, United States Oncology Network. 16% rate of cardiotoxicity (symptomatic and asymptomatic) with a doxorubicin dose of 90 mg/m 2 versus 11% with a dose of 60 mg/m 2. Zambetti et al. [21] detailed a 0.4% incidence of cardiac death in a report from a 14-year follow-up of adjuvant anthracycline regimens. Finally, the Early Breast Cancer Trialists Collaborative Group (EBCTCG) identified a cardiac mortality rate of 0.08% per year with anthracycline-containing adjuvant regimens [22]. Of particular interest are the emerging reports with newer adjuvant regimens incorporating trastuzumab. The recent landmark adjuvant trastuzumab trials documented substantially higher rates of cardiotoxicity: a 1.73% 1-year incidence of symptomatic CHF in the Herceptin Adjuvant trial [23], 4.1% and 2.9% 3-year incidences of New York Heart Association (NYHA) class III/IV CHF or death from cardiac causes in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 and N9831 trials, respectively [24], and a 1.9% 3-year incidence of NYHA class III/IV CHF in the second interim analysis of the Breast Cancer International Research Group (BCIRG) 006 trial [25]. The absolute and relative risks for trastuzumab-associated cardiotoxicities are summarized in Table 2 [23 26]. Because these trials reported results at a median follow-up of

3 952 Anthracyclines in Early-Stage Breast Cancer Table 2. Cardiotoxicity of trastuzumab regimens: Grade 3 or 4 CHF events or fatal cardiac events CHF incidence (%) Study Size Follow-up (yrs) Trastuzumab Control Hazard ratio B-31/NCCTG [24] 3, FinHER [26] HERA [23] 3, BCIRG 006 [25] 3,322 2 AC-TH TCH Abbreviations: AC-TH, doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab; BCIRG, Breast Cancer International Research Group; CHF, congestive heart failure; FinHER, Finnish Herceptin ; HERA, Herceptin Adjuvant; NCCTG, North Central Cancer Treatment Group; TCH, docetaxel, cyclophosphamide, and trastuzumab. only 3 years in women selected to have a low risk for cardiotoxicity, it is likely that the burden of cardiotoxicity will almost certainly be greater with additional follow-up and the broad use in the community of trastuzumab in women who would not necessarily have been eligible for the original adjuvant trastuzumab studies. Table 3. Leukemogenicity of common adjuvant regimens AML/MDS Regimen Study rate (%) Follow-up TAC [14] BCIRG AC-T [11] CALGB dd AC-T [12] CALGB CE 120 F [13] MA TC [16] USON TCH [25] BCIRG AC-TH [25] BCIRG FEC-D [10] PACS CMF [22] EBCTCG 0.02/yr Abbreviations: AC-T, doxorubicin, cyclophosphamide, and paclitaxel; AC-TH, doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab; AML, acute myelogenous leukemia; BCIRG, Breast Cancer International Research Group; CALGB, Cancer and Leukemia Group B; CE 120 F, cyclophosphamide, epirubicin (120 mg/m 2 ), and 5-fluorouracil; CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; ddac-t, dose-dense doxorubicin, cyclophosphamide, and paclitaxel; EBCTCG, Early Breast Cancer Trialists Collaborative Group; FEC-D, 5-fluorouracil, epirubicin, and cyclophosphamide, docetaxel; FE 100 C-D, 5-fluorouracil, epirubicin (100 mg/ m 2 ), cyclophosphamide, and docetaxel; MDS, myelodysplastic syndrome; TAC, docetaxel, doxorubicin, and cyclophosphamide; TC, docetaxel and cyclophosphamide; TCH, docetaxel, cyclophosphamide, and trastuzumab; USON, United States Oncology Network. Leukemogenicity The leukemogenic potential of alkylating agents and radiotherapy has been well established in the cancer literature [26]. The incremental risks for secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) attributable to anthracyclines are apparent, in large part because of the relatively short time to onset of anthracycline-associated AML and MDS (Table 3) [10 14, 16, 22, 25]. Such topoisomerase II inhibitor triggered events are characterized by a clinically and cytogenetically defined form of treatment-related leukemia [27]. In a cohort of 3093 French women who received adjuvant anthracycline chemotherapy, Chaplain et al. [28] found a 0.41% 4-year cumulative incidence of AML/MDS, roughly 11.4 times the risk for women who did not receive adjuvant chemotherapy. The NSABP experience of adjuvant, standarddose, doxorubicin and cyclophosphamide (AC) in 4,483 women revealed a 0.27% 8-year incidence of treatmentinduced leukemia [29]. The EBCTCG 2000 overview found a 0.04% per year leukemogenic risk with anthracycline regimens, twice that seen in women treated with nonanthracycline regimens [22]. Despite the rarity of secondary hematological malignancies, newer regimens incorporating dose-intense anthracyclines may further increase the risk. An analysis of 19 adjuvant epirubicin trials, with 9,796 patients, revealed a clear relationship between epirubicin dose and the risk for AML/MDS: standard regimens carried an 8-year risk of 0.37% compared with a 4.97% risk for patients administered higher cumulative doses of both epirubicin and cyclophosphamide [30]. Although the absolute risk for leukmogenicity is overshadowed by the lower risk for death from breast cancer, the emergence of nonleukogenic alternatives mandates that these risks nonetheless be introduced in clinical discussions when making adjuvant therapy deci-

4 Robson, Verma 953 sions, particularly so if they offer any incremental survival benefit. ADJUVANT ANTHRACYCLINE PRINCIPLES Despite their established toxicities, anthracycline-based regimens have become the mainstay in the management of early breast cancer. First introduced as an alternative to the classic CMF cocktail, subsequent trials, cross-trial comparisons, and much debate have attempted to identify an optimal anthracycline regimen. The most comprehensive and perhaps authoritative analysis came with the EBCTCG 2000 overview [22]. A direct analysis of all registered anthracycline-containing regimens versus nonanthracycline regimens favored the former in terms of disease-free survival (DFS) and overall survival (OS), regardless of age, hormone receptor status, or nodal status, with an absolute benefit of 3% at 5 years, and 4% at 10 years. The adjuvant anthracycline debate, however, has recently resurfaced because of a growing appreciation of long-term toxicities (discussed above), the emergence of nonanthracycline chemotherapy alternatives, and an evolving understanding of the molecular determinants of anthracycline sensitivity. With these new advances, the anthracycline status quo demands re-examination. We discuss the role of adjuvant anthracyclines in the context of three specific early-stage breast cancer subpopulations: human epidermal growth factor receptor (HER)2, HER-2, and hormone receptor positive breast cancers. HER-2 Early Breast Cancer Invasive breast cancer is a heterogeneous disease characterized by several distinct biologic subtypes. Approximately 20% of primary breast cancers have amplification of the HER-2 gene, with resultant overexpression of the HER-2 protein. HER-2 belongs to a family of transmembrane receptor tyrosine kinases that mediate the growth, differentiation, and survival of cells. HER-2 cancers tend to have enhanced growth and proliferation, greater invasive and metastatic capability, and stimulation of angiogenesis. Population-based studies and retrospective analyses have also shown that the HER-2 alteration is associated with poorly differentiated, high-grade tumors, lymph node involvement, and relative resistance to hormonal therapy. Until recently, breast cancer patients in whom overexpression of HER-2 occurred faced a poorer prognosis than those with HER-2 breast cancer. To address whether HER-2 status relates to anthracycline sensitivity, a number of adjuvant trialists have retrospectively analyzed their clinical trial outcome data and primary tumor blocks. To date, this question has been addressed in nine reported clinical trials comparing anthracycline with nonanthracycline regimens [31 39], a pooled analysis of eight of these trials [40], three studies addressing whether escalation of the anthracycline dose relates to outcomes in HER-2 dichotomized populations [41 43], and a single trial that evaluated adjuvant HER-2 therapy combined with a nonanthracycline chemotherapy regimen [25]. Nine reported trials have evaluated the predictive value of HER-2 in studies that compared anthracycline with nonanthracycline regimens (Table 4) [31 39]. In general, those trials had heterogeneous HER-2 testing methodologies, relatively small sample sizes, and, because of their retrospective nature, not all tumor blocks were available for each patient in the trials. Nonetheless, a pooled analysis of eight of those trials revealed that, for those women randomized to anthracycline versus nonanthracycline regimens, the DFS and OS HRs for women with HER-2 primary tumors were markedly superior, at 0.71 (95% confidence interval [CI] ) and 0.73 (95% CI, ), respectively [40]. Because the test for treatment by HER-2 status interaction was significant, the authors concluded that the incremental benefit of adjuvant chemotherapy with anthracyclines was confined to women with HER-2 breast cancers. Three further trials have investigated the predictive value of HER-2 with alternative anthracycline dosing strategies and have come to disparate conclusions. Muss et al. [41] retrospectively analyzed tumor blocks for c-erbb-2 (HER-2) expression from a randomly selected cohort of women enrolled in the CALGB 8541 [43] clinical trial of varying dose cyclophosphamide, doxorubicin, and 5-fluorouracil [40]. A dose-response benefit was restricted to the 29% of women who were c-erbb-2. A similarly designed retrospective analysis of tumor blocks from the Gono- Mig-1 study of standard dose versus dose-dense adjuvant cyclophosphamide, epirubicin (60 mg/m 2 ), 5-fluorouracil (FEC21 versus FEC14) was performed by Del Mastro et al. [42]. The benefit of the dose-dense regimen was again limited to the HER-2 cohort, but it did not reach statistical significance: 5-year event-free survival rate, 62.5% versus 77.7% (p.087) for FEC21 versus FEC14, respectively. Finally, no survival associations were found between HER-2 status and doses of doxorubicin 60 mg/m 2 in a retrospective analysis of the CALGB 9344 data [43, 11]. These results, in aggregate, raise the critical question: why would high sensitivity to anthracyclines be confined to the HER-2 subpopulation of breast cancer patients? Recent investigations have implied a tantalizing molecular explanation. The topoisomerase II (topoiia) gene has been mapped to chromosome 17, adjacent to the HER-2 locus [44]. Several studies using fluorescence in situ hybridiza-

5 954 Anthracyclines in Early-Stage Breast Cancer Table 4. Anthracycline versus nonanthracycline studies: HER-2 subgroup analyses Overall survival hazard ratio (anthracycline Study Regimen versus nonanthracycline) Paik et al. [32], NSABP B11 PAF versus PF 0.66 ( ) Paik et al. [33], NSABP B15 AC versus CMF versus AC-CMF 0.82 ( ) Moliterni et al. [35], Milan CMF-A versus CMF 0.61 ( ) Pritchard et al. [38], NCIC MA5 CEF versus CMF 0.65 ( ) Di Leo et al. [31], Belgian HEC/EC versus CMF Di Laurentiis [34], GUN 3 CMF/EV versus CMF 0.85 ( ) Colozza et al. [36], GOIRC E versus CMF 0.71 ( ) Knoop et al. [37], DBCG 89D FEC versus CMF 0.73 ( ) Bartlett [39], UK NEAT E-CMF versus CMF 0.85 ( ) a a Recurrence-free survival reported only. Abbreviations: AC, doxorubicin and cyclophosphamide; CEF, cyclophosphamide, epirubicin, and 5-fluorouracil; CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; CMF-A, cyclophosphamide, methotrexate, 5-fluorouracil, and doxorubicin; DBCG, Danish Breast Cancer Cooperative Group; E, epirubicin; EC, moderate-dose epirubicin and cyclophosphamide; EV, epirubicin and vinblastine; FEC, 5-fluorouracil, epirubicin, and cyclophosphamide; GOIRC, Gruppo Oncologico Italiano di Ricerca Clinica; GUN, Gruppo Universitario Napoletano; HEC, full-dose epirubicin and cyclophosphamide; NCIC, National Cancer Institute of Canada; NEAT, National Epirubicin Adjuvant Trial; NSABP, National Surgical Adjuvant Breast and Bowel Project; PAF, L-phenylalanine mustard, doxorubicin, and 5-fluorouracil; PF, L-phenylalanine mustard and 5-fluorouracil. Table 5. Anthracycline versus nonanthracycline trials: TopoIIA co-amplification subgroup analyses Hazard ratio (anthracycline versus Study Regimen nonanthracycline) Knoop et al. [37] CEF versus CMF RFS, 0.43 ( ) Tanner et al. [46] FEC 1 versus FEC CTCb RFS, 0.45 (p.049) O Malley [47] CEF versus CMF DFS, 0.49 ( ) Bartlett [48] E-CMF versus CMF RFS, 0.95 ( ) Abbreviations: CEF, cyclophosphamide, epirubicin, and 5-fluorouracil; CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; CTCb, cyclophosphamide, thiotepa, and carboplatin; DFS, disease-free survival; E, epirubicin; E-CMF, epirubicin, cyclophosphamide, methotrexate, and 5-fluorouracil; FEC, standard-dose 5-fluorouracil, epirubicin, and cyclophosphamide; FEC 1, dose-escalated 5-fluorouracil, epirubicin, and cyclophosphamide; RFS, recurrence-free survival. tion (FISH) analysis, albeit retrospective in nature, have revealed significant associations among HER-2/topoIIA coamplification, the use of anthracyclines, and survival outcomes (Table 5) [37, 46 48]. Three such studies revealed that topoiia amplifications (or deletions) were predictive of a greater differential response to anthracycline-containing regimens [37, 46, 47]; however, only one of these trials suggested that topoiia has a greater predictive value than HER-2 amplification [37]. Furthermore, one study found no differential benefit for anthracyclines in a topoiia-expressing population of women treated with adjuvant CMF versus epirubicin plus CMF [48]. A recent meta-analysis of four anthracycline versus nonanthracycline adjuvant trials was similarly inconclusive, where topoiia amplification provided no further predictive benefit for anthracyclines over HER-2 amplification [49]. Emerging reports regarding other putative anthracycline predictive biomarkers, such as chromosome 17 polysomy [39] or topoiia/tissue inhibitor of metalloproteinases (TIMP) coexpression [50], remain to be validated in other retrospective analyses. It should be noted, however, that all of these studies were limited to HER-2 patients treated without trastuzumab the current standard of care for HER-2 early breast cancer. Trastuzumab (Herceptin ; F. Hoffmann-La Roche, Basel, Switzerland) is a humanized monoclonal antibody targeting the extracellular domain of the HER-2 protein. Trastuzumab activates antibody-dependent cell-mediated cytotoxicity and disrupts the signal transduction process through interfering with receptor dimerization, downstream effectors, and receptor internalization and degradation. The BCIRG 006 trial reported the efficacy of adjuvant docetaxel, carboplatin, and trastuzumab (TCH) versus a standard anthracycline regimen with and without trastuzumab doxorubicin and cyclophosphamide followed by do-

6 Robson, Verma 955 cetaxel (ACT) and doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACTH) [25]. Whereas both adjuvant trastuzumab arms resulted in substantially superior outcomes versus the control, there were no significant differences between the trastuzumab-containing arms concerning the 4-year DFS rate: 83% (ACTH) versus 82% (TCH). Nor were there significant 4-year OS rate differences between the two trastuzumab regimens: 92% (ACTH) versus 91% (TCH). However, the global toxicity profiles favored the nonanthracycline TCH regimen, with significantly lower incidences of grade 3 or 4 arthralgia, myalgia, hand foot syndrome, stomatitis, vomiting, neutropenia, and leukopenia. Furthermore, the incidence of cardiotoxicity was fivefold lower with the nonanthracycline regimen: 1.9% versus 0.4% grade 3 or 4 CHF in the ACTH arm versus the TCH arm, respectively (p.0015). In summary, these data suggest that, although adjuvant anthracyclines may provide an incremental efficacy advantage in the HER-2 population in the absence of trastuzumab, this benefit is lost when trastuzumab is introduced. Given the lifealtering potential toxicities of anthracyclines, cardiotoxicity and leukemogenicity, and the substantially greater incidences of cardiotoxicity seen when trastuzumab is used in proximity to anthracyclines, the role for anthracyclines in the HER-2 population is very much in question. HER-2 Early Breast Cancer Treatment for the HER-2 cohort of patients with early invasive breast cancer now differs from that of their HER-2 counterparts, in that trastuzumab is of no proven value. Given the wealth of data in the metastatic setting showing a lack of trastuzumab efficacy in breast cancers neither overexpressing HER-2 via immunohistochemistry nor possessing HER-2 amplification by FISH [51], the role of adjuvant trastuzumab in the HER-2 adjuvant setting remains speculative [52]. Taxane-based regimens are an increasingly accepted alternative to anthracycline-based regimens, with supporting data from two major trials. Jones et al. [53] pitted adjuvant AC for four cycles against docetaxel and cyclophosphamide (TC) for four cycles in a population of early breast cancer patients unselected for HER-2 status. When presented in 2005, the data favored the nonanthracycline regimen (TC) in terms of the 5-year DFS rate, 86% versus 80%, and a trend was emerging for an OS advantage [53]. Seven-year data recently presented at the 2007 San Antonio Breast Cancer Symposium now reveal a significant OS benefit for the TC arm: an 84% (TC) versus 88% (AC) 6-year OS rate (p.045) [16]. A second study examined the use of taxanes as a replacement for a standard regimen with a higher cumulative dose of anthracyclines. The PACS 01 trial compared six cycles of FEC 100 with three cycles of FEC 100 followed by three cycles of docetaxel (FEC-D) [10]. The FEC-D arm had a superior 5-year DFS rate (78.4% versus 73.2%) and OS rate (90.7% versus 86.7%). Thus, the newer taxane-based regimens are increasingly viable and accepted options because of their greater DFS and OS rates, and lower rates of anthracycline-associated toxicities. Estrogen Receptor Positive Early Breast Cancer The primacy of the anthracycline regimens has been further challenged in the estrogen receptor (ER) domain. Elucidation of the role of estrogen in breast carcinogenesis and progression has catalyzed the development of targeted endocrine therapies, including ovarian ablation, ovarian suppression, selective ER modulators, and aromatase inhibitors. Large meta-analyses have focused on the additional benefit of hormonal manipulations to cytotoxic chemotherapy [22, 54, 55]. The EBCTCG 2005 overview explored the role of chemotherapy alone versus chemotherapy in combination with ovarian ablation or suppression. A statistically significant 3.2% 15-year benefit in breast cancer mortality (43.5% versus 40.3%) was found in the combination group. A similar benefit was seen in the analysis of tamoxifen in combination with chemotherapy: a 6.9% 10- year benefit in breast cancer mortality (29.0% versus 22.2%). Few analyses, however, have explored the possibility of hormonal manipulation as an alternative to cytotoxic chemotherapy, and even fewer have used anthracycline regimens as the comparator. In the premenopausal population, three studies have examined combined ovarian ablation/suppression and tamoxifen versus anthracyclines in the high-risk adjuvant setting (Table 6). Roché et al. [56] randomized premenopausal, node-positive women to either ovarian ablation (surgical or radiation) with 2 years of tamoxifen or 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC). After 85 months of follow-up, there was a trend favoring the hormonal manipulation arm in terms of both the DFS rate (82.5% versus 55%) and the OS rate (84% versus 74%). Roché et al. [57] then examined a similar population in the FASG 06 trial, this time with medical oopherectomy and 3 years of tamoxifen versus FEC. Here, a statistically significant benefit in terms of the DFS rate was apparent in the hormonal arm alone versus the anthracycline regimen: 91.7% versus 80.9%, respectively. Finally, the International Breast Cancer Study Group examined a similar premenopausal, node-positive population and evaluated ovarian function suppression with 5 years of tamoxifen versus the same regimen with AC chemotherapy [58]. Although accrual was poor, there was no difference in either the DFS or OS rate with the addition of cytotoxic anthracyclines. Hormonal manipulation has been well studied in the postmenopausal setting because of the high prevalence of

7 956 Anthracyclines in Early-Stage Breast Cancer Table 6. Anthracycline versus hormonal manipulation trials Study Regimen Outcome (endocrine versus anthracycline) Premenopausal Roché [56] Tam OA versus FAC 85-mo DFS, 82.8% (71% 90%) versus 55% (43% 56%) Roché [57], FACS 06 Tam triptoreline versus FEC50 54-mo DFS, 91.7% versus 80.9%; p.12 Thurliman [58], IBCSG OA/OS versus OA/OS AC 48-mo DFS, 88% versus 87%; p.94 Postmenopausal Fisher et al. [59], NSABP B16 Tam versus AC/PAFT 36-mo DFS, 66% versus 84%; p.003 Albain [60], SWOG 8814 Tam versus CAF-Tam versus CAFTam 10-yr DFS, 48% versus 60% versus 53% a Wils et al. [61], ICCG Tam versus E Tam 68-mo RFS, 62.1% versus 73.7%; p.023 Namer et al. [62], FACS 02/07 Tam versus FEC50 Tam 9-yr DFS, 72% versus 84%; p.008 a p-value not reported. Abbreviations: AC, doxorubicin and cyclophosphamide; CAF, cyclophosphamide, doxorubicin, and 5-fluorouracil; DFS, disease-free survival; E, epirubicin; FAC, 5-fluorouracil, doxorubicin, and cyclophosphamide; FACS, French Adjuvant Study Group; FEC, 5-fluorouracil, epirubicin, and cyclophosphamide; IBCSG, International Breast Cancer Study Group; ICCG, International Collaborative Cancer Group; NSABP, National Surgical Adjuvant Breast and Bowel Project; OA, ovarian ablation; OS, ovarian suppression; PAFT, phenylalanine mustard, doxorubicin, and 5-fluorouracil; RFS, relapsefree survival; SWOG, Southwest Oncology Group; Tam, tamoxifen. estrogen-dependent tumors and the desire to diminish adjuvant toxicity. There is, however, a paucity of similarly designed trials comparing adjuvant endocrine therapy with anthracycline regimens, particularly in the node-negative setting because of the marginal benefit of chemotherapy in this relatively low-risk population [22]. Recent advances in molecular profiling have sought to define a cohort of lowrisk women who do not appear to benefit from anthracycline-based adjuvant chemotherapy. The 21-gene recurrence score assay (Oncotype DX ; Genomic Health, Redwood City, CA) has been studied, albeit retrospectively, in both the node-negative and node-positive hormone receptor positive populations [63, 64]. Although the results in the node-negative trial detailed a group of lowrisk women who do not appear to benefit from adjuvant chemotherapy, the comparator arm, from the NSABP B-20 trial, was CMF or MF chemotherapy, and did not contain any anthracyclines [63]. The node-positive analysis was conducted with samples from the INT0100 trial, with an anthracycline-containing cyclophosphamide, doxorubicin, and 5-fluorouracil arm [64]. The results suggest that women with a low recurrence score ( 18), notwithstanding their nodal positivity, can possibly be spared the toxicity of anthracycline-containing chemotherapeutics. CONCLUSIONS Anthracycline regimens have been the mainstay of adjuvant chemotherapy in breast cancer for nearly 20 years. However, increasing recognition of their particular toxicities (cardiac and leukemogenic) has prompted the search for viable alternatives, and for subgroups with preferential benefit. Although the incremental efficacy advantages of anthracycline regimens now appear to be confined to the HER-2 population, the arrival of trastuzumab-based nonanthracycline regimens has successfully challenged their role even in this niche. Furthermore, taxane-based adjuvant regimens have successfully reduced or eliminated the need for anthracycline exposure in the HER-2 population. Finally, the incremental benefit from chemotherapy beyond that of optimal hormonal therapy is in question because of better molecular selection of hormonesensitive populations. In aggregate, these emerging data have deeply undermined the role of adjuvant anthracyclines in modern breast cancer care. AUTHOR CONTRIBUTIONS Conception/Design: Danny Robson, Sunil Verma Collection/assembly of data: Danny Robson, Sunil Verma Data analysis: Danny Robson, Sunil Verma Manuscript writing: Danny Robson, Sunil Verma Final approval of manuscript: Danny Robson, Sunil Verma REFERENCES 1 Di Marco A, Gaetani M, Orezzi P et al. Daunomycin, a new antibiotic of the rhodomycin group. Nature 1964;201: Arcamone F, Cassinelli G, Fantini G et al. Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius. Biotechnol Bioeng 1969;11: Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive lymph nodes. Ten-year results. JAMA 1995;273:

8 Robson, Verma Coombes RC, Bliss JM, Wils J et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary nodepositive operable breast cancer: Results of a randomized trial. The International Collaborative Cancer Group. J Clin Oncol 1996;14: Levine MN, Pritchard KI, Bramwell VH et al. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: Update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol 2005;23: Misset JL, di Palma M, Delgado M et al. Adjuvant treatment of nodepositive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: Final report after a 16-year median follow-up duration. J Clin Oncol 1996; 14: Lord S, Ghersi D, Gattellari M et al. Antitumour antibiotic containing regimens for metastatic breast cancer. Cochrane Database Syst Rev 2004;(4): CD Von Hoff DD, Layard MW, Basa P et al. Risk factors for doxorubicininduced congestive heart failure. Ann Intern Med 1979;91: Fossati R, Confalonieri C, Torri V et al. Cytotoxic and hormonal treatment for metastatic breast cancer: A systematic review of published randomized trials involving 31,510 women. J Clin Oncol 1998;16: Roché H, Fumoleau P, Spielmann M et al. Sequential adjuvant epirubicinbased and docetaxel chemotherapy for node-positive breast cancer patients: The FNCLCC PACS 01 trial. J Clin Oncol 2006;24: 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 2003;21: Citron ML, Berry DA, Cirrincione C et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial J Clin Oncol 2003;21: Burnell M, Levine M, Chapman JA et al. A randomized trial of CEF versus dose dense EC followed by paclitaxel versus AC followed by paclitaxel in women with node positive or high risk node negative breast cancer, NCIC CTG MA. 21: Results of an interim analysis. Presented at the 2006 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 14 17, Martin M, Pienkowski T, Mackey J et al. Adjuvant docetaxel for nodepositive breast cancer. N Engl J Med 2005;352: French Adjuvant Study Group. Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol 2001;19: Jones S, Holmes F, O Shaughnessy J et al. Extended follow-up and analysis by age of the US Oncology Adjuvant trial 9735: Docetaxel/cyclophosphamide is associated with an overall survival benefit compared to doxorubicin/cyclophosphamide and is well-tolerated in women 65 or older. Presented at the 2007 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 13 16, Shapiro CL, Recht A. Side effects of adjuvant treatment of breast cancer. N Engl J Med 2001;344: Pinder MC, Duan Z, Goodwin JS et al. Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol 2007;25: Valagussa P, Zambetti M, Biasi S et al. Cardiac effects following adjuvant chemotherapy and breast irradiation in operable breast cancer. Ann Oncol 1994;5: Fumoleau P, Roché H, Kerbrat P et al. Long-term cardiac toxicity after adjuvant epirubicin-based chemotherapy in early breast cancer: French Adjuvant Study Group results. Ann Oncol 2006;17: Zambetti M, Moliterni A, Materazzo C et al. Long-term cardiac sequelae in operable breast cancer patients given adjuvant chemotherapy with or without doxorubicin and breast irradiation. J Clin Oncol 2001;19: Early Breast Cancer Trialists Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005; 365: Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353: Romond EH, Perez EA, Bryant J et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353: Slamon D, Eiermann W, Robert N et al. BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC3T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC3TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients. Presented at the 2006 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 14 17, Thirman MJ, Larson RA. Therapy-related myeloid leukemia. Hematol Oncol Clin North Am 1996;10: Guillem V, Tormo M. Influence of DNA damage and repair upon the risk of treatment related leukemia. Leuk Lymphoma 2008;49: Chaplain G, Milan C, Sgro C et al. Increased risk of acute leukemia after adjuvant chemotherapy for breast cancer: A population-based study. J Clin Oncol 2000;18: Smith RE, Bryant J, DeCillis A et al. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: The National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol 2003;21: Praga C, Bergh J, Bliss J et al. Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: Correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol 2005;23: Di Leo A, Gancberg D, Larsimont D et al. HER-2 amplification and topoisomerase II gene aberrations as predictive markers in node-positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil. Clin Cancer Res 2002;8: Paik S, Bryant J, Park C et al. erbb-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 1998;90: Paik S, Bryant J, Tan-Chiu E et al. HER2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15. J Natl Cancer Inst 2000;92: De Laurentiis M, Caputo F, Massarelli E. Her2 expression and anthracycline effect: Results from the Naple GUN 3 randomized trial. Proc Am Soc Clin Oncol 2001;20:Abstract Moliterni A, Ménard S, Valagussa P et al. HER2 overexpression and doxorubicin in adjuvant chemotherapy for resectable breast cancer. J Clin Oncol 2003;21:

9 958 Anthracyclines in Early-Stage Breast Cancer 36 Colozza M, Sidoni A, Mosconi AM et al. HER2 expression as a predictive marker in a randomized trial comparing adjuvant cyclophosphamide/ methotrexate/5-fluorouracil with epirubicin in patients with stage I/II breast cancer: Long-term results. Clin Breast Cancer 2005;6: Knoop AS, Knudsen H, Balslev E et al. Retrospective analysis of topoisomerase IIa amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil: Danish Breast Cancer Cooperative Group. J Clin Oncol 2005;23: Pritchard KI, Shepherd LE, O Malley FP et al. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 2006;354: Bartlett JMS, Munro A, Dunn JA et al. Chromosome 17 polysomy (Ch17) as a predictor of anthracycline response: Emerging evidence from the UK NEAT adjuvant breast cancer trial. Presented at the 2008 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 10 14, Gennari A, Sormani MP, Pronzato P et al. HER2 status and the efficacy of adjuvant anthracyclines in early breast cancer: A pooled analysis of randomized trials. J Natl Cancer Inst 2008;100: 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 1994;330: Del Mastro L, Bruzzi P, Nicolò G et al. HER2 expression and efficacy of dose-dense anthracycline-containing adjuvant chemotherapy in breast cancer patients. Br J Cancer 2005;93: Hayes DF, Thor AD, Dressler LG et al. HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med 2007;357: Wood WC, Budman DR, Korzun AH et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 1994;330: Tan KB, Dorman TE, Falls KM et al. Topoisomerase II and topoisomerase II genes: Characterization and mapping to human chromosomes 17 and 3, respectively. Cancer Res 1992;52: Tanner M, Isola J, Wiklund T et al. Topoisomerase II gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial J Clin Oncol 2006;24: O Malley F, Chia S, Tu D, et al. Topoisomerase II alpha protein overexpression has predictive utility in a randomized trial comparing CMF to CEF in premenopausal women with node positive breast cancer (NCIC CTG MA. 5). Presented at the 2006 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 14 17, Bartlett JM, Munro AF, Cameron DA et al. Molecular markers as predictors of breast cancer response to adjuvant chemotherapy in the BR9601 trial. Presented at the 2007 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 13 16, Di Leo A, Isola J, Piette F et al. A meta-analysis of phase III trials evaluating the predictive value of HER2 and topoisomerase II alpha in early breast cancer patients treated with CMF or anthracycline-based adjuvant therapy. Presented at the 2008 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 10 14, Ejlertsen B, Jensen M-B, Nielsen KV et al. TOP2A, TIMP-1 and responsiveness to adjuvant anthracycline containing chemotherapy in high risk breast cancer patients. Presented at the 2008 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 10 14, Wolff AC, Hammond ME, Schwartz JN et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007;25: Paik S, Kim C, Jeong J et al. Benefit from adjuvant trastuzumab may not be confined to patients with IHC 3 and/or FISH-positive tumors: Central testing results from NSABP B-31. Presented at the 2007 American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 1 5, Jones SE, Savin MA, Holmes FA. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 2006;24: Early Breast Cancer Trialists Collaborative Group. Ovarian ablation in early breast cancer: Overview of the randomised trials. Lancet 1996;348: Early Breast Cancer Trialists Collaborative Group. Tamoxifen for early breast cancer: Overview of the randomised trials. Lancet 1998;351: Roché H, Mihura J, de Lafontan B. Castration and tamoxifen versus chemotherapy (FAC) for premenopausal, node and receptors positive breast cancer patients: A randomized trial with a 7 years median follow up. Proc Am Soc Clin Oncol 1996;15: Roché H, Kerbrat P, Bonnetterre J et al. Complete hormonal blockade versus chemotherapy in premenopausal early-stage breast cancer patients (pts) with positive hormone-receptor (HR ) and 1 3 node-positive (N ) tumor: Results of the FASG 06 trial. Proc Am Soc Clin Oncol 2000;19:72a. 58 Thurliman B. Randomized controlled trial of ovarian function suppression plus tamoxifen versus the same endocrine therapy plus chemotherapy: Is chemotherapy necessary for premenopausal women with nodepositive, endocrine responsive breast cancer? First results of International Breast Cancer Study Group Trial Breast J 2001; 10(suppl 3): Fisher B, Redmond C, Legault-Poisson S et al. Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positivenode breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: Results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol 1990;8: Albain K, Barlow W, O Malley F et al. Concurrent (CAFT) versus sequential (CAF-T) chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for postmenopausal, node-positive, estrogen (ER) and/or progesterone (PgR) receptor-positive breast cancer: Mature outcomes and new biologic correlates on phase III intergroup trial 0100 (SWOG-8814). Abstract 37. Presented at the 2004 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 8 11, Wils JA, Bliss JM, Marty M et al. Epirubicin plus tamoxifen versus tamoxifen alone in node-positive postmenopausal patients with breast cancer: A randomized trial of the International Collaborative Cancer Group. J Clin Oncol 1999;17: Namer M, Fargeot P, Roché H et al. Improved disease-free survival with epirubicin-based chemoendocrine adjuvant therapy compared with tamoxifen alone in one to three node-positive, estrogen-receptor-positive, postmenopausal breast cancer patients: Results of French Adjuvant Study Group 02 and 07 trials. Ann Oncol 2006;17: Paik S, Tang G, Shak S et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 2006;24: Albain K, Barlow W, Shak S et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal, node-positive, ERpositive breast cancer. Presented at the 2007 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 13 16, 2007.

10 ERRATUM Anthracyclines in Early-Stage Breast Cancer: Is It the End of an Era? DANNY ROBSON,SUNIL VERMA The Oncologist 2009;14: ; doi: /theoncologist On page 955, data from the 2007 San Antonio Breast Cancer Symposium were misreported in the sixth sentence of the section entitled HER-2 Early Breast Cancer. Here we print the correct text. Seven-year data recently presented at the 2007 San Antonio Breast Cancer Symposium now reveal a significant OS benefit for the TC arm: an 88% (TC) versus 84% (AC) 6-year OS rate (p.045) [16].