SANDRA M. SWAIN. Washington Cancer Institute, Washington, District of Columbia, USA

The Oncologist Chemotherapy: Updates and New Perspectives SANDRA M. SWAIN Washington Cancer Institute, Washington, District of Columbia, USA Key Words. Breast cancer Chemotherapy Taxane Trastuzumab Ki-67 Tau proteins Disclosures: Sandra Swain: Research funding/contracted research: BMS, Genentech, sanofi-aventis to WHC Foundations; Other: Travel: 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 independent peer reviewers. ABSTRACT Treatment options for patients with breast cancer have progressively improved over the past 40 years, from an era of no chemotherapy to the introduction of taxanes, hormonal therapy, and biologic therapy. These advances have resulted in substantial, 15% 20% improvements in clinical outcomes. However, progress has yet to be made to improve the prognosis in many breast cancer patients, and research is currently under way to test new tools, or new applications of older tools, to advance breast cancer management. Chemotherapy clearly remains a cornerstone of adjuvant breast cancer treatment, because breast cancer can be very sensitive to the currently available agents. Meanwhile, the era of a one-size-fits-all approach to breast cancer management is over, and the maximum potential of chemotherapy should now be reached by targeting specific populations. Effective biomarkers are therefore needed to optimize chemotherapy, define more selective populations, and clearly tailor treatment. This paper discusses recent data, including new trials that are more fully incorporating current knowledge with respect to molecular markers and the underlying biology of breast cancer. The Oncologist 2011;16(suppl 1):30 39 INTRODUCTION Over the past 40 years, the therapeutic landscape for breast cancer has progressed from no chemotherapy and many recurrences, to doxorubicin and cyclophosphamide methotrexate fluorouracil (CMF) regimens, with a benefit of about 4%, and then in the 1980s to the anthracyclines, with a benefit of another 4%. The exciting era of the taxanes began in 2000, with about a 5% improvement, and then finally, the most recent breakthrough was using trastuzumab with probably the biggest benefit overall. In total, over the past 20 30 years, there has been a 15% 20% improvement in outcomes in patients with early breast cancer. Although these achievements are satisfying, unmet goals remain in improving outcomes, using both old and new tools. This paper discusses recent data, including new trials that are more fully incorporating current knowledge with respect to molecular markers and the underlying biology of breast cancer. THE POTENTIAL OF CHEMOTHERAPY TO IMPACT BREAST CANCER OUTCOMES Chemotherapy continues to improve outcomes and still plays a leading role in treatment, because breast cancer is very sensitive to the available agents. A recent meta-analy- Correspondence: Sandra M. Swain, M.D., Washington Cancer Institute, Washington Hospital Center, 110 Irving Street NW, Washington, District of Columbia 20010, USA. Telephone: 202-877-8112; Fax: 202-877-8113; e-mail: sandra.m.swain@medstar.net Reprinted from The Oncologist 2010;15(suppl 5):8 17. AlphaMed Press 1083-7159/2010/$30.00/0 doi: 10.1634/theoncologist.2011-S1-30 The Oncologist 2011;16(suppl 1):30 39 www.theoncologist.com

Swain 31 Table 1. Docetaxel meta-analysis: Trials Study Nodes No. Pts Regimen F/U (yr) GEICAM 9805 N0 1060 TAC vs FAC 5 ECOG 2197 N0/N 3 1893/989 AT vs AC 5 USO 9735 N0/N 487/529 TC vs AC 7 UK TACT N0/N 835/3327 FEC-T vs FEC/E-CMF 5 RAPP-01 N0/N 3 627 AT vs AC 5 FinHer N (89%) 1010 T-FEC vs V-FEC 5 BCIRG001 N 1491 TAC vs FAC 4.5 TAXIT 216 N 972 E-T-CMF vs E-CMF 5 PACS01 N 1999 FEC-T vs FEC 5 BIG2-98, TAX315 N 2887 A-T (AT)-CMF vs A(C)-CMF 5 WSG/AGO N 3 1837 EC-T vs FEC 5 HORG N 756 T-EC vs FEC 5 From Laporte S, Jones S, Chapelle C et al. Consistency of effect of docetaxel-containing adjuvant chemotherapy in patients with early stage breast cancer independent of nodal status: Meta-analysis of 12 randomized clinical trials abstract 605. Presented at the 2009 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 11, 2009, with permission. sis by Laporte et al. [1] included 20,000 patients with a follow-up of 5 years in most cases, and demonstrated a clear benefit in terms of disease-free survival (DFS) and overall survival (OS) when docetaxel was added to the chemotherapy regimen (Table 1) [1]. However, although there was a clear benefit in patients with node-positive disease, a clear benefit was not observed in node-negative disease (Fig. 1). Looking at other subgroups, patients who were younger, who were older, who had hormone receptor negative or hormone receptor positive disease, and who were human epidermal growth factor receptor (HER)-2 receptor negative or positive all benefited with the addition of a taxane [1]. The node-negative group was the only group that did not demonstrate a clear benefit, but that group represented only 4,000 patients, and there may have been too few events. In other meta-analyses, a benefit was demonstrated with taxanes, even in patients with node-negative disease (Fig. 2). The PACS-01 study should be mentioned, because many oncologists use the regimen that was investigated [2]. Eight-year follow-up data from the PACS-01 study were recently reported, comparing six cycles of fluorouracil epirubicin cyclophosphamide (FEC) with three cycles of FEC followed by docetaxel. After 8 years of follow-up, there was still a significant, approximately 4% absolute benefit in DFS [3] and also an approximately 5% benefit in OS [4]. With the availability of these data, oncologists now wonder whether the maximum potential of chemotherapy has been reached. Incremental benefits may still be achieved with new strategies that are currently under investigation, such as concurrent treatment versus sequential longer treatments, variations in the number of cycles of treatment, and the choice of agent. The Breast Cancer International Research Group (BCIRG) 005 trial compared four cycles of AC followed by four cycles of docetaxel with six cycles of docetaxel doxorubicin cyclophosphamide (TAC). The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-30 trial compared four cycles of AC followed by four cycles of docetaxel with four cycles of doxorubicin and docetaxel (AT) or four cycles of TAC. Findings from each study were presented back to back recently; the BCIRG 005 trial showed absolutely no difference between regimens, and the NSABP B30 trial showed a benefit in terms of both DFS and OS with AC chemotherapy followed by docetaxel, compared with the other two arms [4, 5]. Importantly, the NSABP B-30 trial showed that those patients who achieved amenorrhea, in a population of 2,500 premenopausal women, actually had a higher survival rate than those who did not achieve amenorrhea [5]. Grade 3 4 toxicities reported with each trial are presented in Table 2. In the BCIRG 005 study, the febrile neutropenia rate with six cycles of TAC without growth factors was almost 18%, so it was higher than with the four cycles of AC followed by four cycles of docetaxel (Table 2A). In the NSABP B30 trial, the neutropenia rate with four cycles of AC followed by docetaxel was 22%, 16% with four cycles of TAC; all arms were with growth factor support (Table 2B). Overall, a substantial number of patients continued to experience febrile neutropenia, despite the use of growth factors. Interestingly, there was a low incidence of heart failure, 1%, in both studies. The vast majority of patients www.theoncologist.com

32 Chemotherapy Updates and New Perspectives Figure 1. Docetaxel meta-analysis: DFS and OS according to nodal status. Abbreviations: CI, confidence interval; DFS, disease-free survival; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; OS, overall survival. From Laporte S, Jones S, Chapelle C et al. Consistency of effect of docetaxel-containing adjuvant chemotherapy in patients with early stage breast cancer independent of nodal status: Meta-analysis of 12 randomized clinical trials [abstract 605]. Presented at the 2009 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 11, 2009, with permission. enrolled in the BCIRG 005 trial, 91%, were able to complete all cycles, even those who received four cycles of the 100-mg/m 2 dose of docetaxel; in the NSABP B30 study, the rate of completion was 86% [4, 5]. Data from the Breast International Group 02 98 trial were also recently presented [6]. Eligible patients had operable, node-positive breast cancer. The study had a complicated design with four arms, including two control arms. Treatment arms included doxorubicin followed by CMF and AC followed by CMF, both of which were administered for seven cycles of treatment. Those regimens were compared with sequential treatment of doxorubicin, docetaxel, and CMF (nine cycles of treatment), versus AT followed by CMF. The updated results showed essentially that patients treated with the sequential AT regimen had the best outcome, but it was not a markedly greater benefit [6]. There were few meaningful differences in that study, but greater differences may result from combining and sequencing available regimens. Overall, the delivery schedule and number of cycles matter, and it is important to give at least six cycles of TAC, but it is likely that the ceiling has been reached for the maximum potential of chemotherapy in an unselected group of patients. Investigators are now interested in focusing on more specific, selected patient populations. CHEMOTHERAPY S POTENTIAL IN SELECTED SUBGROUPS What is the potential of chemotherapy in selected populations? It is important to first review the currently available data. Looking at age subgroups in the U.S. Oncology Trial comparing docetaxel plus cyclophosphamide with AC, for example, women who were older and had estrogen receptor (ER) tumors benefited from chemotherapy [7]. The message here is that if chemotherapy is needed, age should not matter. The forest plot from that trial confirms these findings regarding age [8] (Fig. 3). However, despite these findings, many oncologists are still reluctant to include older patients in clinical trials. The Cancer and Leukemia Group B (CALGB) conducted the important 49907 trial looking at this question of age, with the aim of demonstrating the noninferiority of capecitabine to standard chemotherapy regimens with CMF or AC in older women. The trial was actually terminated prematurely. The relapse-free survival rate with capecitab-

Swain 33 Figure 2. Docetaxel meta-analysis: DFS by subgroup. Abbreviations: CI, confidence interval; DFS, disease-free survival; ECOG, Eastern Cooperative Oncology Group; HER, human epidermal growth factor receptor; HR, hazard ratio; HR, hormone receptor. From Laporte S, Jones S, Chapelle C et al. Consistency of effect of docetaxel-containing adjuvant chemotherapy in patients with early stage breast cancer independent of nodal status: Meta-analysis of 12 randomized clinical trials [abstract 605]. Presented at the 2009 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 11, 2009, with permission. Table 2. Safety: Grade 3 4 toxicity (A): BCIRG 005 Patients (%) Toxicity 6TAC, n 1635 4AC34T, n 1649 p value Febrile neutropenia 17.9 8.3.0001 Neutropenic infection 9.7 8.5 0.25 Diarrhea 2.9 3.1 0.76 CHF 0.1 0.4 0.06 Completion of cycles 94 91 - (B): NSABP B-30 Patients (%) Toxicity 4AC34T (1749) 4AT (1750) 4TAC (1749) p value Febrile neutropenia 22 13 16 0.0001 Infection 8 6 6 0.0036 Diarrhea 5 4 6 0.0012 Cardiotoxicity (ventricular function) 1 1 1 0.89 Completion of cycles AC: 99 T: 86 97 97 - (A): From Eiermann W, Pienkowski T, Crown J et al. BCIRG 005 main efficacy analysis: A phase III randomized trial comparing docetaxel in combination with doxorubicin and cyclophosphamide (TAC) versus doxorubicin and cyclophosphamide followed by docetaxel (AC3T) in women with Her-2/neu negative axillary lymph node-positive early breast cancer [abstract 77]. Presented at the 2008 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 2008. (B): From Swain SM, Jeong JH, Geyer CE Jr et al. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med 2010;362:2053 2065. Copyright 2010 Massachusetts Medical Society. All rights reserved. www.theoncologist.com

34 Chemotherapy Updates and New Perspectives Figure 3. U.S. Oncology Trial 9735: DFS by subgroup. Abbreviations: A, doxorubicin; C, cyclophosphamide; CI, confidence interval; DFS, disease-free survival; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; PR, progesterone receptor; T, docetaxel. From Jones S, Holmes FA, O Shaughnessy J et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research Trial 9735. J Clin Oncol 2009;27:1177 1183. Reprinted with permission 2009 American Society of Clinical Oncology. All rights reserved. ine was worse than that with standard chemotherapy, and the same was true for OS [9]. The message from these and other studies is that, if chemotherapy is needed, age should not matter in fit women. Older patients should get what is considered the standard chemotherapy, and not less chemotherapy, because they do benefit from the best chemotherapy available. IMPORTANT OUTSTANDING QUESTIONS IN HER-2 DISEASE Considering the subpopulation of HER-2 patients, there are really at least three key questions that need to be addressed: the optimal agent or regimen, whether agents should be given concurrently or sequentially, and the duration of treatment or number of cycles. There are many trials that have looked at adjuvant trastuzumab, as summarized in Table 3. The Herceptin Adjuvant (HERA) trial investigated a sequential regimen of trastuzumab after chemotherapy, and the NSABP B-31 and North Central Cancer Treatment Group (NCCTG) 9831 trials studied trastuzumab with or without concurrent paclitaxel. The NCCTG 9831 trial also included another sequential arm, discussed below. The BCIRG 006 trial used a nonanthracycline regimen with docetaxel carboplatin trastuzumab (TCH), and the Finnish Herceptin (FinHer) trial used a shorter regimen. It is valuable to have this range of different trials that looked at different ways of administering trastuzumab, because this provides clinicians with many important therapeutic answers. The third analysis from the BCIRG study was presented by Slamon and colleagues in 2009 [10]. The DFS analysis revealed that there was a benefit when compared with no trastuzumab, both with TCH and with the anthracycline docetaxel plus carboplatin trastuzumab (AC-TH) regimen, but there was an absolute difference of about 3% at 5 years Table 3. BCIRG 006: Cardiotoxicity N 3222 AC-T AC-TH TCbH Cardiac-related death, n 0 0 0 CHF Grade 3 4, n 7 21 4 p-value (AC-TH vs TCbH).001 10% relative LVEF decline, % 11 19 9 p-value (AC-TH vs TCbH).001 From Slamon D, Eiermann W, Robert N et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide fol- lowed 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: BCIRG 006 study abstract 62. Presented at the 2009 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 12, 2009. between the TCH and the AC-TH regimens. Although the groups should not be directly compared from a statistical standpoint, the DFS rate was numerically less for the TCH group. The same held true for OS, with about a 1% difference between the two groups [10]. In terms of drug toxicity, there were clearly more heart failure events in the AC-TH arm 21 events, versus four events in the TCH arm. This difference was very significant, with a significant difference in the decline in ejection fraction as well, 19%, versus 9% with TCH. There were also several leukemia cases in the two anthracycline-containing arms [10] (Table 3). Overall, the risk benefit analysis suggested that there is a benefit from TCH when heart failure and leukemia events are taken into consideration. Based on these findings, clinicians may want to discuss with their patients the potential benefit of AC-TH over TCH in terms of known drug toxicities.

Swain 35 Figure 4. Topo IIa may represent biomarker for anthracycline activity: Disease-free survival by arm, coamplified (A) and noncoamplified (B) for Topo IIa. Abbreviations: CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; Topo IIa, topoisomerase IIa. Based on Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659 1672. Copyright 2005 Massachusetts Medical Society. All rights reserved. The BCIRG investigators also presented data on the biomarker topoisomerase (Topo)-IIa in the trial; DFS was similar in patients who were coamplified and noncoamplified for Topo-IIa, as shown in Figure 4. Although there was no significant difference in DFS among the three treatment groups coamplified for Topo-IIa, the data suggest that, in this group of patients, an anthracycline might be adequate without the addition of trastuzumab. Patients who were noncoamplified or amplified for HER-2 but not Topo-IIa did need to have trastuzumab to gain a benefit [11] (Fig. 4). Although this study represented approximately 3,000 patients, more data are needed before treatment decisions could be dictated by Topo-IIa status, and most clinicians are understandably uncomfortable administering an anthracycline alone when trastuzumab is available. Another important question is the decision to administer concurrent versus sequential chemotherapy. Many oncologists use sequential treatment, as in the HERA study. In this setting, it is important to address recently updated data, as well as NCCTG 9831 data comparing AC followed by weekly paclitaxel with sequential versus concurrent trastuzumab. A 4-year update of the HERA study was presented by Gianni and colleagues in 2009, and still shows a very significant difference in DFS with the use of sequential trastuzumab, with the survival benefit being slightly diminished [11 13] (Fig. 5). The 2-year trastuzumab HERA data have not yet been presented. At the time the combined data were presented, the investigators reported findings from many patients that had crossed over to receive trastuzumab, and the analysis that was presented was looking at those patients who crossed over versus those who did not. This crossover of treatment could have occurred a substantial period of time after the patient had received chemotherapy. In this exploratory analysis, there was a benefit to using trastuzumab in the crossover period [14]. The Tykerb Evaluation After Chemotherapy trial investigated lapatinib, a dual tyrosine kinase inhibitor, after chemotherapy in patients who did not receive trastuzumab. The trial has been completed but the data have not yet been reported. Another study investigated the use of neratinib, another tyrosine kinase inhibitor, for HER-2 patients after adjuvant trastuzumab. These trials illustrate the outstanding questions that are being asked regarding maintenance HER- 2 targeted therapy. Perez et al. [15] presented a data update from the NCCTG 9831 trial comparing the safety and efficacy of the addition of trastuzumab to AC chemotherapy and paclitaxel. AC chemotherapy was administered first, followed by trastuzumab, either following or administered concurrently with paclitaxel. At 5 years, the DFS rate was higher, 84% versus 80%, when trastuzumab was administered concurrently with paclitaxel [15]. Importantly, additional data need to be presented, including the HERA 2-year data, before an absolute conclusion can be made. However, based on the synergy demonstrated so far with chemotherapy, many clinicians, particularly in the U.S., would prefer to use concurrent trastuzumab therapy. What about the duration of treatment? The FinHer study looked at docetaxel plus FEC or vinorelbine plus FEC and they actually gave the trastuzumab with the taxane first, for www.theoncologist.com

36 Chemotherapy Updates and New Perspectives Figure 5. HERA: Disease-free survival and overall survival over time. Abbreviations: DFS, disease-free survival; HERA, Herceptin Adjuvant; H, trastuzumab; HR, hazard ratio; OS, overall survival. Based on Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659 1672; copyright 2005 Massachusetts Medical Society; all rights reserved; and Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007;369:29 36. Reprinted from The Lancet, Copyright 2007, with permission from Elsevier; and Gianni L et al. St Gallen 2009; Abstract S25. Table 4. FinHer: Adjuvant chemotherapy plus short trastuzumab; updated (5-year) results in HER-2 patients Chemo Chemo trastuzumab HR (95% CI) p-value Distant disease-free survival, % 73.0 83.3 0.65 (0.38, 1.12) 0.12 Overall survival, % 82.3 91.3 0.55 (0.27, 1.11) 0.094 Based on Joensuu H, Bono P, Kataja V et al. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatment of breast cancer: Final results of the FinHer Trial. J Clin Oncol 2009;27:5685 5692. only 9 weeks. The HERA trial, as discussed, was for 1 year versus 2 years, and the NSABP and NCCTG 9831 trial designs were for 1 year of treatment in both study arms. In the 5-year update of the FinHer study, both the distant DFS and OS rates were no longer significant, compared with the initially published data [16] (Table 4). A caveat to this study is that it was a very small study, with only approximately 200 patients. The trial was very underpowered, and most likely there was still a benefit that was too small to detect. Fortunately, there are many ongoing trials looking at this question to address the ideal duration of adjuvant trastuzumab therapy. The Short-HER study (Italy) is looking at 1 year versus 9 weeks; the SOLD study (Finland) is also comparing 1 year versus 9 weeks; and three studies, including the Hellenic Group (Greece), PHARE (France), and PERSEPHONE (U.K.), are all looking at 1 year versus 6 months [18] (Table 5). With data from these trials, plus the HERA 1-year versus 2-year data, there will be more information forthcoming to help determine how long trastuzumab should be continued. To summarize, in HER-2 disease, it is critical to identify the optimal chemotherapy partner, to answer the question of whether concurrent or sequential therapy is ideal, and to define the best duration of treatment. With the subgroup definition of HER-2 status, investigators found many more pronounced differences, and clinicians were excited because the survival curves actually separated more than had ever been seen in other clinical trials. OTHER IMPORTANT THERAPEUTIC SUBTYPES Additional breast cancer subtypes have been identified as therapeutically important. Berry et al. [19] recently looked at HER-2 and ER status in the group of patients enrolled in the CALGB 8541 trial. In patients with ER HER-2 tumors, it did not matter if they received low-dose or high-dose cyclophosphamide doxorubicin fluorouracil, suggesting that chemotherapy really may not be important for this group overall [19]. Likewise, an analysis of data from the CALGB 9344 trial found that AC, with or without sequential paclitaxel, resulted in similar outcomes in patients with HER-2 ER disease

Swain 37 Table 5. Ongoing trials assessing adjuvant trastuzumab duration Short-HER (Italy) AC or EC 4 3 taxane 4 trastuzumab 1 year versus Docetaxel 3 trastuzumab 9 weeks 3 FEC 3 SOLD (Finland) Docetaxel -FE 75 C with trastuzumab 1 year versus Docetaxel -FE 75 C with trastuzumab 9 weeks Hellenic Group (Greece) FEC 4 3 docetaxel 4 trastuzumab 1 year versus FEC 4 3 docetaxel 4 trastuzumab 6 months PHARE (France) Chemotherapy 4 cycles trastuzumab 1 year versus Chemotherapy 4 cycles trastuzumab 6 months PERSEPHONE (UK) Chemotherapy trastuzumab 1 year versus Chemotherapy trastuzumab 6 months From www.clinicaltrials.gov; and Guarneri V, Frassoldati A, Bruzzi P et al. Multicentric, randomized phase III trial of two different adjuvant chemotherapy regimens plus three versus twelve months of trastuzumab in patients with HER-2-positive breast cancer (Short-HER Trial; NCT00629278). Clin Breast Cancer 2008;8:453 456. A pakt-negative, ER-Positive 100 Adjusted DFS (%) 20 20 HR 1.06; P = 0.64 HR 0.82; P = 0.24 0 0 0 2 4 6 8 10 0 2 4 6 8 10 Years from Randomization Years from Randomization C pakt-negative, ER-Negative D pakt-positive, ER-Negative 100 100 Adjusted DFS (%) 80 60 40 80 60 40 With Paclitaxel Without Paclitaxel With Paclitaxel Without Paclitaxel 20 HR 1.04; P = 0.79 0 0 2 4 6 8 10 Years from Randomization Adjusted DFS (%) B pakt-positive, ER-Positive 100 Adjusted DFS (%) 80 60 40 80 60 40 With Paclitaxel Without Paclitaxel With Paclitaxel Without Paclitaxel 20 HR 0.88; P = 0.052 0 0 2 4 6 8 10 Years from Randomization Figure 6. Taxanes and Akt phosphorylation in B-28. Abbreviations: AC, doxorubicin plus cyclophosphamide; BC, breast cancer; DFS, disease-free survival; ER, estrogen receptor; HR, hazard ratio. From Yang SX, Costantino JP, Kim C et al. Akt phosphorylation at Ser473 predicts benefit of paclitaxel chemotherapy in node-positive breast cancer. J Clin Oncol 2010;28:2974 2981, with permission. [20]. The CALGB 9344 investigators also used tissue microarrays and immunohistochemistry to demonstrate that there was no benefit to paclitaxel for patients with HER-2 ER disease [19]. Meanwhile, data from the BCIRG 001 study, comparing TAC with FAC, reported that patients with HER-2 disease and either low expression of Ki-67 or an ER status did not benefit from the addition of docetaxel chemotherapy. These subtypes are similar to luminal A type tumors. Other subtypes of patients, including those with HER-2 ER disease, HER-2 ER disease, high Ki-67, or highly proliferative lesions (luminal B type tumors), all seemed to benefit from the addition of a taxane [21]. These findings are similar to those reported in the trials discussed earlier, and suggest that further definition according to both HER-2 and hormone receptor status does identify what appears to be a lack of efficacy in the HER-2 ER subset of patients treated with chemother- www.theoncologist.com

38 Chemotherapy Updates and New Perspectives apy, taxane chemotherapy, or even anthracycline chemotherapy. However, these were all retrospective substudy analyses. The EBCTCG overview, which incorporates thousands of data points, does show a benefit of chemotherapy in ER tumors. OTHER BIOMARKERS AND RESPONSE TO THERAPY Biomarkers are now being investigated as tools to predict therapeutic response. Investigators from the PACS-01 study, comparing FEC followed by three cycles of docetaxel with six cycles of FEC, evaluated Ki-67 status. They found that patients with the highest rate of DFS were those with a high Ki-67 expression level receiving three cycles of FEC followed by three cycles of docetaxel (arm B). There was a definite difference in DFS between arm B and arm A for patients who were ER and had a high Ki-67 expression level but did not receive docetaxel [22]. This suggests that Ki-67 can help further differentiate ER patients, in that patients with highly proliferative ER lesions, like luminal B type tumors, seem to benefit from the addition of docetaxel. The other biomarker that has been investigated in at least three studies is Tau expression. In the U.K. TACT trial, there was no interaction between docetaxel and Tau expression [23]. One study by Tanaka et al. [24] did find that Tau levels could predict a lack of paclitaxel efficacy in metastatic breast cancer patients, which has been the leading hypothesis. Meanwhile, in an analysis of data from the NSABP B28 trial, comparing chemotherapy with or without paclitaxel, there was no interaction between taxane response and Tau expression [25]. Consequently, Tau does REFERENCES 1 Laporte S, Jones S, Chapelle C et al. Consistency of effect of docetaxelcontaining adjuvant chemotherapy in patients with early stage breast cancer independent of nodal status: Meta-analysis of 12 randomized clinical trials [abstract 605]. Presented at the 2009 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 11, 2009. 2 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;24:5664 5671. 3 Coudert B, et al. Benefit of the sequential administration of docetaxel after standard FEC regimen for node-positive breast cancer: Long-term follow-up results of the FNCLCC-PACS 01 trial [abstract 603]. Presented at the 2009 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 11, 2009. 4 Eiermann W, Pienkowski T, Crown J et al. BCIRG 005 main efficacy analysis: A phase III randomized trial comparing docetaxel in combination with doxorubicin and cyclophosphamide (TAC) versus doxorubicin and cyclophosphamide followed by docetaxel (AC3T) in women with Her-2/neu negative axillary lymph node-positive early breast cancer [abstract 77]. not appear to be a useful marker to predict resistance to taxane therapy. Another analysis by my group of the B28 study looked at Akt phosphorylation, finding that patients with tumors that were Akt ER did have a benefit with taxane therapy whereas those whose tumors were phosphorylated Akt did not [26] (Fig. 6). This research represents just some of the ways in which the community is working to further differentiate these groups of patients. Biomarkers are needed to better define populations who will benefit the most from a given therapy. It is now critical to characterize the right treatment for the right patient at the right time, and this really concerns all therapies, including chemotherapy, hormonal therapy, and biologic therapy. Based on available data, Ki-67 is predictive for docetaxel efficacy in ER disease, Tau is probably not, and activated Akt, which is downstream to many of these receptors, may predict taxane sensitivity in ER disease. CONCLUSIONS Chemotherapy clearly remains a critical component of adjuvant breast cancer treatment and will always be in use because breast cancer is very sensitive to the available agents. Meanwhile, the era of a one-size-fits-all approach to breast cancer management is over, and the maximum potential of chemotherapy should now be reached by targeting specific populations, as demonstrated with the trastuzumab story. Effective biomarkers are now needed to optimize chemotherapy, define more selective populations, and clearly tailor treatment. 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Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-Year follow-up of US Oncology research trial 9735. J Clin Oncol 2009;27:1177 1183. 9 Muss HB, Berry DA, Cirrincione CT et al. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 2009;360:2055 2065.

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