Predicting response to systemic treatments: Learning from the past to plan for the future

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  • The Breast (2005) 14, 582593

    THEBREAST

    sLearning from the past to plan for the future

    Meredith M. Regan,

    IBCSG Statistical Center, DepaDana-Farber Cancer Institute,

    chemotherapy provides little additional benefit. By contrast, adding chemotherapyto tamoxifen provides additional benefit for patients with node-positive disease and

    should be presented primarily according to steroid hormone receptor status and

    the role of chemotherapy, tamoxifen, ovarianablation, etc.rather than patient population

    ARTICLE IN PRESS

    KEYWORDSBreast cancer;Predictive factors;Estrogen receptors;Progesteronereceptors;Adjuvant therapy;Chemotherapy;Tamoxifen;STEPP

    Corresponding author. Tel.: +1 617 632 2471;fax: +1 617 632 2444.focused. Patient age has been used as an easily

    0960-9776/$ - see front matter & 2005 Elsevier Ltd. All rights reserved.doi:10.1016/j.breast.2005.08.021

    E-mail address: mregan@jimmy.harvard.edu (M.M. Regan).future studies should be designed as tailored treatment investigations.& 2005 Elsevier Ltd. All rights reserved.

    Introduction

    Historically, adjuvant therapies for operable breastcancer have been studied across the board with

    little or no effort made to tailor clinical trials topopulations of patients that might have the bestchance of benefiting from the therapies beingstudied. Clinical trials and meta-analyses havebeen treatment focusedfor example, assessingtumors expressing intermediate levels of ER. Identification of chemosensitivetargets, e.g., absence of PgR, in tumors with intermediate ER expression is requiredto further tailor, adding chemotherapy within this otherwise endocrine-responsivecohort. Age is not a therapeutic target. Thus, the biological bases for treatmentresponsiveness must be defined. All findings from clinical trials and meta-analysesRichard D. Gelber

    rtment of Biostatistics and Computational Biology,44 Binney St., Boston, MA 02115, USA

    Summary Therapeutic effects of adjuvant therapies for breast cancer have beenassessed across the board and implemented using the principle that if a treatmentis effective on average then it is effective for all patients. Exploration andimproved understanding of the biological basis for predicting response to availableadjuvant therapies is essential to enhance patient care. As illustration, we considerthe effects of chemotherapy and tamoxifen in two International Breast Cancer StudyGroup (IBCSG) trials for postmenopausal women. The level of estrogen receptor (ER)expression in the primary tumor is a powerful predictor of response to adjuvanttherapy. Absence of ER identifies a chemosensitive cohort for which concurrenttamoxifen significantly blunts the large chemotherapy effect. High levels of ERexpression are associated with good results using tamoxifen alone; addingORIGINAL ARTICLE

    Predicting response to sy temic treatments:

    www.elsevier.com/locate/breast

  • chemotherapy to tamoxifen among patients withlymph node-positive disease. From 1986 to 1993,

    ARTICLE IN PRESS

    Predicting response to systemic treatments: Learning from the past to plan for the future 583identifiable feature for subgroup analyses, whichhas led to substantial misunderstanding and in-appropriate use of age as a criterion for treatmentchoice.Estrogen receptor (ER) and progesterone recep-

    tor are the most important factors used today totailor adjuvant therapies.1 Unfortunately, steroidhormone receptor status has not been routinelyused when results of clinical trials assessingchemotherapy effects are presented. Separateanalyses for patients with endocrine-responsiveand endocrine-nonresponsive disease are essentialto better understand the effectiveness of che-motherapy in conjunction with effective endocrinetreatments. Quantifying the level of ER and PgRexpression, rather than simply relying on positiveand negative designations that produce a mixtureof the degree of endocrine responsiveness, may beimportant to better define treatment response. Forexample, a growing body of evidence, includingobservations from clinical trials24 as well as geneprofiling studies,5 indicate that ER- and PgR-absenttumors (those expressing no ER or PgR) are distinctfrom other forms of breast cancer. Endocrinetherapies provide no benefit for patients with ER-and PgR-absent tumors; chemotherapy alone is veryeffective for this cohort.1

    We present information relating to the role ofadjuvant chemotherapy for postmenopausal pa-tients with early stage breast cancer to illustratehow information from the past can be used to planfor the future. Data from two International BreastCancer Study Group (IBCSG) trials serve as illustra-tion. Our analyses are restricted to patients whowere clearly postmenopausal at the time ofenrollment in the clinical trial, rather than usingan age cut-off of 50 years or older. In this way weeliminate the endocrine effects of chemotherapyassociated with ovarian function suppression amongolder premenopausal women, and thereby providean unconfounded assessment relevant for thepostmenopausal cohort.Key factors we consider are the level of ER

    expression in the primary tumor, the level ofprogesterone receptor (PgR) expression in theprimary tumor, whether or not tamoxifen is giveneither sequentially or concurrently with che-motherapy, and finally nodal status. ER and PgRexpression are predictive factors that are inextric-ably linked to the specific treatment for whichresponsiveness is defined. For example, endocrinetherapies provide benefit in the presence of ER orPgR expression, but the magnitude of the benefitassociated with tamoxifen may differ from that ofan aromatase inhibitor depending on the level of ERand/or PgR expression.1212 eligible postmenopausal patients with node-positive disease were randomized to receive one offour treatments: tamoxifen alone for five years;tamoxifen plus three courses of classical CMF inmonths 1, 2, and 3; tamoxifen plus three delayedcourses of CMF in months 9, 12, and 15; ortamoxifen plus both early and delayed CMF.11

    Tamoxifen was given concurrently with the che-motherapy and was administered for a duration offive years in all treatment groups. The randomiza-tion was prospectively stratified by the ER status ofthe primary tumor. Approximately 95% of trialpatients had ER and PgR measured by an extractiveassay and are included in these analyses.To explore the trends in treatment effect

    differences according to hormone receptor levelsWe assert that current approaches for presentingresults of clinical trials and meta-analyses areinadequate for properly tailoring treatments. TheSubpopulation Treatment Effect Pattern Plots(STEPP) method explores the patterns of treatmenteffects across subpopulations defined by a covari-ate, e.g., ER level, to help identify features thatpredict responsiveness to the treatments understudy in a randomized clinical trial or meta-analysis.68 Generation of biologically plausiblehypotheses to be tested further using datasetsfrom other clinical trials is recommended.9 Weapply the STEPP method to the two IBCSG trialsconducted for postmenopausal women to explorethe role of ER and PgR in predicting response tochemotherapy.

    Patients and methods

    IBCSG Trial IX investigated the role of adjuvantchemotherapy administered prior to tamoxifen forpatients with lymph node-negative disease. From1988 to 1999, 1669 eligible postmenopausal pa-tients with node-negative breast cancer wererandomized to receive either tamoxifen for fiveyears or three 28-day courses of classical CMFfollowed by tamoxifen to complete five years oftreatment.10 The randomization was prospectivelystratified according to ER status of the primarytumor. Approximately 70% of the trial patients hadER and PgR measured by an extractive assay (fmol/mg cytosol protein) and are included in theseanalyses, because of increasing use of immunohis-tochemistry during the final years of accrual to thetrial.IBCSG Trial VII investigated the value of adding

  • We reported previously,10 at a median follow-up of

    IBCSG Trial VII

    Exploratory analyses incorporating PgR

    ARTICLE IN PRESS

    M.M. Regan, R.D. Gelber584six years, that CMF followed by tamoxifen signifi-cantly improved DFS compared with tamoxifenalone (RR 0.80; 95% CI 0.641.00). However, theeffectiveness of adding CMF to the adjuvanttreatment regimen was observed exclusively amongpatients with ER-negative disease (RR 0.52, 95%CI 0.340.79); no treatment difference was ob-served for patients with ER-positive tumors(RR 0.99; 95% CI 0.751.30). A recent reanalysisof the NSABP B-20 study confirmed the absence ofbenefit of adding chemotherapy to tamoxifen forpostmenopausal women with lymph node-negative,ER-positive breast cancer.12

    Figure 1A shows the STEPP analysis of five-yearDFS according to quantitative values of ER forIBCSG Trial IX; each subpopulation contains ap-proximately 200 patients and changes by approxi-mately 15 patients. The large benefit of adding CMFprior to commencing tamoxifen is clearly evidentfor the lowest values of ER. In particular, when CMFis given sequentially prior to tamoxifen amongpatients with tumors expressing no ER, the five-year DFS is improved from 67% without CMF to 85%with CMF (n 20 and 26, respectively). For values(based on extractive assays), we used the nonpara-metric Subpopulation Treatment Effect Pattern Plot(STEPP) methodology.68 STEPP involves definingseveral overlapping subgroups of patients on thebasis of a covariate of interest and studying theresulting pattern of the treatment effects estimatedwithin each subpopulation. Here, ER and PgR werethe covariates of interest. For a STEPP analysis, thesubpopulations contained a fixed number of patientsand each subpopulation was formed by moving leftto right by dropping approximately 1015 patientswith the lowest covariate value and adding approxi-mately 1015 with the next higher covariate value.The x-axis indicated the median covariate value (ERor PgR on the log-scale) for patients in eachsubpopulation; the y-axis indicated the five-yeardisease-free survival (DFS) percentage estimatedusing the Kaplan-Meier method on data of patientsin each subpopulation.Five-year DFS percentages were estimated with

    the Kaplan-Meier method and Greenwoods formulawas used for the calculation of standard errors.Hazard ratios (RR) and confidence intervals wereestimated by using a proportional hazards model.

    Results

    IBCSG Trial IXOne explanation for the different patterns ofresponse according level of ER expression (especiallyWe previously reported a detrimental effect of lateinitiation of CMF at 9, 12, and 15 months concurrentwith tamoxifen that had been initiated nine monthsearlier.7,11 This detrimental effect was seen exclu-sively among patients with ER-negative tumors.Those with ER-positive disease benefited from theaddition of chemotherapy together with tamoxifenirrespective of the timing and duration of thechemotherapy.13 Median follow-up was ten years.Figures 1BD show the STEPP analyses according

    to ER for the three pairwise comparisons of CMFadded to tamoxifen versus tamoxifen alone; eachsubpopulation contains approximately 120 patientsand changes by approximately 10 patients. Thepatterns of CMF treatment effect according to ERare very different for Trial VII (node-positive,concurrent CMF and tamoxifen) compared withTrial IX (node-negative, sequential CMF followed bytamoxifen). Specifically, little benefit of the CMF isobserved for patients with the lowest values of ERexpression. This is quite noteworthy consideringthe large CMF benefit observed in Trial IX for lowvalues of ER expression, as well as the effect of asingle cycle of perioperative CMF observed forpostmenopausal women with node-negative, ER-negative disease in IBCSG Trial V.3

    As the ER values move into an intermediaterange, the effects of adding CMF together withtamoxifen become sizeable. The five-year DFSpercentages for the tamoxifen alone arm increasecompared with the low expression values of ER, butthose for each of the three arms that include CMFincrease more rapidly. When the ER expressionvalues are quite high, the five-year DFS achieved bytamoxifen alone reaches the level achieved by theCMF-containing arms. Thus, a pattern emerges forpostmenopausal patients with node-positive dis-ease: with low values of ER, chemotherapy giventogether with tamoxifen makes no substantialimpact; high values of ER indicate that tamoxifenalone is a potent treatment, leaving little oppor-tunity for CMF to contribute added benefit; inter-mediate values of ER indicate an opportunity forCMF to add to the benefit of tamoxifen.of ER exceeding 9 fmol/mg cytosol protein, nobenefit of added CMF is observed for any of thesubpopulations defined in the STEPP analysis.

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    Predicting response to systemic treatments: Learning from the past to plan for the future 5850

    20

    40

    60

    80

    100

    TAM ALONECMF --> TAM

    5-yr

    DFS

    Per

    cent

    Subpopulations by ER (log scale)3 6 10 13 18 24 34 45 61 82 108 149 204 285 3874

    (A)

    100for the node-positive Trial VII) is that tamoxifen aloneis not as potent for patients with intermediate ERlevels as it is for high levels of ER expression. Anotherexplanation, however, is that intermediate ER levelsindicate the presence of chemosensitive targetswithin the tumor. As one possibility, we investigatedthe relationship between ER and PgR degree ofpositivity. Using cut-offs suggested from the STEPPanalysis of ER level, ER was divided into three groups(ERo10, 1099, andX100 fmol/mg cytosol protein).Within each of these groups we undertook STEPPanalyses for PgR expression; in addition, we summar-ized outcome among two PgR groups (PgR o10 andPgR X10 fmol/mg cytosol protein). Two rather thanthree PgR groups were considered and the three CMF-containing groups in Trial VII were combined becauseof sample size limitations.

    0

    20

    40

    60

    80

    4 12 17 28 40 54 69 88 119 165 225 305 457

    TAM ALONETAM + CMF (Delayed)

    5-yr

    DFS

    Per

    cent

    Subpopulations by ER (log scale)7

    (C)

    Figure 1 Subpopulation Treatment Effect Pattern Plots (STEPER values (fmol/mg cytosol protein) of the primary tumor.tamoxifen alone in Trial IX; (B) early CMF plus tamoxifen vtamoxifen versus tamoxifen alone in Trial VII; (D) early plus dVII. Numbers on the x-axis refer to the median value of ERsubpopulations. (Adapted from Colleoni et al.13 with permiss0

    20

    40

    60

    80

    100

    132 192 265 396

    TAM ALONETAM + CMF(Early)

    5-yr

    DFS

    Per

    cent

    Subpopulations by ER (log scale)3 7 9 13 17 24 35 52 72 95

    (B)100Table 1 shows results with respect to DFS fordifferent groups defined by ER and PgR expressionin Trials IX and VII. For the node-negative Trial IX,71% of patients with intermediate ER levels had PgRX10 fmol/mg cytosol protein, compared with 58%for the node-positive Trial VII. In general, moreheterogeneity of PgR expression within cohortsdefined as ER-positive (i.e., intermediate or high)was observed for women with node-positive com-pared with node-negative disease.For Trial IX, STEPP analyses reveal that PgR did

    not appear to influence the degree of response toCMF over and above that defined accor...