- Email: [email protected]
The European Experience with Docetaxel in the Treatment of Early-Stage Breast Cancer
The European Experience with Docetaxel in the Treatment of Early-Stage Breast Cancer Angelo Di Leo Abstract This article summarizes the European experience with docetaxel in the adjuvant treatment of breast cancer patients. Four categories of trials evaluating the role of docetaxel are discussed: (1) 2-arm trial in which an anthracycline-based regimen administered for 6-8 cycles is compared to 3-4 cycles of the same regimen followed by full doses of 3-4 cycles of docetaxel; (2) 2-arm trial in which anthracycline-based polychemotherapy is compared to an anthracycline/docetaxel–based regimen; (3) 4-arm trial in which 2 different concepts are under evaluation: the role of docetaxel and the comparison between different anthracycline/docetaxel–based regimens, in which the 2 drugs are administered either in combination or sequentially; (4) translational research prospective trials aiming to identify a specific subgroup of patients deriving the largest benefit from the use of docetaxel. While it is expected that these trials will show the superiority of the docetaxelbased treatment, it is also anticipated that the benefit related to the use of docetaxel will not be of the same magnitude in all patients. For this reason, it will be extremely important to identify subgroups of patients deriving the highest benefit from the use of docetaxel. In the past few years, substantial progress has been made in the area of molecular biology, and several molecular markers that could predict the efficacy of docetaxel have been identified. The p53 gene mutations seem to be the most promising predictive markers because preclinical data suggest that taxane-induced apoptosis is p53 independent. Other molecular markers of potential interest are the microtubule-associated parameters, which might confer different degrees of sensitivity to a docetaxel-based therapy, depending on the pattern of expression. Clinical Breast Cancer, Vol. 3, Suppl. 2, S59-S62, October 2002 Key words: 5-fluorouracil, Doxorubicin, Anthracylines, Taxanes, Cyclophosphamide, Polychemotherapy, Sequential therapy, p53 gene
The European Trials The efficacy of docetaxel in the treatment of metastatic breast cancer has been proven in first- and second-line therapy and has prompted several cooperative groups to conduct adjuvant trials evaluating the activity of docetaxel.1-4 These trials started on both sides of the Atlantic about 5 years ago and had a very efficient accrual. Preliminary efficacy results should be available in 2002 and could have an impact on our current clinical practice. In Europe, adjuvant trials evaluating docetaxel can be grouped into 4 distinct categories according to their study designs: (1) trials evaluating the efficacy of docetaxel administered sequentially after anthracyclines, (2) trials comparing anthracycline-based polychemotherapy to anthracycline/docetaxel–based polychemotherapy, (3) trials examining the role of docetaxel and comparing anthracycline/docetaxel regimens administered either in combination or seJules Bordet Institute, Brussels-Belgium Submitted: Mar. 1, 2002; Revised: Sep. 19, 2002; Accepted: Sep. 23, 2002 Address for correspondence: Angelo Di Leo, MD, Jules Bordet Institute, Rue Heger-Bordet 1, 1000 Brussels, Belgium Fax: 32-2-541-3090; e-mail: [email protected]
quentially, and (4) translational research trials aimed at identifying a specific subgroup of patients who derive significant benefit from docetaxel-based therapy.
Trials Evaluating Docetaxel Administered Sequentially After Anthracyclines Several 2-arm trials have evaluated an anthracyclinebased regimen administered for 6-8 cycles compared to the same regimen (3-4 cycles) followed by full doses of docetaxel for 3-4 cycles (Table 1). The French study probably will be the first of these trials to produce results. This study has recruited 2000 node-positive breast cancer patients; preliminary efficacy results should be available in the last quarter of 2002. In the French study, 6 cycles of FEC (5-fluorouracil/epirubicin/cyclophosphamide) 100, a standard adjuvant therapy for node-positive breast cancer patients in most European countries, were compared with 3 cycles of the same regimen followed by 3 courses of docetaxel (100 mg/m2 every 3 weeks). In this trial, an absolute increase of 7.5% in the 5-year diseasefree survival (DFS) is expected from the use of docetaxel. The magnitude of the effect is comparable to the benefit hypothesized in most adjuvant trials evaluating the efficacy of doc-
Clinical Breast Cancer Supplement October 2002 • S59
Docetaxel in the Treatment of Breast Cancer Sequential Versus Concomitant Administration of Anthracycline/Docetaxel–Based Regimens
Table 1 European Adjuvant Trials with or Without Docetaxel Group French (n = 2000) ICCG (n = 800) Italian (n = ± 1000)
TACT (n = 3340)
Design
Status
FEC 100 for 6 cycles FEC 100 for 3 cycles → Docetaxel for 3 cycles Epirubicin for 8 cycles Epirubicin for 4 cycles → Docetaxel for 4 cycles
Closed to accrual
Ongoing
Epirubicin 120 for 4 cycles → CMF for 4 cycles Ongoing
Epirubicin 120 for 4 cycles → Docetaxel for 4 cycles → CMF for 4 cycles FEC 60 for 8 cycles FEC 60 for 4 cycles → Docetaxel for 4 cycles
Ongoing
Abbreviation: CMF = cyclophosphamide/methotrexte/5-fluorouracil; FEC = 5-fluorouracil/ epirubicin/cyclophosphamide; ICCG = International Cancer Cooperative Group; TACT = Taxotere as Adjuvant Chemotherapy
etaxel. Noteworthy, the United Kingdom Taxotere as Adjuvant Chemotherapy (TACT) trial will be the largest study (> 3000 patients) in this specific group of clinical trials.
Anthracycline-Based Polychemotherapy Versus Anthracycline/Docetaxel–Based Polychemotherapy This study class contains 2-arm trials in which anthracycline-based polychemotherapy (FAC [5-fluorouracil/doxorubicin/cyclophosphamide]) is compared to an anthracycline/docetaxel–based polychemotherapy (TAC [docetaxel/doxorubicin/cyclophosphamide]). The Spanish study by the Grupo Español de Investigación en Cáncer de Mama group offers a good example in this particular context. In this trial, 6 cycles of FAC will be compared to 6 cycles of TAC; interestingly, the study will be addressed to patients with node-negative breast cancer. The planned sample size is about 1000 patients, and as of February 2002, almost 800 patients have been randomized.
A 4-arm trial is evaluating 2 different concepts: the role of docetaxel and the comparison between different anthracycline/docetaxel–based regimens in which the two drugs are administered either in combination or sequentially. The Breast International Group (BIG) 02-98 study is the only representative of this specific group of trials, although it is not a fully European study because groups and centers located in Australia, New Zealand, South Africa, South America, and the Middle East have largely contributed to the accrual. The study design is reported in Table 2. The primary endpoint of this study is to evaluate the role of docetaxel regardless of its mode of administration (arms A1 and A2 vs. arms B and C). With 1820 patients in the experimental groups (arms B and C) and 910 patients in the control groups (arms A1 and A2), using a significance level of 0.05, this study will have a power of about 99% to detect a DFS absolute increase of 8.3% at 5 years. The comparison between the 2 different docetaxel-based regimens (sequential vs. polychemotherapy) evaluates whether both treatments are equivalent in terms of DFS. This means that the 2-sided 95% confidence interval of the hazard ratio should be between 0.80 and 1.25. With 910 patients in each arm, using a significance level of 0.05, this comparison will have a power of 86% to meet this equivalence. Interestingly, the same cumulative doses of docetaxel and very similar cumulative doses of doxorubicin will be administered in the 2 study arms, while a relevant increase in the dose intensity of both drugs is expected with the sequential approach, which also has a longer duration (6 weeks more; Table 2). The accrual of this study was completed in June 2001, and the first interim analysis is planned for the first quarter of 2003 (405 observed events).
Translational Medicine Trials Recent translational research trials have aimed to identify a specific subgroup of patients deriving a large benefit
Table 2 The BIG 02-98 Trial: Sequential Versus Polychemotherapy Arm A1: Doxorubicin every 3 weeks for 4 cycles → CMF for 3 cycles
Versus
Arm B: Doxorubicin every 3 weeks for 4 cycles → Docetaxel every 3 weeks for 3 cycles → CMF for 3 cycles Arm C: Doxorubicin/Docetaxel every 3 weeks for 4 cycles → CMF for 3 cycles
Arm A2: AC every 3 weeks for 4 cycles → CMF for 3 cycles
Planned Dose-Intensity and Cumulative Doses Dose Intensity (mg/m2/week)
Arm B: Doxorubicin → Docetaxel Arm C: Doxorubicin/Docetaxel
Increase in Dose Intensity
Cumulative Doses (mg/m2)
Doxorubicin
Docetaxel
Doxorubicin
Docetaxel
Doxorubicin
Docetaxel
25
33.3
51%
33.2%
225
300
16.6
25
–
–
200
300
Abbreviations: AC = doxorubicin/cyclophosphamide; BIG = Breast International Group; CMF = cyclophosphamide/methotrexate/5-fluorouracil
S60 • Clinical Breast Cancer Supplement October 2002
Angelo Di Leo ties could exist in testing this concept in the ongoing adjuvant trials. Indeed, in all of these trials, frozen tumor samples will be R A available only for a minority of patients; acLocal ± Tamoxifen FEC 100 or Canadian FEC N Eligibility Criteria: therapy cordingly, p53 gene sequencing, which is D Large operable better performed on frozen samples, will O tumors M not be feasible in most of the cases. MoreLocal ± Tamoxifen Docetaxel for 3 cycles → I therapy Epirubicin/Docetaxel for 3 cycles over, it is well known that immunohistoZ chemistry (IHC), although feasible on fixed E tumor samples, does not represent a relip53 Analysis Sample 1: Standard fixation able method to evaluate p53 mutations beIncisional biopsy (functional Sample 2: Snap frozen cause of its poor sensitivity and specificity.9 assay) HER2 and estrogen receptor alpha (ERα) Target accrual = 1308 (872 p53 negative, 436 p53 positive) could represent valid surrogate markers for Hypothesis: DFS at 3 years by 5% in p53 negative patients and by 20% in p53 positive patients p53 status. Indeed, it has been reported that while a direct correlation exists between p53 Abbreviations: BIG = Breast International Group; DFS = disease-free survival; EORTC = European Organization mutations and HER2 gene amplifications, for Research and Treatment of Cancer; FEC = 5-fluorouracil/epirubicin/cyclophosphamide an inverse correlation generally is found between p53 mutations and ERα expression.10 from the use of docetaxel-based therapy. The BIG 01-00/EuSome data correlating taxane efficacy with HER2 or ERα ropean Organization for Research and Treatment of Cancer status have been reported.11,12 In a German trial comparing (EORTC) 10994 trial belongs to this group of studies. This EC (epirubicin/cyclophosphamide) with ET (epirubicin/paclitrial, which began in the second half of 2001, aims to test a taxel) in metastatic breast cancer patients, the ET regimen biological hypothesis in the clinical setting: the advantage of seems to be more effective than EC in HER2-amplified tua taxane-based therapy over an anthracycline-based regimen mors, while the 2 regimens have similar efficacy in HER2would be confined to the subgroup of patients with p53-munonamplified tumors.11 5-7 tated tumors. This hypothesis is supported by in vitro data. Moreover, a subgroup analysis of the Cancer and In this study, patients with large operable tumors are ranLeukemia Group B 9344 trial, which compares 4 cycles of domly treated either with an anthracycline-based therapy doxorubicin/cyclophosphamide with the same regimen folfor 6 cycles or with 3 courses of docetaxel (100 mg/m2 every lowed by 4 cycles of paclitaxel in the adjuvant setting, has 3 weeks) followed by 3 cycles of docetaxel/epirubicin (Figure suggested that paclitaxel’s benefit would be confined to the 1). Local treatment is provided after neoadjuvant therapy, subgroup of patients with ERα-negative tumors.12 Although and tamoxifen is administered after local treatment in the some hints support the value of both HER2 and ERα in precase of endocrine-responsive tumors. A pretreatment biopsy dicting the efficacy of a taxane-based regimen, current data is performed, and 1 frozen sample is used to evaluate the p53 are not conclusive to recommend the predictive use of these status through a functional assay.8 2 biological markers in current clinical practice. This trial, which will enroll 1300 patients, aims to demonMicrotubule-associated parameters (MTAPs) like α-tubustrate that in p53-mutated tumors, the docetaxel-based regilin and β-tubulin units, β-tubulin isotypes (class II, III, and men will increase the DFS by 20% at 3 years, while in p53 wild-type tumors, the efficacy of the 2 evaluated regimens Figure 2 Translational Research in Taxane-Based Trials: will be almost equivalent. This trial represents a considerable Which Markers Are Predictive? step forward in the context of clinical trials because it The TAX 303 Trial prospectively tests a biological hypothesis; moreover, this trial could demonstrate that treatment tailoring according to Doxorubicin Eligibility Criteria: 75 mg/m2 every 3 weeks tumor biological profile is a feasible approach. Relevant efMetastatic forts are done worldwide to identify molecular markers that disease could predict the efficacy of taxanes in breast cancer patients.
Figure 1 The BIG 01-00/EORTC 10994 Trial
(n = 326)
Do We Have Molecular Markers for Predicting the Efficacy of Taxanes? The evaluation of p53 status could have predictive value. Indeed, different in vitro experiments have shown that while the efficacy of taxanes is not compromised, the activity of anthracyclines is drastically reduced in the case of p53 gene mutations.5-7 While the BIG 01-00/EORTC 10994 trial will attempt to demonstrate this hypothesis, substantial difficul-
Docetaxel 100 mg/m2 every 3 weeks
Archival samples collected for 54% (n = 176) Markers Under Evaluation
HER-2, ERα (p53 Surrogates?) Topoisomerase IIα Microtubule-associated parameters
Abbreviation: ERα = estrogen receptor alpha
Clinical Breast Cancer Supplement October 2002 • S61
Docetaxel in the Treatment of Breast Cancer IV), and some microtubule-associated proteins like the Tau protein, are molecular markers that could predict the efficacy of docetaxel. MTAPs are involved in the process of microtubule stabilization, and it has been hypothesized that the expression of a certain MTAP pattern could cause hyperstabilization, while the expression of another pattern could be responsible for hypostabilization. It is known that docetaxel has a stabilizing effect on microtubules, and accordingly, an interesting hypothesis is that the efficacy of this drug could be modulated by the MTAP expression pattern.13 It has been reported in animal models that the poor expression of the Tau protein, which has a stabilizing effect on microtubules, could be associated with resistance to docetaxel.14 We have performed preliminary clinical experiences evaluating MTAPs as predictive markers.15 In a series of 41 advanced breast cancer patients treated with docetaxel, an inverse correlation seems to exist between the level of expression of the class II β-tubulin isotype evaluated by IHC on primary tumor samples and docetaxel activity (if immunostaining in ≤ 50% of cells, response rate 79%; if immunostaining in > 50% of cells, response rate 39%; P = 0.04).15 To test the predictive value of MTAPs in the context of a randomized trial, our group has recently gathered primary tumor samples from 54% of 326 patients entered in a phase III trial comparing single-agent doxorubicin to single-agent docetaxel as first- and second-line treatment in metastatic breast cancer patients. A panel of biological markers, including MTAPs, is under evaluation in the attempt to identify predictive factors (Figure 2). Interestingly in this study, topoisomerase IIα will be evaluated. This molecular marker is the target of anthracyclines, and topoisomerase IIα gene aberrations (mainly gene amplifications) are found in primary breast cancer samples in about one third of HER2-amplified tumors.16 In the same study, no topoisomerase IIα gene aberrations have been observed in HER2-nonamplified breast cancer.16 Moreover, a preclinical study suggests that the efficacy of anthracyclines is significantly increased in topoisomerase IIα gene-amplified tumors.17 Thus, it could be hypothesized that in HER2amplified and topoisomerase IIα–nonamplified tumors, docetaxel will be more effective than doxorubicin, while in HER2-amplified and topoisomerase IIα–amplified tumors, doxorubicin will be at least as effective as docetaxel. The ongoing study (Figure 2), in which both HER2 and topoisomerase IIα will be evaluated could shed some light on this provocative hypothesis.
Conclusion The European experience with docetaxel in the adjuvant therapy of breast cancer is still ongoing, and preliminary efficacy results from randomized trials (BIG 02-98 and the French study) should be available in the last quarter of 2002. In the meantime, an increasing effort is ongoing to identify molecular markers that could predict the efficacy of doc-
S62 • Clinical Breast Cancer Supplement October 2002
etaxel in breast cancer patients. This approach could identify a specific subgroup of early-stage breast cancer patients who gain the highest benefit from a docetaxel-based adjuvant therapy. It is critical to gather frozen tumor samples from patients entered into clinical trials to allow for the use of the most updated technology like gene microarrays; the latter could identify genetic profiles associated with increased or poor sensitivity to commonly used adjuvant regimens.
References 01. Nabholtz JM, Senn HJ, Bezwoda WR, et al. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. The 304 Study Group. J Clin Oncol 1999; 17:1413-1424. 02. Chan S, Friedrichs K, Noel D, et al. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. The 303 Study Group. J Clin Oncol 1999; 17:2341-2354. 03. Nabholtz J, Falkson G, Campos D, et al. A phase III trial comparing doxorubicin (A) and docetaxel (T) (AT) to doxorubicin and cyclophosphamide (AC) as first line chemotherapy for MBC. Proc Am Soc Clin Oncol 1999; 18:127a (Abstract #485). 04. Nabholtz JM, Paterson A, Dirix L, et al. A phase III randomized trial comparing docetaxel (T), doxorubicin (A) and cyclophosphamide (C) (TAC) to FAC as first line chemotherapy (CT) for patients (Pts) with metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 2001; 20:22a (Abstract #83). 05. Aas T, Borresen AL, Geisler S, et al. Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med 1996; 2:811-814. 06. Fan S, Cherney B, Reinhold W, et al. Disruption of p53 function in immortalized human cells does not affect survival or apoptosis after taxol or vincristine treatment. Clin Cancer Res 1998; 4:1047-1054. 07. Lanni JS, Lowe SW, Licitra EJ, et al. p53 independent apoptosis induced by paclitaxel through an indirect mechanism. Proc Natl Acad Sci U S A 1997; 94:9679-9683. 08. Ishioka C, Frebourg T, Yan YX, et al. Screening patients for heterozygous p53 mutations using a functional assay in yeast. Nat Genet 1993; 5:124-129. 09. Sjogren S, Inganas M, Norberg T, et al. The p53 gene in breast cancer: prognostic value of complementary DNA sequencing versus immunohistochemistry. J Natl Cancer Inst 1996; 88:173-182. 10. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001; 98:10869-10874. 11. Konecny G, Thomssen C, Pegram M, et al. HER-2/neu gene amplification and response to paclitaxel in patients with metastatic breast cancer. Proc Am Soc Clin Oncol 2001; 20:23a (Abstract #88). 12. Henderson IC, Berry D, Demetri G, et al. Improved disease-free (DFS) and overall survival (OS) from the addition of sequential paclitaxel (T) but not from the escalation of doxorubicin (A) dose level in the adjuvant chemotherapy of patients with node-positive primary breast cancer (BC). Proc Am Soc Clin Oncol 1998; 17:101a (Abstract #390). 13. Dumontet C and Sikic BI. Mechanisms of action of and resistance to antitubulin agents: microtubule dynamics, drug transport, and cell death. J Clin Oncol 1999; 17:1061-1070. 14. Veitia R, Bissery MC, Martinez C, et al. Tau expression in model adenocarcinomas correlates with docetaxel sensitivity in tumour-bearing mice. Br J Cancer 1998; 78:871-877. 15. Bernard C, Fellous A, Di Leo A, et al. Evaluation of microtubule associated parameters as predictive markers for advanced breast cancer patients treated with docetaxel. Eur J Cancer 2001; 37 (suppl 6):S182 (Abstract #666). 16. Jarvinen TA, Tanner M, Barlund M, et al. Characterization of topoisomerase II alpha gene amplification and deletion in breast cancer. Genes Chromosomes Cancer 1999; 26:142-150. 17. Jarvinen TA, Tanner M, Rantanen V, et al. Amplification and deletion of topoisomerase II alpha associate with ErbB-2 amplification and affect sensitivity to topoisomerase II inhibitor doxorubicin in breast cancer. Am J Pathol 2000; 156:839-847.
The European Trials The efficacy of docetaxel in the treatment of metastatic breast cancer has been proven in first- and second-line therapy and has prompted several cooperative groups to conduct adjuvant trials evaluating the activity of docetaxel.1-4 These trials started on both sides of the Atlantic about 5 years ago and had a very efficient accrual. Preliminary efficacy results should be available in 2002 and could have an impact on our current clinical practice. In Europe, adjuvant trials evaluating docetaxel can be grouped into 4 distinct categories according to their study designs: (1) trials evaluating the efficacy of docetaxel administered sequentially after anthracyclines, (2) trials comparing anthracycline-based polychemotherapy to anthracycline/docetaxel–based polychemotherapy, (3) trials examining the role of docetaxel and comparing anthracycline/docetaxel regimens administered either in combination or seJules Bordet Institute, Brussels-Belgium Submitted: Mar. 1, 2002; Revised: Sep. 19, 2002; Accepted: Sep. 23, 2002 Address for correspondence: Angelo Di Leo, MD, Jules Bordet Institute, Rue Heger-Bordet 1, 1000 Brussels, Belgium Fax: 32-2-541-3090; e-mail: [email protected]
quentially, and (4) translational research trials aimed at identifying a specific subgroup of patients who derive significant benefit from docetaxel-based therapy.
Trials Evaluating Docetaxel Administered Sequentially After Anthracyclines Several 2-arm trials have evaluated an anthracyclinebased regimen administered for 6-8 cycles compared to the same regimen (3-4 cycles) followed by full doses of docetaxel for 3-4 cycles (Table 1). The French study probably will be the first of these trials to produce results. This study has recruited 2000 node-positive breast cancer patients; preliminary efficacy results should be available in the last quarter of 2002. In the French study, 6 cycles of FEC (5-fluorouracil/epirubicin/cyclophosphamide) 100, a standard adjuvant therapy for node-positive breast cancer patients in most European countries, were compared with 3 cycles of the same regimen followed by 3 courses of docetaxel (100 mg/m2 every 3 weeks). In this trial, an absolute increase of 7.5% in the 5-year diseasefree survival (DFS) is expected from the use of docetaxel. The magnitude of the effect is comparable to the benefit hypothesized in most adjuvant trials evaluating the efficacy of doc-
Clinical Breast Cancer Supplement October 2002 • S59
Docetaxel in the Treatment of Breast Cancer Sequential Versus Concomitant Administration of Anthracycline/Docetaxel–Based Regimens
Table 1 European Adjuvant Trials with or Without Docetaxel Group French (n = 2000) ICCG (n = 800) Italian (n = ± 1000)
TACT (n = 3340)
Design
Status
FEC 100 for 6 cycles FEC 100 for 3 cycles → Docetaxel for 3 cycles Epirubicin for 8 cycles Epirubicin for 4 cycles → Docetaxel for 4 cycles
Closed to accrual
Ongoing
Epirubicin 120 for 4 cycles → CMF for 4 cycles Ongoing
Epirubicin 120 for 4 cycles → Docetaxel for 4 cycles → CMF for 4 cycles FEC 60 for 8 cycles FEC 60 for 4 cycles → Docetaxel for 4 cycles
Ongoing
Abbreviation: CMF = cyclophosphamide/methotrexte/5-fluorouracil; FEC = 5-fluorouracil/ epirubicin/cyclophosphamide; ICCG = International Cancer Cooperative Group; TACT = Taxotere as Adjuvant Chemotherapy
etaxel. Noteworthy, the United Kingdom Taxotere as Adjuvant Chemotherapy (TACT) trial will be the largest study (> 3000 patients) in this specific group of clinical trials.
Anthracycline-Based Polychemotherapy Versus Anthracycline/Docetaxel–Based Polychemotherapy This study class contains 2-arm trials in which anthracycline-based polychemotherapy (FAC [5-fluorouracil/doxorubicin/cyclophosphamide]) is compared to an anthracycline/docetaxel–based polychemotherapy (TAC [docetaxel/doxorubicin/cyclophosphamide]). The Spanish study by the Grupo Español de Investigación en Cáncer de Mama group offers a good example in this particular context. In this trial, 6 cycles of FAC will be compared to 6 cycles of TAC; interestingly, the study will be addressed to patients with node-negative breast cancer. The planned sample size is about 1000 patients, and as of February 2002, almost 800 patients have been randomized.
A 4-arm trial is evaluating 2 different concepts: the role of docetaxel and the comparison between different anthracycline/docetaxel–based regimens in which the two drugs are administered either in combination or sequentially. The Breast International Group (BIG) 02-98 study is the only representative of this specific group of trials, although it is not a fully European study because groups and centers located in Australia, New Zealand, South Africa, South America, and the Middle East have largely contributed to the accrual. The study design is reported in Table 2. The primary endpoint of this study is to evaluate the role of docetaxel regardless of its mode of administration (arms A1 and A2 vs. arms B and C). With 1820 patients in the experimental groups (arms B and C) and 910 patients in the control groups (arms A1 and A2), using a significance level of 0.05, this study will have a power of about 99% to detect a DFS absolute increase of 8.3% at 5 years. The comparison between the 2 different docetaxel-based regimens (sequential vs. polychemotherapy) evaluates whether both treatments are equivalent in terms of DFS. This means that the 2-sided 95% confidence interval of the hazard ratio should be between 0.80 and 1.25. With 910 patients in each arm, using a significance level of 0.05, this comparison will have a power of 86% to meet this equivalence. Interestingly, the same cumulative doses of docetaxel and very similar cumulative doses of doxorubicin will be administered in the 2 study arms, while a relevant increase in the dose intensity of both drugs is expected with the sequential approach, which also has a longer duration (6 weeks more; Table 2). The accrual of this study was completed in June 2001, and the first interim analysis is planned for the first quarter of 2003 (405 observed events).
Translational Medicine Trials Recent translational research trials have aimed to identify a specific subgroup of patients deriving a large benefit
Table 2 The BIG 02-98 Trial: Sequential Versus Polychemotherapy Arm A1: Doxorubicin every 3 weeks for 4 cycles → CMF for 3 cycles
Versus
Arm B: Doxorubicin every 3 weeks for 4 cycles → Docetaxel every 3 weeks for 3 cycles → CMF for 3 cycles Arm C: Doxorubicin/Docetaxel every 3 weeks for 4 cycles → CMF for 3 cycles
Arm A2: AC every 3 weeks for 4 cycles → CMF for 3 cycles
Planned Dose-Intensity and Cumulative Doses Dose Intensity (mg/m2/week)
Arm B: Doxorubicin → Docetaxel Arm C: Doxorubicin/Docetaxel
Increase in Dose Intensity
Cumulative Doses (mg/m2)
Doxorubicin
Docetaxel
Doxorubicin
Docetaxel
Doxorubicin
Docetaxel
25
33.3
51%
33.2%
225
300
16.6
25
–
–
200
300
Abbreviations: AC = doxorubicin/cyclophosphamide; BIG = Breast International Group; CMF = cyclophosphamide/methotrexate/5-fluorouracil
S60 • Clinical Breast Cancer Supplement October 2002
Angelo Di Leo ties could exist in testing this concept in the ongoing adjuvant trials. Indeed, in all of these trials, frozen tumor samples will be R A available only for a minority of patients; acLocal ± Tamoxifen FEC 100 or Canadian FEC N Eligibility Criteria: therapy cordingly, p53 gene sequencing, which is D Large operable better performed on frozen samples, will O tumors M not be feasible in most of the cases. MoreLocal ± Tamoxifen Docetaxel for 3 cycles → I therapy Epirubicin/Docetaxel for 3 cycles over, it is well known that immunohistoZ chemistry (IHC), although feasible on fixed E tumor samples, does not represent a relip53 Analysis Sample 1: Standard fixation able method to evaluate p53 mutations beIncisional biopsy (functional Sample 2: Snap frozen cause of its poor sensitivity and specificity.9 assay) HER2 and estrogen receptor alpha (ERα) Target accrual = 1308 (872 p53 negative, 436 p53 positive) could represent valid surrogate markers for Hypothesis: DFS at 3 years by 5% in p53 negative patients and by 20% in p53 positive patients p53 status. Indeed, it has been reported that while a direct correlation exists between p53 Abbreviations: BIG = Breast International Group; DFS = disease-free survival; EORTC = European Organization mutations and HER2 gene amplifications, for Research and Treatment of Cancer; FEC = 5-fluorouracil/epirubicin/cyclophosphamide an inverse correlation generally is found between p53 mutations and ERα expression.10 from the use of docetaxel-based therapy. The BIG 01-00/EuSome data correlating taxane efficacy with HER2 or ERα ropean Organization for Research and Treatment of Cancer status have been reported.11,12 In a German trial comparing (EORTC) 10994 trial belongs to this group of studies. This EC (epirubicin/cyclophosphamide) with ET (epirubicin/paclitrial, which began in the second half of 2001, aims to test a taxel) in metastatic breast cancer patients, the ET regimen biological hypothesis in the clinical setting: the advantage of seems to be more effective than EC in HER2-amplified tua taxane-based therapy over an anthracycline-based regimen mors, while the 2 regimens have similar efficacy in HER2would be confined to the subgroup of patients with p53-munonamplified tumors.11 5-7 tated tumors. This hypothesis is supported by in vitro data. Moreover, a subgroup analysis of the Cancer and In this study, patients with large operable tumors are ranLeukemia Group B 9344 trial, which compares 4 cycles of domly treated either with an anthracycline-based therapy doxorubicin/cyclophosphamide with the same regimen folfor 6 cycles or with 3 courses of docetaxel (100 mg/m2 every lowed by 4 cycles of paclitaxel in the adjuvant setting, has 3 weeks) followed by 3 cycles of docetaxel/epirubicin (Figure suggested that paclitaxel’s benefit would be confined to the 1). Local treatment is provided after neoadjuvant therapy, subgroup of patients with ERα-negative tumors.12 Although and tamoxifen is administered after local treatment in the some hints support the value of both HER2 and ERα in precase of endocrine-responsive tumors. A pretreatment biopsy dicting the efficacy of a taxane-based regimen, current data is performed, and 1 frozen sample is used to evaluate the p53 are not conclusive to recommend the predictive use of these status through a functional assay.8 2 biological markers in current clinical practice. This trial, which will enroll 1300 patients, aims to demonMicrotubule-associated parameters (MTAPs) like α-tubustrate that in p53-mutated tumors, the docetaxel-based regilin and β-tubulin units, β-tubulin isotypes (class II, III, and men will increase the DFS by 20% at 3 years, while in p53 wild-type tumors, the efficacy of the 2 evaluated regimens Figure 2 Translational Research in Taxane-Based Trials: will be almost equivalent. This trial represents a considerable Which Markers Are Predictive? step forward in the context of clinical trials because it The TAX 303 Trial prospectively tests a biological hypothesis; moreover, this trial could demonstrate that treatment tailoring according to Doxorubicin Eligibility Criteria: 75 mg/m2 every 3 weeks tumor biological profile is a feasible approach. Relevant efMetastatic forts are done worldwide to identify molecular markers that disease could predict the efficacy of taxanes in breast cancer patients.
Figure 1 The BIG 01-00/EORTC 10994 Trial
(n = 326)
Do We Have Molecular Markers for Predicting the Efficacy of Taxanes? The evaluation of p53 status could have predictive value. Indeed, different in vitro experiments have shown that while the efficacy of taxanes is not compromised, the activity of anthracyclines is drastically reduced in the case of p53 gene mutations.5-7 While the BIG 01-00/EORTC 10994 trial will attempt to demonstrate this hypothesis, substantial difficul-
Docetaxel 100 mg/m2 every 3 weeks
Archival samples collected for 54% (n = 176) Markers Under Evaluation
HER-2, ERα (p53 Surrogates?) Topoisomerase IIα Microtubule-associated parameters
Abbreviation: ERα = estrogen receptor alpha
Clinical Breast Cancer Supplement October 2002 • S61
Docetaxel in the Treatment of Breast Cancer IV), and some microtubule-associated proteins like the Tau protein, are molecular markers that could predict the efficacy of docetaxel. MTAPs are involved in the process of microtubule stabilization, and it has been hypothesized that the expression of a certain MTAP pattern could cause hyperstabilization, while the expression of another pattern could be responsible for hypostabilization. It is known that docetaxel has a stabilizing effect on microtubules, and accordingly, an interesting hypothesis is that the efficacy of this drug could be modulated by the MTAP expression pattern.13 It has been reported in animal models that the poor expression of the Tau protein, which has a stabilizing effect on microtubules, could be associated with resistance to docetaxel.14 We have performed preliminary clinical experiences evaluating MTAPs as predictive markers.15 In a series of 41 advanced breast cancer patients treated with docetaxel, an inverse correlation seems to exist between the level of expression of the class II β-tubulin isotype evaluated by IHC on primary tumor samples and docetaxel activity (if immunostaining in ≤ 50% of cells, response rate 79%; if immunostaining in > 50% of cells, response rate 39%; P = 0.04).15 To test the predictive value of MTAPs in the context of a randomized trial, our group has recently gathered primary tumor samples from 54% of 326 patients entered in a phase III trial comparing single-agent doxorubicin to single-agent docetaxel as first- and second-line treatment in metastatic breast cancer patients. A panel of biological markers, including MTAPs, is under evaluation in the attempt to identify predictive factors (Figure 2). Interestingly in this study, topoisomerase IIα will be evaluated. This molecular marker is the target of anthracyclines, and topoisomerase IIα gene aberrations (mainly gene amplifications) are found in primary breast cancer samples in about one third of HER2-amplified tumors.16 In the same study, no topoisomerase IIα gene aberrations have been observed in HER2-nonamplified breast cancer.16 Moreover, a preclinical study suggests that the efficacy of anthracyclines is significantly increased in topoisomerase IIα gene-amplified tumors.17 Thus, it could be hypothesized that in HER2amplified and topoisomerase IIα–nonamplified tumors, docetaxel will be more effective than doxorubicin, while in HER2-amplified and topoisomerase IIα–amplified tumors, doxorubicin will be at least as effective as docetaxel. The ongoing study (Figure 2), in which both HER2 and topoisomerase IIα will be evaluated could shed some light on this provocative hypothesis.
Conclusion The European experience with docetaxel in the adjuvant therapy of breast cancer is still ongoing, and preliminary efficacy results from randomized trials (BIG 02-98 and the French study) should be available in the last quarter of 2002. In the meantime, an increasing effort is ongoing to identify molecular markers that could predict the efficacy of doc-
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etaxel in breast cancer patients. This approach could identify a specific subgroup of early-stage breast cancer patients who gain the highest benefit from a docetaxel-based adjuvant therapy. It is critical to gather frozen tumor samples from patients entered into clinical trials to allow for the use of the most updated technology like gene microarrays; the latter could identify genetic profiles associated with increased or poor sensitivity to commonly used adjuvant regimens.
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