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THE BREAST

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doi:10.1016/j.br

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(C. Vogel).

The Breast 16 (2007) S127–S131

www.elsevier.com/locate/breast

Review

Benefit from adjuvant taxanes and endocrine responsivenessin breast cancer

Miguel Martina,�, John Mackeyb, Charles Vogelc

aServicio de Oncologıa Medica, Hospital Universitario San Carlos, 28040 Madrid, SpainbDepartment of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Canada T6G 1Z2

cBreast Cancer for Aptium Oncology, Boca Raton, FL, USA

Abstract

Several phase III trials have been coincident in showing a benefit with adjuvant taxanes in node-positive breast cancer (BC). These

trials provide level I evidence of the efficacy of these drugs. The absolute 5-year DFS gain obtained with the taxane-containing regimens

in the positive studies ranged from 4% to 7%. However, the regimens including taxanes are more toxic than the conventional

anthracyline-containing combinations. Therefore, the pre-treatment identification of the small proportion of patients who actually

benefit from taxanes is of major importance. Several attempts have been made to identify the biological peculiarities of the BC patients

who benefit most with taxanes, largely based on retrospective subset analyses. Hormone receptor (HR) status, one of the critical

determinants of BC biology, had been suggested to be a factor modulating response to adjuvant chemotherapy in general and taxanes in

particular.

Unfortunately, none of the first-generation adjuvant taxane trials was designed to address the question of the differential efficacy of

taxanes in the specific subgroups of HR positive and HR negative BC patients. Indirect (retrospective, unplanned) analysis suggest that

the magnitude of benefit from taxanes is somewhat more in the HR negative subset, but the benefit also exists, and is clinically relevant,

in patients with HR positive cancers. Therefore, the predictive value of HR status in the selection of patients for adjuvant taxane therapy

is low. The predictive value of HER2 status in addition to HR status to select patients for the same purpose remains controversial.

r 2007 Elsevier Ltd. All rights reserved.

Keywords: Breast cancer; Adjuvant taxanes; Endocrine responsiveness

Introduction

Several randomized clinical trials and a large meta-analysis have demonstrated that postsurgical chemother-apy significantly decreases the risk of recurrence and deathin women with node-positive operable breast cancer (BC).1

CMF-like regimens were able to reduce the annual oddsof recurrence and death of operable BC patients by 24%(+/� 3%) and 14% (+/� 4%), respectively. In the late1970 and 1980s, anthracycline-containing combinationswere tested in prospective randomized adjuvant trials and

e front matter r 2007 Elsevier Ltd. All rights reserved.

east.2007.09.001

ing author. Tel.: +3491 3303546.

esses: mmartin@geicam.org (M. Martin),

cerboard.ab.ca (J. Mackey), drcvogel@aol.com

found to be slightly but significantly superior to CMF-likeregimens. The anthracycline regimens (5-fluorouracil,doxorubicin, cyclophosphamide (FAC), 5-fluorouracil,epirubicin, cyclophosphamide (FEC), doxorubicin, cyclo-phosphamide (AC) and others) resulted in an additionalreduction in annual odds of relapse and death of 12%(+/�4%) and 11% (+/�5%), respectively, comparedwith CMF,2 and became the standard adjuvant treatmentof node-positive operable BC. In the 1990s, the taxanes,docetaxel and paclitaxel, were incorporated to the standardarmamentarium for metastatic BC and were soon tested inthe adjuvant setting. The taxanes are partially non cross-resistant with anthracyclines3,4 and, therefore, severalregimens using taxanes and anthracyclines (either incombination or in sequence) were tested in the adjuvantsetting. The results of nine pure adjuvant trials comparing

ARTICLE IN PRESSM. Martin et al. / The Breast 16 (2007) S127–S131S128

anthracycline-containing combinations with taxane-containing combinations (the so-called ‘‘first-generationtaxane trials’’) have been reported.5–11 Six of them wereclearly positive in terms of disease-free survival (DFS) infavour of the taxane arm.5–11 The ECOG 2197 trial did notfind any significant DFS difference between AT (doxor-ubicin plus docetaxel) and AC (doxorubicin and cyclopho-sphamide) after a median follow-up of 53 months, but thenumber of DFS events was lower than expected.9 Finally,the two more recently reported trials (the TAXIT 216 andthe BIG 2-98) found a difference in favour of the taxanearms of borderline significance for the primary endpoint(p values of 0.0576 and 0.051, respectively)12,13 andprobably will become positive when more DFS eventsoccur. Overall, these trials provide level I evidence of theefficacy of taxanes in the adjuvant treatment of node-positive BC. The absolute 5-year DFS gain obtained withthe taxane-containing regimens in the positive studiesranged from 4% to 7%. On the other side of the coin,the regimens including taxanes (particularly docetaxel) areclearly more toxic than the conventional anthracyline-containing combinations, particularly in terms of myelo-suppression, asthenia, and peripheral neuropathy. Whilemyelosuppression and its complications can be lifethreatening,14 in aggregate the additional taxane sideeffects may produce a transient but significant deteriora-tion of the quality of life while women undergo therapy.15

Because only 4–7% of patients obtain a DFS benefitwith adjuvant taxanes (when compared to the less toxicanthracycline-containing combinations), the pre-treatmentidentification of that subset of patients would be of majorimportance for the individualization of therapy. Severalattempts have been made to identify the biologicalpeculiarities of the BC patients who benefit most withtaxanes, largely based on retrospective subset analyses.Hormone receptor status, one of the critical determinantsof BC biology, had been suggested to be a factormodulating response to adjuvant chemotherapy in gener-al16 and taxanes in particular.17 We review here therelationship between the hormone receptor status ofprimary breast cancers and the benefit obtained withtaxanes in the reported adjuvant clinical trials.

Methodological problems

None of the first-generation adjuvant taxane trialsincluded among their endpoints a prospectively plannedsubgroup analysis of outcomes based on HR status. Thisfact constitutes a major methodological mistake, consider-ing our current understanding of BC as a biologicallyheterogeneous disease. Despite the recognition in the1970’s of the biological relevance of the presence offunctional hormonal receptors (HR) in breast tumors,HR status had not been commonly used in the randomizedphase III adjuvant chemotherapy trials as a stratificationfactor. Consequently, the vast majority of adjuvantrandomized phase III chemotherapy trials included a

relatively unselected population of BC patients, and usedthe number of axillary lymph nodes as the primary variablein the stratification of patients; only one of the ninerecently reported first-generation adjuvant taxane trialsused hormone receptor status as a stratification factor.9

This oversight makes retrospective analysis of subsetsbased on hormonal status somewhat unreliable.Additionally, the definition of ‘hormone responsiveness’

and hormone receptor status is not a simple issue. HRswere first determined using ligand binding assays (LBA), aquantitative method, and the magnitude of benefit fromendocrine therapy was shown to be related to the quantityof ER produced by the tumor. Because of reduced cost,and ease of specimen handling, and gradual reduction inthe mean size of primary tumors, immunohistochemical(IHC) testing of hormone receptors largely replaced thequantitative LBA, and is now the standard method inclinical diagnostic laboratories. While IHC performsreasonably well in differentiating HR-positive versusHR-negative cases and minimizes the likelihood of false-negative results, it is markedly less reliable for quantifyingHR, because it is not an intrinsically quantitativemethod.18 Albain et al.16 shown that quantification ofestrogen receptors (ER) by IHC (using Allred0s score) maybe of value in helping to identify patients with ER-positivetumors who may benefit from adjuvant FAC chemo-therapy. Furthermore, there is a clinically relevant inter-center variability in the determination of HR. To achievereliable HR results using ICH, assays should be performedin a central reference laboratory, assessed by experiencedpathologists, and, with two notable exceptions, this has notbeen the case in the first-generation taxane trials.These three problems (lack of prospectively planned

analysis of powered HR-based subsets, lack of stratifica-tion according to HR status, and lack of centraldetermination and quantification of HR) limit the confi-dence one can place in the search for a relationship betweenHR status and benefit from adjuvant taxanes.

Results from first generation clinical trials

Table 1 summarizes the results of the nine reported first-generation adjuvant taxane trials, in terms of relative risk(RR) of recurrence (non-taxane/taxane arms) and therelationship with HR status. We note that only one trial(the ECOG 2197) stratified patients according to HR statusand only the BCIRG 001and the GEICAM 9906 trialsperformed a central determination of HR.In general, the RR of recurrence with taxanes was

numerically lower within the group of HR negativepatients, but patients with HR positive tumors alsoobtained a clinically relevant reduction in recurrences withthe taxane arms.The CALGB 9344 trial was the first-taxane study

reporting results according to HR status. In an unplannedsubset analysis, the addition of paclitaxel was more clearlybeneficial in patients with hormone HR-negative or

ARTICLE IN PRESS

Table 1

Relative risk of recurrence according to hormonal receptor status in first generation taxane trials

Study Design No pt Stratification by

hormone receptor

status

RR of recurrence (non

taxane/taxane arm),

hormone receptor

positive pt

RR of recurrence (non

taxane/taxane arm),

hormone receptor

negative pt

CALGB 93445,17 AC versus AC-paclitaxel 3121 No 0.88 0.75

NSABP B286 AC versus AC-paclitaxel 3060 No* 0.77 0.90

BCIRG 0017 FAC versus TAC 1491 No 0.72 0.69

PASC 018 FEC versus FEC-docetaxel 1999 No 0.81 0.79

GEICAM 990610 FEC versus FEC-weekly paclitaxel 1248 No 0.79 0.76

USO 973511 AC versus TC 1016 No 0.71 0.64

ECOG 21979 AT versus AC 2778 Yes 0.99*** 1.21***

TAXIT 21612 E-CMF versus E-T-CMF 997 No NR** NR**

BIG 2–9813 A-CMF versus AC-CMF versus

AT-CMF versus A-T-CMF

2887 No NR NR

P values are not shown since these were unplanned and often underpowered subset analyses. RR: relative risk. A: doxorubicin. C: cyclophosphamide. E:

epirubicin. T: docetaxel. F: 5-fluorouracil. NR: not reported.

*Patients aged 450 with hormone receptor positive tumors and all patients who were 50 years or older regardless of hormone receptor status were given

tamoxifen concomitantly with chemotherapy; tamoxifen use was a stratification factor.

**The biostatistician of the group refused to perform subset analyses, since they were not planned in the protocol.

***RR of AT vs AC; RR41 favors the taxane arm.

M. Martin et al. / The Breast 16 (2007) S127–S131 S129

unknown HR tumors than in those with HR-positivetumors (hazard ratio of 0.72 versus 0.91, respectively, in thefirst published report of the trial). However, the differencesbetween the effects in these subsets were not significantafter adjustment for multiple comparisons. Berry et al.17

analyzed the influence of HR status on the results of threeconsecutive CALGB phase III adjuvant trials, includingthe CALGB 9344 trial. The first one (CALGB 8541)compared three different dose–intensity regimens of CAF,the CALGB 9344 trial compared AC with AC followed bypaclitaxel and the CALGB 9741 compared sequentialversus concomitant administration and conventional every3 weeks with dose-dense every 2 weeks administration ofAC and paclitaxel. The authors found that the three trialsindependently and consistently showed the same finding:the benefit of the best chemotherapy arm was clearly moremarked in the ER negative subset of patients, although thiswas particularly apparent in the dose-dense trial withrelatively short follow-up. The reductions in the RR ofrecurrence in ER negative versus ER positive patients were21% versus 9% (CALGB 8541), 25% versus 12%(CALGB 9344) and 24% versus 8% (CALGB 9741).Comparing the results of the worse arm of the first trial(the low-dose CAF regimen of the CALGB 8541) withthose of the best arm of the last trial (the dose-dense arm ofthe CALGB 9741), ER negative patients had an improve-ment in 10-year DFS of 25.8% versus 10% for ER positivepatients. However, this analysis raises several concerns.A retrospective, unplanned identification of these sub-groups by means of multiple comparisons can lead tospurious treatment correlations. No stratification accord-ing to HR status was done in the trials, raising thepossibility of imbalance between treatment arms. HR werenot determined centrally or quantitatively, and did not useuniform methodology over the 14 years (1985–99) of

accrual spanned by these trials. The populations of patientstreated with adjuvant hormonal therapy evolved duringthese trials to include premenopausal women, not allwomen with ER positive cancers received hormonaltherapy, and the type and duration of hormonal therapywere not protocol specified in CALGB 9741. The follow-upof the three trials is very different and relatively short(about 5 years) in the CALGB 9741. This could be relevantsince the DFS curves of HR positive patients from theprior trial (CALGB 9344) diverged in favour of thepaclitaxel arm only after 5 years. While the authorsconclude that the benefit of chemotherapy in general andtaxanes in particular is mostly seen in ER negative patients,multiple methodologic concerns undermine the relevanceof these conclusions and their applicability to currentpractice.The results of the NSABP B28 trial6 provide a

demonstration of the weaknesses of unplanned retro-spective analysis. With a design very similar to that ofCALGB 9344 (4 cycles of AC versus 4 cycles of ACfollowed by 4 cycles of paclitaxel), the results werequalitatively different: HR positive patients had a biggerreduction of the RR of recurrence with paclitaxel than HRnegative patients (0.77 and 0.90, respectively).The BCIRG 001 compared 6 cycles of the FAC regimen

with the same number of cycles of TAC as adjuvantpostsurgical therapy in node-positive BC patients.7 At amedian follow-up of 55 months, the 5-year DFS wassignificantly better with TAC than with FAC (75% versus68%, respectively, p ¼ 0.001). This trial is unique since thedetermination of HR was done centrally and was availablein all patients. The relative reduction in risk of relapse wasvery similar in HR positive and HR negative patients (0.72and 0.69, respectively). Retrospectively it has been deter-mined that the rate of chemotherapy-induced amenorrhea

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in premenopausal TAC-treated patients was higher thanFAC, adding yet another confounding variable. Unfortu-nately, HR status was not a stratification factor in thistrial.

The interim results of the Spanish trial GEICAM 9906were presented at the 2005 San Antonio BC Symposium.11

Female patients with node-positive operable BC wererandomized after surgery to receive 6 cycles of FE90Cchemotherapy or 4 cycles of the same FEC regimenfollowed by 8 weekly administration of paclitaxel. After amedian follow-up of 46 months, FEC followed bypaclitaxel produced a statistically significant reduction inthe risk of recurrence (hazard ratio 0.63, po0.0008). In thistrial, a central determination of HR was available in 889patients (71% of total). Among them, the RR of recurrencewith paclitaxel was also very similar in HR positive andHR negative patients (0.79 and 0.75, respectively).

The results of the French PACS 001 study were reportedby Roche et al.8 at San Antonio BC Symposium in 2004.Patients with node-positive BC were randomized to receive6 cycles of FE100C or 3 cycles of FE100C followed by 3cycles of docetaxel. At a median follow-up of 60 months,the respective 5-year DFS rates were 78.4% (FEC-docetaxel) and 73.2% (FEC), for a hazard ratio of 0.82(p ¼ 0.012). The RR of recurrence for HR positive and HRnegative patients with docetaxel were again very similar(0.81 and 0.79, respectively). However, an unspecifiednumber of premenopausal patients with HR positivetumors did not receive tamoxifen after chemotherapy,potentially confounding this analysis.

The US Oncology 9735 trial compared 4 cycles of AC to4 cycles of TC (docetaxel plus cyclophosphamide) inpatients with node-negative and node-positive disease.The projected 5-year DFS was superior with TC(86% versus 80%, HR for recurrence 0.67 p ¼ 0.015).The RR of recurrence of HR positive and negative patientswere 0.71 and 0.64, respectively.11

The study ECOG 2197 compared doxorubicin pluscyclophosphamide (AC) and doxorubicin plus docetaxel(AT) in patients with node positive (1–3 axillary lymphnodes) and high-risk node-negative BC (65%).9 At amedian follow-up of 59 months, there were many fewerrecurrences than expected in the control arm and nostatistically significant differences in terms of DFS or OSbetween the two treatments were found. Patients with HRnegative tumors treated with AT had a 21% reduction inRR of recurrence, while patients with HR positive tumorshad practically the same RR of recurrence with bothtreatments. These results are particularly interesting, sinceHR was a stratification factor in the trial, although noprospective and powered subset analysis were planned inthe protocol. Unfortunately, no central determination ofHR status was done. The follow-up of the study is stillshort for this low-risk population and a long-term benefitin HR positive patients cannot be ruled out.

Finally, two studies presented in meetings did notcommunicate subgroup analysis.12,13 Of particular interest,

the biostatistician of the Italian trial TAXIT 216 refused todo unplanned, retrospective subset analysis based on HRstatus and this anecdote is illustrative of the low credibilitythat these analyses have among biostatisticians—(it seemsthat the clinicians are much more prone to accept them).Overall, this review suggests that patients with HR

negative tumors may derive somewhat more benefit fromadjuvant taxanes than the HR positive counterparts,although the benefit in the latter group seems to beclinically relevant as well. Therefore, allocating taxanetreatment on the basis of HR status alone is not justified bythe currently available data.

Hormone receptor status, HER2 status and benefit from

taxanes

The combination of HER2 amplification/overexpressionand HR status (the two most relevant molecular markersidentified in BC so far) defines four groups of BC patientswith different biological features. Hayes et al.19 haveanalyzed the correlation of HER2/HR status and outcomein the CALBG 9344 trial comparing AC to AC followed bypaclitaxel. The study had a double randomization process,first to three different doses of doxorubicin (60, 75 and90mg/m2) and then to paclitaxel versus no paclitaxel. Theyhypothesized than HER2 status might predict benefit fromhigher doses of doxorubicin or from paclitaxel. Tumorblocks were collected from 2800 out of the 3121 patientsincluded in the trial. Two sets of 750 patients each wererandomly selected from the overall population and 643 and679 tissue specimens were available in sets 1 and 2. Theanalyses were done first in set 1 and confirmed in thecombination of sets 1 and 2. There was no interaction at allbetween doxorubicin dose and HER2 status. On the otherhand, the interaction between HER2 and outcome withpaclitaxel was statistically significant. Patients with HER2positive tumors had a benefit in 5-year DFS with paclitaxelof 22%, versus only 2% in HER2 negative patients(p ¼ 0.0013). This was seen in set 1 and in the combinationof sets 1 and 2. A further subset analysis combiningHER2 and HR status showed that the benefit of addingpaclitaxel to AC was greater in HER2 positive-HRnegative patients (31% absolute increase in 5-year DFS).The subsets of HER2 negative-HR negative and HER2positive-HR positive patients still obtained some benefit(8–9% absolute increase in 5-year DFS) while theremaining patients with HER2 negative-HR positivetumors did not benefit. The authors considered the latteranalysis only hypothesis generating and will proceed tofurther validation in the remaining cases in CALGB 9344and other paclitaxel trials. The main weakness of thisanalysis is that the two study arms of CALGB 9344differed in two variables (paclitaxel or not and duration ofchemotherapy—4 versus 8 cycles). The better outcome ofHER2 positive patients in the paclitaxel arm could be dueto either paclitaxel itself or to the longer duration ofchemotherapy in the paclitaxel arm.

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To confirm these findings, the GEICAM recently did asimilar analysis of the GEICAM 9906 trial comparing6 cycles of FEC to 4 cycles of FEC followed by 8 weeklyadministration of paclitaxel. In this trial, the duration ofboth treatments was similar and, overall, FEC followed bypaclitaxel was superior to FEC in 5-year DFS. Tissuemicroarrays were available from 889 patients (71%). Aftera central determination of HR and HER2 (by FISH), thesuperiority of FEC-paclitaxel over FEC was present only inthe HER2 negative subgroups (particularly in the HER2negative-HR negative or triple negative subgroup)(unpublished data). These findings suggest that theduration of chemotherapy, rather that the use of paclitaxelitself, is the most likely explanation for the CALGB 9344results.

In a similar vein, the French PASC 01 trialists compared6 cycles of FEC to 3 cycles of FEC followed by 3 cycles ofdocetaxel, and report the DFS benefit of the sequentialFEC-docetaxel arm is mainly confined to the basal-likesubtype of patients (HER2 negative, HR negative, EGFR1positive, Pcadherin positive).20

The BCIRG group has recently performed a subsetanalysis based on HER2 and HR in the BCIRG 001 dataset (unpublished results). All subgroups (HR+/her2+,HR+/her2�, HR�/her2+ and HR�/her2�) obtained aclinically relevant reduction of risk of recurrence with TAC.

Conclusions

Unfortunately, none of the first-generation adjuvanttaxane trials was designed to address the question of thedifferential efficacy of taxanes in the specific subgroupsof HR positive and HR negative BC patients. Indirect(retrospective, unplanned) analysis suggest that the magni-tude of benefit from taxanes is somewhat more in the HRnegative subset, but the benefit also exists, and is clinicallyrelevant, in patients with HR positive cancers. Therefore,the predictive value of HR status in the selection of patientsfor adjuvant taxane therapy is low. The predictive value ofHER2 status in addition to HR status to select patients forthe same purpose remains controversial.

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