adjuvant breast cancer treatment: evolution or revolution?...sistent with the atac (arimidex,...

Volume 7 Number 2Spring 2005

For years, clinicians have appreciated that breast canceris not one disease, but a family of diseases, each with adistinct natural history and response to treatment. Yet,

over the past two decades, adjuvant trials have largelyenrolled patients on the basis of tumour size and lymphnode status, rather than by biologic features. There were rel-atively few concessions to the biologic heterogeneity ofbreast cancer in the design of clinical trials. Admittedly,patients with hormone responsive tumours were generallygiven tamoxifen in addition to chemotherapy, but only a fewlarge trials focused exclusively on questions in receptor-positive or receptor-negative cohorts.1,2

This issue of the Breast International Group (BIG)Newsletter focuses upon recent progress in adjuvant breastcancer treatment. Martine Piccart and Kathleen Pritchardreview the evidence for the use of aromatase inhibitors (AI)in postmenopausal women with receptor-positive breastcancer. Maureen Trudeau discusses the role of taxanes.Brian Leyland-Jones and Soheyl Baban outline advances ingenomics and proteomics. What is clear from these articlesis that the care of patients with breast cancer has evolvedsubstantially. However, if we want to achieve more dramat-ic advances, new and more innovative approaches to clinicaltrial design will be required.

Adjuvant Breast Cancer Treatment: Evolution or Revolution?Nancy Lin, MD, and Eric Winer, MD, Dana-Farber Cancer Institute, Boston

CONTENTS

Adjuvant Breast Cancer Treatment–Evolution or Revolution? ................................... 1BIG Studies for Older Patients............................. 18Updates on Other BIG Trials ............................... 22News from BIG Groups ...................................... 28TRANSBIG News ................................................ 29Upcoming Events................................................ 30

This issue was made possible through the generous

support in the form of an unrestricted educational grant

from Schering-Plough.

Adjuvant Breast Cancer Treatment—Evolution or Revolution?

(continued on page 3)

We have used this issue to focus on some of theimportant messages coming from the mostrecent San Antonio Breast Cancer Symposium

and the St. Gallen International Consensus Conference,both among today’s most exciting breast cancer confer-ences. We are particularly pleased that Drs. Nancy Lin andEric Winer, colleagues from the Dana-Farber CancerInstitute in Boston, have written the editorial for this issue.This underscores the importance of the transatlantic col-laborations that have developed over the years. One of theinspirations for the creation of BIG back in 1996 was, infact, the Breast Cancer Intergroup of North America(TBCI), a network of National Cancer Institute (NCI)-sponsored Clinical Trials Cooperative Groups. We arepleased that our transnational collaborations continue togrow and are confident that this is the way to move forwardto effectively address the types of challenges (stemmingfrom many of our successes!) outlined in the editorial andother articles in this issue.

Martine PiccartCarolyn Straehle

Breast International Group (BIG) Newsletter ~ Volume 7 Number 2, Spring 2005

22

Volume 7 Number 2 Spring 2005

EDITORMartine Piccart, MD, PhD

MANAGING EDITORSCarolyn Straehle, PhD

Margaret Gardner

EDITORIAL BOARDAron Goldhirsch, MD

Monica Castiglione, MDKathleen Pritchard, MD

Gunter von Minckwitz, MDPatrick Therasse, MD

The Breast International Group Newsletter (ISSN is 1712-2910) is pub-

lished quarterly by BC Decker Inc, 20 Hughson Street South, PO Box 620

LCD 1, Hamilton, Ontario, L8N 3K7.

The opinions or conclusions stated or implied in the articles herein are

those of the authors and do not necessarily reflect those of the publisher.

Inquires regarding the Newsletter should be sent to:

Breast International Group

Institut Jules Bordet

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Tel: +32 2 541 3146

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© BC Decker Inc 2005 All rights reserved. No part of this publication may be

reproduced in any form without written permission of the publisher.

Note From the Editors

Watch for upcoming issues on patient advocacy, the EU Clinical Trials Directive,

and clinical trials for populations such as the elderly and the young.

Are there other topics you would like to see discussed in future BIG Newsletters?

Don’t hesitate to contact us ([email protected]) with your ideas and feedback!

Adjuvant Breast Cancer Treatment–Evolution or Revolution?

33

As detailed by Drs. Piccart and Pritchard, the use of anAI at some point in the course of treatment of post-menopausal women with receptor-positive breast cancerresults in an absolute gain of 2 to 5% in disease-free sur-vival.3–7 The early results of BIG 1-98 are remarkably con-sistent with the ATAC (Arimidex, Tamoxifen, Alone or inCombination) study. AIs represent an evolution fromtamoxifen, a new class of drugs that also target the hormonereceptor (HR) pathway. However, ongoing trials have alsosparked a change in our thinking about receptor-positivebreast cancer. Although extending tamoxifen beyond 5 yearsdoes not improve outcomes,8,9 the results of MA-17 havereopened the question of extended endocrine therapy,3 andrenewed our awareness of the persistently high risk of recur-rence over time faced by women with receptor-positive dis-ease. Furthermore, exploratory analyses of some of the AItrials, most notably the ATAC trial, suggest that the benefitsof specific hormonal therapies may vary according to thebiologic features of the tumour.10 Outcomes according tohuman epidermal growth factor receptor-2 (HER-2) statushave not been reported from the large adjuvant AI trials;however, limited data from neoadjuvant studies suggest thatHER-2 may modulate the benefit of tamoxifen.11,12

Characteristics of the host may also be important in makingthese decisions, particularly with regard to the risk of toxic-ity. Both clinical data and the results of gene profiling stud-ies suggest that HR-positive breast cancer is remarkably het-erogeneous.13 Quantitative estrogen levels explain some ofthe variability,14 but the existence of co-activators and co-repressors result in a far more complex landscape.15

It is becoming increasingly apparent that a “one size fitsall” strategy does not work for adjuvant chemotherapy. Aspointed out by Dr. Trudeau, NSABP B-27 and PACS-01, aswell as other more mature studies, have demonstrated abenefit from the addition of a taxane to standardchemotherapy. A key challenge at this time is to identifythose women who will benefit to maximize disease out-comes while minimizing unnecessary treatment.

Several groups have recently presented analyses ofchemotherapy benefit according to biomarkers—andalthough the studies were exploratory, the results are com-pelling. Berry and colleagues reported a striking differencein chemotherapy benefit according to estrogen receptor(ER) status in three sequential CALGB adjuvantchemotherapy trials.16 Compared to the low dose arm ofCALGB 8541, women with ER-negative tumours treatedon the experimental arm of CALGB 9741 achieved a 63%relative reduction in the risk of recurrence, and a 59% rel-ative reduction in the risk of death. The benefit in womenwith ER-positive tumours was far less pronounced. Albainand colleagues found that low or intermediate ER scorewas predictive of benefit for CAF (cyclophosphamide,doxorubicin, and fluorouracil) chemotherapy in post-

menopausal receptor-positive patients who also receivedtamoxifen.2 Paik and colleagues analyzed the utility of the21-gene recurrence score assay to predict the benefit ofchemotherapy in NSABP B-20.14 Although the analysiswas based on a small number of events, chemotherapy ledto a 22% absolute reduction in the risk of recurrence inpatients with high scores; there was no benefit in patientswith low scores. Finally, the influence of both tumourgrade and ER status is also reflected in the likelihood of apathological complete response (pCR) to preoperativechemotherapy. In six consecutive neoadjuvant studies con-ducted at M.D. Anderson Cancer Center, the pCR rate wasconsistently higher in women with ER-negative tumours.17

Taken together, these data strongly indicate thatchemotherapy is, on average, less effective against ER-positive breast cancers than ER-negative cancers, but thereis likely a subgroup of patients with ER-positive tumourswho derive substantial benefit from chemotherapy. It isuncertain if the benefits from chemotherapy in this sub-group of ER-positive tumours are similar to, less, orgreater than those seen in patients with ER-negativetumours. It is also uncertain how these benefits vary acrossdifferent chemotherapy regimens.

As we move forward, many challenges lie ahead. Asreviewed by Drs. Leyland-Jones and Baban, both cliniciansand scientists recognize the extraordinary heterogeneityacross breast cancer, but devising clinically relevant classifi-cation systems remains complex. Should we define sub-groups on the basis of single gene markers, genomic profile,or proteomic profile? Once defined, classification tech-niques must be tested and validated. For example, Piccartand colleagues recently presented results of an external val-idation of the Amsterdam 70-gene prognostic signaturedeveloped by Van’t Veer and colleagues.18 Such efforts arecrucial, and it will be important to mandate collection of tis-sue blocks as part of ongoing studies. Neoadjuvant studiesmay provide a more rapid platform for both gene discoveryand validation than adjuvant studies; to this end, NSABP B-40 will incorporate research biopsies before and duringneoadjuvant therapy.

Despite the uncertainty regarding the “best” classifica-tion technique, we are in a position to start asking biologi-cally based questions in clinical trials. The MINDACT studyis powered to examine the utility of the Amsterdam signa-ture in assigning patients to chemotherapy, compared toclinical-pathological criteria. It is hypothesized that fewerwomen in the “gene signature” arm will receive chemother-apy, but that outcomes in the two arms will be equivalent.The planned Breast Cancer Intergroup (TBCI) trial(PACCT) proposes to test the value of chemotherapy inaddition to endocrine therapy in a group of women with anintermediate recurrence score on the 21-gene assay(Oncotype Dx). In both TBCI and the Breast InternationalGroup, distinct clinical trials have been developed forpatients with HER-2 positive disease, recognizing the unique

(continued from page 1)

clinical and biological features of this important subtypeand the availability of a targeted therapy. We would arguethat it is also time to consider focused trials in the following:a) women with triple negative or basal-like cancers; and b)women with high grade, ER-positive, HER-2-negativetumours. It is possible that principles that have been estab-lished in unselected patients (eg, the benefits of anthracy-cline-based regimens) will need to be reevaluated as wereclassify breast cancer. We may need to discard some of ourdearly held assumptions. Intriguing findings from retro-spective analyses, both positive and negative findings, needto be tested in prospective trials.

The revolution in breast cancer treatment is both aboutdeveloping new drugs and in the way we design future stud-ies, with the ultimate goal of rapidly improving outcomes bybeing wiser and more selective in the way we match specificdrugs with specific patients. The limitations of the tradi-tional approach are multiple: (1) we may prematurely dis-card new agents if they are effective only within a small sub-group of patients; (2) we may waste precious financial andpatient resources by conducting excessively large trials withnew treatments that have their greatest hope of working in asubset; (3) we may falsely conclude that a regimen should begiven to all women, when in fact, only a small subgroupbenefits; and (4) we may falsely conclude that progress isbeing made in all patients, when only small subgroups maybe benefiting.

The good news is that with the molecular tools that arenow available, we are in a better position than ever to homein on specific, prospectively defined subgroups of breastcancer, and to design “tailored” adjuvant trials. The revolu-tion will only occur if we make a concerted effort to incor-porate breast cancer biology in the design of future trials,launch bold trials that may challenge old assumptions, andcontinue to nurture close collaborations across disciplinesand between institutions.

REFERENCES

1. Fisher B, Redmond C, Dimitrov NV, et al. A randomized clinical trialevaluating sequential methotrexate and fluorouracil in the treatmentof patients with node-negative breast cancer who have estrogen-receptor-negative tumors. N Engl J Med 1989;320:473–8.

2. Albain K, Barlow W, O’Malley F, et al. Concurrent (CAFT) versussequential (CAF-T) chemohormonal therapy (cyclophosphamide,doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for post-menopausal, node-positive, estrogen (ER) and/or progesterone(PgR) receptor-positive breast cancer: mature outcomes and newbiologic correlates on phase II intergroup trial 0100 (SWOG-8814). San Antonio Breast Cancer Symp 2004. Abstract 37.

3. Goss PE, Ingle JN, Martino S, et al. Updated analysis of the NCICCTG MA.17 randomized placebo (P) controlled trial of letrozole(L) after five years of tamoxifen in postmenopausal women withearly stage breast cancer [abstract]. Proc Am Soc Clin Oncol2004;23:87.

4. Howell A, ATAC Trialist’s Group: The ATAC (‘Arimidex’,Tamoxifen, Alone or in Combination) trial in postmenopausalwomen with early breast cancer—updated efficacy results based

on a median follow-up of 5 years [abstract]. Breast Cancer ResTreat 2004;88(Suppl 1):S7.

5. Jakesz R, Kaufmann M, Gnant M, et al. Benefits of switchingpostmenopausal women with hormone-sensitive early breastcancer to anastrazole after 2 years adjuvant tamoxifen: combinedresults from 3,123 women enrolled in the ABCSG Trial 8 and theARNO 95 Trial [abstract]. Breast Cancer Res Treat 2004;88(Suppl 1):S7.

6. Coombes RC, Hall E, Snowdon CF, et al. The IntergroupExemestane Study: a randomized trial in postmenopausalpatients with early breast cancer who remain disease-free aftertwo to three years of tamoxifen-updated survival analysis[abstract]. Breast Cancer Res Treat 2004;88(Suppl 1):S7.

7. Boccardo F, Rubagotti A, Amoroso D, et al. Anastrazole appears tobe superior to tamoxifen in women already receiving adjuvanttamoxifen treatment [abstract]. Breast Cancer Res Treat2003;82(Suppl 1):S6.

8. Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more thanfive years of tamoxifen for lymph node-negative breast cancer:updated findings from the National Surgical Adjuvant Breast andBowl Project B-14 randomized trial. J Natl Cancer Inst2001;93:684–90.

9. Tormey DC, Gray R, Falkson HC. Postchemotherapy adjuvanttamoxifen therapy beyond five years in patients with lymphnode-positive breast cancer. J Natl Cancer Inst 1996;88:1128–33.

10. Dowsett M, ATAC Trialists’ Group. Analysis of time to recurrencein the ATAC (arimidex, tamoxifen, alone or in combination) trialaccording to estrogen receptor and progesterone receptor status[abstract]. Breast Cancer Res Treat 2003;82(Suppl 1):S7.

11. Ellis MJ, Coop A, Singh B, et al. Letrozole is a more effectiveneoadjuvant endocrine therapy than tamoxifen for ErbB-1-and/or ErbB2-positive, estrogen receptor-positive primary breastcancer: evidence from a phase III randomized trial. J Clin Oncol2001;19:3808–16.

12. Smith I, Dowsett M. Comparison of anastrazole vs tamoxifenalone and in combination as neoadjuvant treatment of estrogenreceptor-positive (ER+) operable breast cancer in post-menopausal women: the IMPACT trial [abstract]. Breast CancerRes Treat 2003;82(Suppl 1):S6.

13. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patternsof breast carcinomas distinguish tumor subclasses with clinicalimplications. Proc Natl Acad Sci USA 2001;98:10869–74.

14. Paik, S, Shak S, Tang G, et al. Expression of the 21 genes in the recur-rence score assay and prediction of clinical benefit from tamoxifenin NSABP study B-14 and chemotherapy in NSABP study B-20[abstract]. Breast Cancer Res Treat 2004;88 (Suppl 1):S15.

15. Smith CL, O’Malley BW. Coregulator function: a key to under-standing tissue specificity of selective receptor modulators.Endocrine Rev 2004;25:45–71.

16. Berry DA, Cirrincione C, Henderson IC, et al. Effects of improve-ments in chemotherapy on disease-free and overall survival ofestrogen-receptor negative, node-positive breast cancer: 20-yearexperience of the CALGB & U.S. Breast Intergroup [abstract].Breast Cancer Res Treat 2004;88(Suppl 1):S17.

17. Buzdar AU, Valero V, Theriault RL, et al. Pathological completeresponse to chemotherapy is related to hormone receptor status[abstract]. Breast Cancer Res Treat 2003;82(Suppl 1):S69.

18. Piccart MJ, Loi S, Van’t Veer L, et al. Multi-center external valida-tion study of the Amsterdam 70-gene prognostic signature innode negative untreated breast cancer: are the results still outper-forming the clinical-pathological criteria? San Antonio BreastCancer Symposium 2004. Abstract 38.


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Breast Cancer Adjuvant Endocrine Therapy in2005: A Pandora’s Box or a Goldmine?Martine J. Piccart, MD, PhD, Jules Bordet Institute, Brussels Belgium, andKathleen Pritchard, MD, Toronto Sunnybrook Regional Cancer Centre,Toronto, Canada

How many of us—who were already practicing oncol-ogists in the 1980s—would have predicted the cur-rent revolution that is taking place in adjuvant

endocrine therapy for breast cancer? In just a few months’time we have moved from the comfortable position of pre-scribing tamoxifen to almost all women with hormonereceptor (HR)-positive disease to a daily struggle of assessingwhich patients need the incorporation of a third-generation aromatase inhibitor (AI) into their adjuvantendocrine treatment scheme. Some of us, perhaps, are stilltrying to resist the strong current that is pushing our familiar,cheap, and relatively safe standard endocrine treatment—fiveyears of adjuvant tamoxifen—out of our oncology world andoppose the optimists who are ready to abandon this old friendin favour of the AIs. An intermediate group feels strongly thata sequence of 2 to 3 years of tamoxifen followed by an AI isthe treatment of choice for a majority of women with HR-positive disease. The debate will continue until the maturedata of the large randomized trials do or do not show a sur-vival gain associated with the use of AIs, and provide a reliableassessment of their long-term side effects.

Given the history of our adjuvant clinical trials in breastcancer, in which disease-free survival (DFS) improvementshave usually matched overall survival gains with longer fol-low-up, it is very likely that AIs will end up improving long-term survival of women with HR-positive breast cancer. Incontrast, there is a real, although small, possibility that theirprolonged use might unveil serious toxicities. While bonehealth is an obvious source of concern, slightly increasednumbers of cardiac events and cognitive sequelae cannot beruled out at present. These open questions make pharmaco-genetic research a priority, because this work has the poten-tial to identify individuals at higher risk for the developmentof some of these worrisome side effects.

There are already a number of important conclusions todraw from the results generated by the five large adjuvanttrials shown in Figures 1 and 2.

• Women who have completed 5 years of tamoxifen retaina 2 to 4% annual risk of relapse in years 6 through 10following tamoxifen discontinuation and benefit from“extended therapy” with an AI (in this case, letrozole).This means that we need to start thinking about sequen-tial, non–cross-resistant endocrine therapies coveringmore than a 5-year period.

• Following the 2004 San Antonio Breast CancerSymposium meeting, we know of two large trials provid-ing level 1 evidence that switching women on tamoxifenfor 2 to 3 years to an AI (in these cases exemestane oranastrozole) is better than continuing tamoxifen in termsof DFS. In the absence of reliable molecular markerstelling us whether the tumour will remain tamoxifen-sensitive for another 2 years, most physicians will adoptthe early sequencing strategy (tamoxifen for 2 years fol-lowed by AI) rather than the late one (tamoxifen for 5 years followed by AI).

Figure 1

Figure 2


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• Following the 2005 St. Gallen Consensus Conference,there was a second trial, BIG 1-98 / IBCSG 18-98, sup-porting the results of the ATLAS trial. This study showedthat starting endocrine therapy with an AI after surgeryinstead of tamoxifen reduces the risk of a relapse in gen-eral and of distant relapse in particular. This suggeststhat a survival gain may emerge with longer follow-up.This survival gain, however, has not yet been seen forATAC, which now has a median follow-up of 68 months.

The biggest challenge to patients and physicians, there-fore, is the upfront choice between an AI and a sequence oftamoxifen for 2 to 3 years, followed by an AI. For thosewomen whose disease recurs during years 1 to 3 years oftamoxifen, when that would have been prevented by anas-trozole, the upfront AI would seem preferable. Nevertheless,the question of the optimal approach will remain open untilthe BIG 1-98 / IBCSG 18-98 study releases its mature resultsin 2007. But even then, we will only get a global answer forthe whole trial population.

Is this answer going to be satisfactory? In the era ofmolecular oncology, we have doubts that it will. We are insearch of “tailored” therapies and by “tailored” we mean ther-apies that take into account the genetic makeup of thetumour as well as the unique characteristics of its host. Ourpast and recent clinical trials have not been powered to lookat differential benefits in biologically relevant subsets ofpatients. Retrospective and suboptimal translational researchstudies already suggest marked heterogeneity of endocrineresponsive breast cancer to tamoxifen and AIs, withimproved responses to the latter in case of PgR negativity orHER-2 positivity. A multi gene array based on RT-PCR hasrecently been shown to accurately predict for the occurrenceof distant metastases in tamoxifen-treated women withnode-negative, estrogen receptor-positive disease. Similarefforts using other modern technologies are ongoing.

The strong message here is that it is no longer ethical torun large clinical trials without proper collection of bloodand tumour material. This is because understanding hetero-geneity in the magnitude of treatment benefit is of utmostimportance to our patients and to the whole of society,which will soon be unable to afford expensive treatments foreveryone for the benefit of only a few.

In the meantime, our tasks as clinicians will be to“guesstimate” whether the landscape of endocrine respon-siveness of a given tumour is closer to Figure 3 or 4.

In the first instance, it is only by using the bicycle(tamoxifen) and the expensive car (AI) in sequence that thejourney can be accomplished. In the second instance, theuse of the car upfront is the only way to get over the moun-tain, while uncertainty remains as to whether the sequential

use of a second expensive vehicle (fulvestrant?) might beneeded. These two models are based on the realistic assump-tion that AIs are not miracle drugs, and, hence, the car hasonly a limited amount of fuel.

In conclusion, the limits of breast cancer endocrinetherapy have been pushed far ahead. This is great news forour patients and a source of optimism for us all. Currentlyavailable data suggest that an AI should now be included asa part of adjuvant endocrine therapy for the vast majority ofHR-positive postmenopausal women. This progress shouldbe viewed as a goldmine rather than a Pandora’s box. Butcareful follow-up of women on adjuvant AIs remains a highpriority. This underscores the crucial importance of closecollaboration between industry and the academic worlds inthe conduct of these expensive and labour-intensive trialsthat require decades of proper patient follow-up.

Figure 3

Figure 4


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San Antonio Breast Cancer Symposium 2004:The Taxane StudiesMaureen Trudeau, MD, Toronto Sunnybrook Regional Cancer Centre, Canada

At the San Antonio Breast Cancer Symposium(SABCS) in December 2004, two important studiesinvolving taxanes were presented. The first was the

neoadjuvant study of the National Surgical Adjuvant Breastand Bowel Project (NSABP) B-27, a study investigating theaddition of docetaxel (pre- or postoperatively) to AC (adri-amycin/ cyclophosphamide) standard preoperative therapyin palpable, operable breast cancers over 1 cm.1,2 The secondwas the Programme d’Actions Concertées dans le Cancer duSein (PACS-01) study conducted in France and Belgium, astudy comparing fluorouracil/epirubicin/cyclophosphamide(FEC) 100 for 6 cycles to FEC100 for 3 cycles followedsequentially by docetaxel for 3 cycles.3

The B-27 trial was a 3-arm study involving 2,411 women(2,403 evaluated). Of these, 801 were randomized to AC pre-operatively in standard doses (60 mg/m2 and 600 mg/m2),803 were randomized to AC followed by 4 cycles of docetax-el (100 mg/m2) preoperatively, and the third group of 799was randomized to AC preoperatively followed by docetaxelpostoperatively. The study asked the following questions: 1)does docetaxel add to preoperative AC chemotherapy interms of disease-free survival (DFS), overall survival (OS),pathologic complete response (pCR) rates, and rates ofbreast conservation? and 2) does preoperative versus post-operative treatment with docetaxel make a difference withregard to the same outcomes? The trial showed that the pCRin the breast was 13.6% with AC preoperatively (combineddata from arms 1 and 3). This is very similar to the resultspreviously obtained in the NSABP B-18 trial of AC preoper-atively.4 The pCR in those women who received docetaxelpreoperatively was 26.1% (Table 1).

Rates of breast conserving surgery were slightlyimproved with the addition of docetaxel to AC, but were notsignificantly different from those obtained with AC alone.

Toxicities associated with the sequential addition of doc-etaxel were those usually attributed to docetaxel, includingfebrile toxicity, mucositis, and nail changes.

OUTCOMES

• Pathologic response rate correlated with outcome (DFS,OS) with those obtaining pCR having better prognosisthan those who did not achieve pCR.

• Those patients who obtained a pCR whether with ACalone or with AC plus docetaxel had no difference interms of outcome. This would suggest that it is impor-tant to know which patients have a complete pathologicresponse with their first 4 cycles of treatment in order toavoid potentially unnecessary therapy, although thisinvolves a small number of patients.

• The number of axillary lymph nodes involved withmetastatic disease at operation correlated best with out-come irrespective of pCR in the breast.

Overall survival was not significantly different amongthe three groups. This may be because: 1) the study wasunderpowered to show significant differences—the fact that26% of patients achieved a pCR rate was unlikely to trans-late into survival differences in the size of population stud-ied, and 2) patients also received concurrent tamoxifentreatment, and this may have impacted negatively on differ-ences in the chemotherapy treatments.

In operable breast cancer, neoadjuvant therapy remains,for the most part, a treatment given on study to increaseoperability to allow for breast conserving surgery, whereasin locally advanced or inflammatory tumours, neoadjuvanttherapy is generally the primary therapy. The B27 trial againconfirmed improvement in survival for those who achieved

pCR in Breast AC → Surgery AC → D → Surgery AC → Surgery → D

n = 801 n = 803 n = 799

Only DCIS 3.7% 7.2% 4.4%

No Invasive/No DCIS 9.1% 18.9% 9.9%

Total 12.8% 26.1% 14.3%

AC = adriamycin/cyclophosphamide; D = docetaxel; DCIS = ductal carcinoma in situ.

TABLE 1:NSABP B-27—Results for Pathologic Complete Response (pCR)


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a complete pathologic response to treatment, AC ± docetax-el. The neoadjuvant setting remains one that is fruitful forinvestigating prognostic factors, response to therapy, molec-ular features of tumours, and potentially, targeted therapies.Functional imaging may also be incorporated in these stud-ies to try and determine which tumours will respond totreatment and which will not, so that unnecessary treatmentcan be aborted or avoided.

The PACS-01 trial showed improved DFS and OS at 5years for patients who received FEC100 followed by doc-etaxel rather than FEC100 alone. The patient populationwas pre- and postmenopausal women with a median age ofabout 50 years. In an intent-to-treat analysis, the 5-year dif-ferences in DFS and OS were significantly improved for thesequential therapy (Table 2).

All tumours were node positive, with about 60% involv-ing 1 to 3 nodes in both treatment groups. There was animbalance between estrogen receptor-positivity in bothgroups as well as in the number of tumours that were recep-tor negative (ie, more estrogen receptor positive, fewer hor-mone receptor negative in the sequential therapy arm).Premenopausal patients initially did not receive tamoxifenpost-chemotherapy for receptor-positive disease. The trialwas later modified to include tamoxifen in this group ofpatients. In an analysis by number of involved nodes, trendswere seen for benefit for 5-fluorouracil, epirubicin, andcyclophosphamide (FEC) → docetaxel in the 1 to 3 and ≥ 4nodal subsets. In a subset analysis by age, comparing ageunder 50 to age 50 or over, there was significant benefit forsequential treatment in the older group of women but notin the younger group. In the younger group there appearedto be no difference between the two treatments. Whetherthis result is real, whether it reflects the lack of tamoxifentreatment in a subgroup of those patients, or whether it issecondary to a statistical anomaly, is uncertain.

There was significantly more febrile neutropenia forpatients on FEC → docetaxel compared to those receivingFEC × 6 (4.6%, 1%; p < .001), but fewer cases of leukemia;less neutropenia in cycles 4 to 6 and less granulocyte colonystimulating factor per cycle (8.9%, 14.7%; p < .001); less con-gestive heart failure but more edema and nail disorders.

Chemotherapy-induced amenorrhea was similar (68.4% ver-sus 72.4%). This would suggest that the taxane-containingregimen is at least as good for all women and probably lesstoxic. FEC → docetaxel will become one of the standards ofcare in treatment of node-positive breast cancer, once issuesof funding and guideline development are addressed.

The taxanes, docetaxel and paclitaxel, have been shownto improve survival in sequential regimens compared tostandard anthracycline regimens. The AC followed by pacli-taxel regimen of the CALGB 9344 study demonstratedimprovement in survival with 8 cycles versus 4 cycles oftherapy. The PACS-01 study showed improvement in sur-vival with the addition of the taxane sequentially after theanthracycline-based regimen, independent of number ofcycles of treatment. FEC100 × 6 would be considered a moreoptimal regimen than AC × 4, although an ongoing compar-ison of the two is being undertaken in the NSABP. The deci-sion as to who would benefit most from a taxane is yet to befully understood. The EORTC 10994/BIG 1-00 trial is inves-tigating p53 as a prognostic marker to determine if there isan improved response to taxanes in those tumours withmutant p53. There may be other molecular profiles that willpredict for response to taxanes. At the present time, theknowledge as to which patients require chemotherapy,which require an anthracycline, which require a taxane, andwhich require both is evolving. This is an area of ongoinginvestigation through multiple clinical trials with biologiccorrelates, and hopefully we will be able to determine thebest patient populations for whom the toxicity and cost ofchemotherapy is warranted. At the present time, the finaldecision as to which treatment to use will depend on thetraining of the investigator, patient preference, and cost.

REFERENCES

1. Bear HD, Anderson S, Smith RE, et al. A randomized trial compar-ing preoperative (preop) doxorubicin/cyclophosphamide (AC) topreop AC followed by preop docetaxel (T) and to preop AC fol-lowed by postoperative (postop) T in patients (pts) with operablecarcinoma of the breast: results of NSABP B-27 [abstract]. BrCancer Res Treatment 2004;88(Suppl 1):S16.

2. Bear HD, Anderson S, Brown A, et al. The effect on tumorresponse of adding sequential preoperative docetaxel to preoper-ative doxorubicin and cyclophosphamide: preliminary resultsfrom National Surgical Adjuvant Breast and Bowel ProjectProtocol B-27. J Clin Oncol 2003; 21:4165–74.

3. Roché H, Fumoleau P, Spielmann M, et al. Five years analysis ofthe PACS 01 trial: 6 cycles of FEC100 vs 3 cycles of FEC100 fol-lowed by 3 cycles of docetaxel (D) for the adjuvant treatment ofnode positive breast cancer [abstract]. Br Cancer Res Treatment2004;88(Suppl 1):S16.

4. Fisher B, Bryant J, Wolmark N, et al. Effect of preoperativechemotherapy on the outcome of women with operable breastcancer. J Clin Oncol 1998;16:2672–85.

5 Year FEC100 × 6 FEC100 × 3 → D × 3 p

DFS 73.2% 78.3% .014OS 90.7% 86.7% .017

D = docetaxel; DFS = disease-free survival; FEC = fluorouracil/epirubicin/cyclophosphamide;OS = overall survival.

TABLE 2:PACS-01—5-Year Results of Disease-Free andOverall Survival


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Genomics and Proteomics for OncologicTreatment Tailoring, 2005Brian Leyland-Jones, MD and Soheyl Baban, MS, MBADepartment of Oncology, McGill University, Montreal, Canada

Although large clinical trials have confirmed the valueof systemic therapy, it is not possible to identify at theoutset those patients who are likely to respond to

adjuvant treatment or which type of treatment should beused. For example, adjuvant therapy significantly improvesdisease-free survival (DFS) and overall survival (OS) inbreast cancer patients with both lymph node negative (LN–)and lymph node positive (LN+) disease. It is generallyaccepted that breast cancer patients with poor prognosiswould gain the most benefit from adjuvant therapy (eg,those with invasion into axillary LNs). However, results ofseveral studies show that 22 to 33% of breast cancer patientswith no detectable LN involvement and classified into agood prognosis subgroup develop recurrence of diseaseafter a 10-year follow-up. Therefore, accurate identificationof breast cancer patients over and above current prognosticand predictive markers is critically important for rationaltreatment decision-making and improved clinical outcomein the individual patient.

Microarray-based gene expression profiling of humancancers has rapidly emerged as a new powerful screeningtechnique. Recently, breast cancer gene expression signa-tures have been identified that are associated with the estro-gen receptor (ER) and LN status of patients and can aid inclassifying breast cancer patients into subgroups with differ-ent clinical outcomes after therapy. Moreover, gene expres-sion signatures have been shown to predict response to par-ticular chemotherapy regimens. The advantage of themicroarray technologies is the ability to measure theribonucleic acid expression of thousands of genes at onetime, and to relate how the expression pattern of one genecorrelates to the expression of other genes in or between dif-ferent tumour samples.

Van’t Veer and colleagues1 have used DNA microanalysison primary breast tumours of 98 young patients and appliedsupervised classification to identify a 70–gene-expressionsignature strongly predictive of a short interval to distantmetastasis in LN– patients. The poor prognosis signatureconsisted of genes regulating cell cycle, invasion, metastasis,and angiogenesis. Van de Vijver and colleagues2 subsequent-ly used this 70-gene prognosis profile to classify a series of295 consecutive patients with primary breast carcinomas ashaving a gene-expression signature associated with either apoor or a good prognosis. All patients had stage I or II breastcancer and were younger than 53 years old; 151 had LN–

disease, and 144 had LN+ disease. The predictive power ofthe prognosis profile was validated using univariable andmultivariable statistical analyses. Among the 295 patients,180 had a poor-prognosis signature and 115 had a good-prognosis signature, and the mean (±SE) overall 10-year sur-vival rates were 54.6 ± 4.4% and 94.5 ± 2.6%, respectively. At10 years, the probability of remaining free of distant metas-tases was 50.6 ± 4.5% in the group with a poor-prognosissignature and 85.2 ± 4.3% in the group with a good-progno-sis signature. The estimated hazard ratio (HR) for distantmetastases in the group with a poor-prognosis signature, ascompared with that for the group with the good-prognosissignature, was 5.1 (95% confidence interval (CI), 2.9 to 9.0;p < .001). This ratio remained significant when the groupswere analysed according to LN status. Multivariable Coxregression analysis showed that the prognosis profile was astrong independent factor in predicting disease outcome.The resulting gene-expression profile was a more powerfulpredictor of the outcome of disease in young patients withbreast cancer than standard systems based on clinical andhistologic criteria.

Piccart and colleagues3 have recently presented the val-idation of the Amsterdam 70-gene prognostic signature inLN– untreated breast cancer at the San Antonio BreastCancer Symposium (SABCS). This validation was per-formed as part of preparation for the launch of the largeprospective randomised clinical trial (MINDACT) for LN–breast cancer powered to look at the utility in clinical prac-tice of the Amsterdam 70-gene prognostic signature. Thisexternal validation was performed on frozen archivaltumour material of LN– patients aged < 60 years old. HRwere calculated under a proportional hazards model tocompare event rates in high risk versus low risk groups. Theevents of interest were time to distant metastases (TDM),DFS, distant metastases (DMFS) free survival and OS. Riskgroups were defined on the basis of clinical/pathologicaldata according to the 2003 St. Gallen criteria or theNottingham Prognostic Index (NPI), and on the basis ofthe 70-gene signature. Assuming no statistically significantheterogeneity in clinical HR, the validation criteria set apriori specified the following thresholds for the gene signa-ture HR: 1) HR > 3.0 for TDM, and 2) HR > 2.0 for DFS orOS. In addition, the group classified as low risk by the genesignature was required to have a 5-year DMFS > 90%.Three hundred and one patients, followed for a median of


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10 years, were included in the present analysis. One hun-dred loco-regional relapses, 75 distant relapses, and 76deaths were recorded. The cross-classification of clinicalversus genetic risk groups revealed discordant results for37% of women using the St. Gallen criteria and for 41%using the NPI. Significant heterogeneity between theAmsterdam and the external validation samples was foundand is currently being investigated; however, the 70-geneprognostic signature outperformed both the NPI and theSt.Gallen criteria in predicting (1) TDM (HR 1.85 [CI1.14–3.0] versus HR 1.46 [CI 0.87–2.47] versus HR 1.2 [CI0.59–2.43]), and (2) OS (HR 2.13 [CI 1.3–3.5] versus HR1.46 [CI 0.87–2.45] versus HR 0.94 [CI 0.45–1.95]). Inaddition, women of the present series classified as low riskby the gene signature had a projected 5 year DMFS of 95%.Multivariate analyses, central pathology review, and a com-parison between the 70-gene prognostic signature and theAdjuvant! Online tool are in progress. While the overall per-formance of the 70-gene prognostic signature was inferiorin this external validation series compared to the originalAmsterdam series, the results provide level 3 evidence forthe clinical value of this new genomic tool and are encour-aging to mobilize forces for the conduct of MINDACT(Figure 1).

Real-time reverse transcription-polymerase chain reac-tion (RT-PCR) technology represents a second genomicplatform that has great sensitivity and specificity, covers awide dynamic range, and requires minute amounts of cellsor tissue. While RT-PCR has significant diagnostic potential,it has to date been limited to viral diagnostics. GenomicHealth Inc (GHI) in collaboration with National SurgicalAdjuvant Breast and Bowel Project (NSABP)4 researchershas recently developed and commercialized a predictivegene signature (Oncotype DX [ODX]) that uses this tech-nology, measuring the expression of 21 genes on archivalpathology blocks. GHI/NSABP researchers selected 250 can-cer related genes from published sources and public data-bases and developed a signature based on 16 cancer and 5reference genes using 3 breast cancer studies to develop aRecurrence Score (RS) algorithm. This RS was subsequentlyprospectively tested in the NSABP B-14 study and wasshown to provide accuracy and precision in predicting thelikelihood of distant recurrence. Moreover, the RS perform-ance exceeded standard measures such as age, tumour size,and tumour grade, both in prognostic power and in repro-ducibility5; this technology has been recently approved bythe US Food and Drug Administration (FDA) for clinicalapplication.

Figure 1 Ctx = chemotherapy; EU FP VI NoE = European Framework Programme VI Network of Excellence; PRC =Protocol Review Committee; R = randomisation; Tam = tamoxifen


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Since then, this technique has undergone extensive test-ing regarding validation and prognostic capabilities: (1) thepreviously described RS has been shown to predict responseto chemotherapy.6 This work demonstrated that a higher RSis associated with a higher likelihood of pathologic completeresponse in patients treated with doxorubicin/paclitaxelneoadjuvant therapy in locally advanced breast cancer(LABC); (2) RS was shown to be not only prognostic fortamoxifen(tam)-treated patients, but also strongly predic-tive of response and benefit from tamoxifen in NSABP B-14(p-value interaction: tam treatment × ER < .001)7; 3) more-over, RS predicted the magnitude of chemotherapy benefitsin NSABP B-20: patients with tumours that had low RSderived minimal if any benefit from chemotherapy. Patientswith tumours that had high RS derived a large absolute ben-efit from chemotherapy (similar results with both CMF andMF); 4) The initial B-14 prognostic data has been subse-quently confirmed in a validation study8 of 220 evaluablecases and 570 matched controls in the Northern CaliforniaKaiser Permanente. RS was strongly prognostic of breastcancer specific mortality (BCSM) in this population withrelative risk estimates and estimates of BCSM similar tothose found in the B-14 population. Finally, 5) The RSresults from NSABP B-14 were correlated and comparedwith 10-year outcome data estimated using Adjuvant!Online (AO).9 RS and AO predicted-BCSM correlated rela-tively weakly (concordance = 48%) with RS appearing tocorrelate more strongly with outcome than AO. Hence, eachalgorithm/assay clearly contains independent prognostic

information; it would therefore be reasonable to combinethese information sets in future prognostic and predictivealgorithms.

Rapidly emerging proteomic technology is currentlybeing applied to individualize oncologic therapy. Ourunderstanding of proteomic networks in human tissue issomewhat limited at present; moreover, how these networkstruly interact (eg regular, random, and/or scale-free) and areperturbed in the disease microenvironment will become acritical component of effective therapeutic interventionstrategies and clinical trial design. In the past, a critical bot-tleneck for translational application of proteomics has beenthe paucity of validated antibodies with high specificity tothe activated signalling molecules. Happily, within the pastfew years, a large compendium of well-characterized andcarefully validated phospho-specific antibodies has becomecommercially available. A number of proteomic technolo-gies that utilize affinity capture reagents that enrich forphosphorylated proteins, followed by mass spectrometry-based sequencing, are being used for phosphoproteomicdiscovery.

Protein microarrays can be used to profile the workingstate of cellular signal pathways in a manner over and abovethat which is possible with gene microarrays, because post-translational modifications cannot be accurately portrayedby global gene expression patterns alone. Protein microarrayformats can be divided into two major classes: forward phasearrays (FPA) and reverse phase arrays (RPA) (Figures 2 and3). In the FPA format, the analyte of interest is captured from

Figure 2 Protein microarray formats. Protein microarrays consist of an array of protein samples,or protein baits, immobilized on a solid phase. The array can be queried with a mixture of labeledproteins containing analytes of interest. The analyte proteins are captured and can be detectedusing colorimetric, fluorescent, or chemiluminescent means. (Taken from Petricoin et al, NatureReviews 1:683-695, 2002.)


1212 the solution phase by a capture molecule, usually an anti-body, which is immobilized on a substratum and acts as abait molecule. Using FPA, each spot contains one type ofimmobilized antibody or bait protein. Each array is incubat-ed with one test sample, such as a cellular lysate or serumsample representing a specific treatment condition, and mul-tiple analytes from that sample are measured simultaneous-ly. In contrast, the RPA format immobilizes an individualcomplex test sample in each array spot, such that an arraycomprises hundreds of different patient samples or cellularlysates. With RPA, each array is incubated with one detectionprotein (ie, antibody): a single analyte endpoint is measuredand directly compared across multiple samples. Probingmultiple arrays spotted with the same lysate concomitantlywith different phospho-specific antibodies provides theeffect of generating a multiplex read-out. The RPA platformhas been employed to explore a variety of signalling path-ways involved in malignant progression and tumour biology.For example, in a study of prostate tissue, pathway profilingof microdissected cells from normal stromal and prostatetumours revealed that activation of protein kinase C alpha isdown-modulated in prostate cancer progression.

Sheehan and colleagues10 at the FDA-National CancerInstitute Clinical Proteomics program have recently usedRPA technology to profile a matched cohort of primary andmetastatic ovarian carcinomas. In characterizing signalpathway alterations between the two tissue microenviron-ments, they hoped to gain insights into the aberrant sig-nalling that maintains shed neoplastic ovarian cells at sec-

ondary sites. Fifteen frozen tissue samples were obtainedfrom 9 patients with a diagnosis of stage III or IV epithelialovarian cancer. Six patients had matched primary ovariantissue and omental metastases obtained during cytoreduc-tive surgery. The histological diagnoses comprised papillaryserous, endometrioid and mixed carcinomas, and one pri-mary peritoneal carcinoma. Epithelial cells were microdis-sected from frozen tumour sections and printed on arrays.The slides were probed with 26 phospho-specific antibodiesto proteins involved in mitogenesis, including growth factorreceptors, signal-transducing proteins, and nuclear tran-scription factors in order to profile the phosphoproteomicsignal pathway circuitry. Analysis of multiple differentkinase substrates, detected by phosphorylation-specificantibodies, revealed a striking degree of heterogeneity in theactivity of the signalling cascades within each patient.Unsupervised hierarchical clustering analysis revealed thatthe samples were divided into two large groups—one inwhich the majority of endpoints were activated, and theother in which they were not. This division was not based onprimary or metastatic tissue origin or by histologic type.Interestingly, the primary peritoneal carcinoma did not dis-play a significantly different phospho-proteomic portraitfrom that of primary ovarian tumours. Secondly, it wasobserved that comparison of cell signalling within the pri-mary group (or indeed, the metastatic group) demonstratedconsiderable variation in the level of signal pathway activa-tion, ie, no common pattern was specific to either of the tis-sue microenvironments.

Figure 3 Reverse-phase protein arrays. A new class of proteinarray is the reverse-phase array, which immobilizes the cellu-lar lysate sample to be analyzed. Lysates are prepared fromcultured cells or microdissected tissues and are arrayed inminiature dilution curves. The analyte molecule contained inthe sample is detected by a separate labeled probe (e.g., anti-body) applied to the surface of the array. The array is highly lin-ear, very sensitive and requires no labeling of the sample pro-teins. (Taken from Petricoin & Liotta, J. Nutr. 133:2476S-2484S, 2003.)


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The First Annual San Antonio Breast CancerSymposium was held November 11, 1978 duringBreast Cancer Awareness Week, and was part of an

intensive 3-year outreach program of public and profession-al education designed to significantly reduce the death ratecaused by breast cancer in San Antonio and surroundingcounties. It was sponsored by Cancer Therapy and ResearchCenter (CTRC) and the American Cancer Society, TexasDivision, in conjunction with The University of TexasHealth Science Center at San Antonio (UTHSCSA) and theBexar County Medical Society.

History of the San Antonio Breast CancerSymposium (SABCS)Adapted from the SABCS Web site, with Rich Markow, Symposium Director

That all-day course for physicians and surgeons wasorganized and co-directed by Charles A. Coltman Jr., MDand William L. McGuire, MD, both Professors of Medicineat UTHSCSA. It featured invited presentations by a panel ofinternationally known specialists and was attended by 141physicians and surgeons from a 5-state area.

Three years later, in 1981, the meeting was expanded to2 days, a call for abstracts was distributed worldwide, andproffered papers for slide and poster presentations wereincorporated into the program, thereby broadening itsscope to both attract and draw from a larger, international

Finally, the most intriguing finding was that themetastatic signatures were dramatically changed comparedto their matched primary counterparts, with entirely differ-ent portraits emerging. Each patient’s proteomic patternhad evolved as the tumour spread to a secondary site. Theadditional discovery that metastatic cell signalling is so dis-similar to the primary tumour highlights the critical needfor patient-tailored therapy that is designed to specificallytarget disseminated metastatic cells because it is the aber-rant pathways of the latter that most closely reflect diseasebehaviour within the patient. In this small cohort, each ofthese patients may have responded quite differently to con-ventional chemotherapy, despite being very similar in termsof disease stage. Acquired change in the tumoural proteomemay well be associated with drug resistance. The primaryquestion currently being addressed is whether metastasis todifferent secondary site (eg, liver or lung) shows the samedegree of signalling heterogeneity, demonstrating organ- orpatient-specific phosphorylation patterns.

Current studies such as TransHERA11 will employ directcomparisons of expression array, RT-PCR, and proteomicplatforms in order to evaluate their relative contributions inindividualizing therapy at this critical juncture in person-alised medicine.

REFERENCES

1. Van’t Veer LJ, Dai H, van de Vijver, et al. Gene expression profil-ing predicts clinical outcome of breast cancer. Nature2002;31:530–6.

2. Van de Vijver MJ, He YD, Van ‘t Veer LJ, et al. A gene expressionsignature as a predictor of survival in breast cancer. N Engl J Med

2002;347:1999–2009.3. Piccart MJ, Loi S, Van’t Veer LJ, et al. Multi-center external valida-

tion study of the Amsterdam 70-gene prognostic signature innode negative untreated breast cancer: are the results still outper-forming the clinical-pathological criteria? San Antonio BreastCancer Symposium, December 2004. Abstract #38.

4. Paik S, Shak S, Tang G, et al. A multigene assay to predict recur-rence of tamoxifen-treated, node-negative breast cancer. N Engl JMed 2004;351:2817–26.

5. Paik S, Shak S, Tang G, et al. Multi-gene RT-PCR assay for pre-dicting recurrence in node negative breast cancer patients NSABPstudies B-20 and B-14. Br Cancer Res Treatment [abstract]2003;82(Suppl 1):S10.

6. Gianni L, Zambetti M, Clark K, et al. Gene expression profiles ofparaffin-embedded core biopsy tissue predict response tochemotherapy in patients with locally advanced breast cancer.San Antonio Breast Cancer Symposium, December 2004.

7. Paik S, Shak S, Tang G, et al. Expression of the 21 genes in theRecurrence Score assay and prediction of clinical benefit fromtamoxifen in NASBP study B-14 and chemotherapy in NSABPstudy B-20 [abstract]. Br Cancer Res Treatment 2004;88(Suppl 1):S15.

8. Habel LA, Quesenberry CP, Jacobs MK, et al. A large case-controlstudy of gene expression and breast cancer death in NorthernCalifornia Kaiser Permanente [abstract]. Br Cancer ResTreatment 2004;88(Suppl 1):S118.

9. Bryant J. Is the “standard adjuvant regimen” good for all? PrimaryTherapy of Early Breast Cancer Conference, St. GallenSwitzerland 2005.

10. Sheehan KM , Calvert VS, Kay EW, et al. Use of reverse phase pro-tein microarrays and reference standard development for molec-ular network analysis of metastatic ovarian carcinoma. Mol CellProteomics 2005. Jan 25; [Epub ahead of print]

11. Baban S, Leyland-Jones B, and Dowsett M. Translational researchand HERA. BIG Newsletter 2005;7(1):8–9.


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9th St. Gallen International ConsensusConference on Primary Therapy of Early BreastCancer 2005: A Preliminary SummaryProf. Dr. med. Hans-Jörg Senn, MD, Center for Tumordetection + Prevention(ZeTuP), St. Gallen, Switzerland, and PD Dr. Beat Thürlimann, MD, Head ofSenology Center of Eastern Switzerland, Kantonsspital, St. Gallen, Switzerland

CONFERENCE SETTING

The 9th St. Gallen International Consensus Conference onPrimary Therapy of Early Breast Cancer took place onJanuary 26–29, 2005, in the OLMA Conference Center in St.Gallen. Close to 4,200 breast cancer specialists from variousmedical disciplines and from 83 countries worldwide partici-pated at this important event,* which was followed by theannual meeting of the International Breast Cancer StudyGroup (IBCSG). As in the past, the conference was chaired byRichard D. Gelber (Boston, USA), Aron Goldhirsch (Lugano,Switzerland and Milano, Italy) and Hans-Jörg Senn (St.Gallen, Switzerland), together with Beat Thürlimann (St.Gallen, Switzerland), the new president of the FoundationCouncil of the IBCSG as Scientific Secretary General.

CONFERENCE AIM AND APPROACH

The aim of the St. Gallen Consensus was again to provide aperiodic—now bi-annual—update of internationally usefultreatment guidelines for the optimal therapy of patients

with early (operable) breast cancer. These conferences arenot intended to provide a “list of recipes,” but rather a set ofopinions and guidelines for the treatment of patients out-side of clinical trials (in most countries more than 95% ofall newly diagnosed patients). The St. Gallen Consensus isnot perfect, nor will it satisfy everyone or solve all therapeu-tic controversies. But it intends to help many patients andtheir physicians to discuss the available scientific evidenceand expert opinions for reasonably balanced primary treat-ment decisions.

ST. GALLEN CONSENSUS: A PUBLICPROFESSIONAL EVENT

The St. Gallen Consensus conferences are public profession-al events, open on a global scale to all interested physicians,surgeons, and researchers. After 3 days of lectures by topinvited experts and scientific satellite workshops, an inter-disciplinary panel of 30 breast cancer experts from aroundthe world generates a reasonable treatment recommenda-

base. Renowned experts gave formal plenary lectures, andaccepted abstracts were published for the first time in thepeer-reviewed journal Breast Cancer Research andTreatment. Case discussion lunches offered opportunity fordiscussion of complex clinical problems in the managementof primary and metastatic disease by a panel of physiciansfrom different disciplines.

Although some modifications have been made in theformat, such as incorporating mini-symposia and, in 1997,the prestigious Brinker International Award for CancerResearch program of the Susan G. Komen Breast CancerFoundation, the overall format remains very much thesame. This reflects the objective of the Symposium, which isto provide state-of-the-art information on the experimentalbiology, etiology, prevention, diagnosis, and therapy ofbreast cancer and premalignant breast disease, to an interna-tional audience of academic and private physicians andresearchers.

In 1990, CTRC and UTHSCSA formally entered into acollaboration known as the San Antonio Cancer Institute (an

NCI-designated Clinical Cancer Center), which in 1995assumed direct sponsorship of the Symposium. The UTHSC-SA Medical School, through the Office of Continuing MedicalEducation, continues to be the provider of continuing med-ical education sponsorship for this premier breast cancersymposium. The SABCS has grown tremendously since 1990,when there were 526 registrants. The 2004 conference regis-tered 6,810 participants from 86 countries. Fifty percent ofSABCS attendance is from outside the United States.

All administrative functions are the responsibility of thesymposia director and occur in the symposium operationsoffice, which is located at CTRC, 7979 Wurzbach, Suite U-524, San Antonio, Texas 78229. All proceeds from registra-tion and abstract fees, industry educational grants, andexhibit fees are used for symposium development and oper-ations, and for support of its staff, which consists of thesymposia director, the meeting planner and the assistantmeeting planner.

For more information, please consult


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tion compromise, which should satisfy the needs of the next2 to 3 years. Other consensus approaches and statements,such as the Oxford Overviews or the National Institutes ofHealth Consensus, have different aims and settings.

IMPORTANT DIFFERENCES FROM PAST ST.GALLEN PANELS/AREAS OF DISCUSSION

The St. Gallen Consensus Panel 2005† integrated severalfundamental changes compared to previous consensusmeetings:

• It moved away from only discussing “pure level-I evi-dence” with long-term overall survival data as themandatory basis for treatment selection and recognizedlower evidence levels to generate the “set of opinionsand guidelines” for discussing available therapeuticoptions and expert opinions for balanced treatmentdecisions in daily routine.

• It also moved away from risk of relapse as the main cri-terion for treatment choice, but introduced endocrineresponsiveness as the most important selection factor forboth adjuvant chemo- (CT) and endocrine (HT) thera-py treatments in node-negative and node-positive dis-ease. It recognized that even the magnitude of the effectof adjuvant CT regimens is related to the endocrineresponsiveness of the primary tumour. The panel alsoaccepted that endocrine responsiveness is not dependentonly on estrogen and progesterone receptor staining, buton a more complex interaction between known andunknown factors. It furthermore introduced the catego-ry of unclear degree of endocrine responsiveness.

Discussions also focused the following key issues:

• The division of the risk of relapse estimation in node-negative disease into two categories: “minimal” (lower)risk and “intermediate” (formerly average) risk, the latterintegrating also node-positive 1–3 node cases, whilepatients with clear-cut human epidermal growth factorreceptor-2 (HER-2)-overexpression and/or > 4 positive

axillary nodes fall into the “high-risk” category. Althoughviewed as scientifically interesting, neither the coagula-tion markers (PAI-1/uPI) nor the elaborated “Oncotype”system were presently accepted as risk selection parame-ters (lack of standardisation, missing long-term results,and lack of availability on an international scale).

• The optimal use of aromatase inhibitors in the treat-ment of postmenopausal women with endocrineresponsive or doubtful endocrine responsive diseasewhere no consensus was reached. It was agreed, howev-er, that tamoxifen is not out of the therapeutic arma-mentarium for adjuvant HT in postmenopausal womenwith hormone-sensitive breast cancer.

• The 30 panelists continued to have a fairly conservativeapproach regarding the use of taxanes and dose denseregimens in the adjuvant CT setting.

• The fact that no data are available to recommend adju-vant trastuzumab in HER-2-overexpressed patients.

PRELIMINARY CONCLUSIONS ANDPUBLICATION OF CONSENSUS 2005

Overall, the St. Gallen Consensus Panel 2005 adopted a morepractical approach compared to previous meetings, and thepanel more intensively recognized the heterogeneous andcomplex biology of breast cancer. It tried to recommendtreatment selections mainly according to expected treatmentoutcome on the basis of endocrine responsiveness. The avail-ability of an electronic voting device for the whole panel withimmediately projected majority votes transformed the clos-ing consensus session into a spectacular exercise. The sum-mary as presented in this article is only a preliminary state-ment: the final manuscript will be available in the Journal ofClinical Oncology (JCO); the Consensus Statement is to beexpected on line in May/June and officially published inJuly/August 2005. Once accepted by the JCO Editorial Office,the Consensus Statement 2005 will also be available on thehome pages of St. Gallen Oncology Conferences or theCenter for Tumordetection + Prevention (ZeTuP) St. Gallen: or

* The first such conference took place in Wildhaus/St. Gallen in1978 and was attended by 79 delegates. In the last decade, confer-ence attendance has increased substantially, from 1,250 in 1995 towell over 4,000 in 2005. The next St. Gallen conference will takeplace on 14 – 17 March, 2007.† K. Albain, USA; J. Bergh, Sweden; M. Castiglione-Gertsch,Switzerland; A. Coates, Australia; A. Costa, Italy; J. Cuzik, UK; N.Davidson, USA; J. Forbes, Australia; R.Gelber, USA; J. Glick, USA,co-chair; A. Goldhirsch, Switzerland & Italy, co-chair; P. Goss,USA; J. Harris, USA; A. Howell, UK; J. Ingle, USA; R. Jakesz,Austria; E. Rutgers, Netherlands; J. Jassem, Poland; M. Kaufmann,Germany; M. Martin, Spain; L. Mauriac, France; M. Morrow, USA;H. Mouridsen, Denmark; M. Namer, France; M. Piccart / D. deValeriola, Belgium; K. Possinger, Germany; K. Pritchard, Canada;B. Thürlimann, Switzerland; G. Viale, Italy; A. Wallgreen, Sweden;W. Wood, USA.


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PURPOSE BIG 1-98 is the first clinical trial designed to incorporate both a head-to-head compari-son of letrozole with tamoxifen during the first 5 years following breast cancer surgery,and a sequencing of both agents to determine the most effective approach to minimizethe risk of recurrence and of side effects.

SCOPE The BIG 1-98 study is being conducted in 27 countries and involves 8,028 post-menopausal women with early breast cancer.

The study was conducted under the umbrella of the Breast International Group (BIG),coordinated and managed by the International Breast Cancer Study Group (IBCSG),in collaboration with the Danish Breast Cancer Group, the Fédération Nationale desCentres de Lutte Contre le Cancer (FNCLCC), the Yorkshire Group, and many otherindependent centres.

DESIGN Multinational, phase III, double-blind, double-dummy, randomised trial administeringadjuvant therapy (therapy used to prevent recurrence after surgery) following completesurgical removal of the tumour (resection). All patients will be monitored for the restof their life to assess long-term efficacy, including overall survival and tolerability.

RANDOMISATION BIG 1-98 compares the following randomisation arms:

A. tamoxifen for 5 yearsB. letrozole for 5 yearsC. tamoxifen for 2 years followed by letrozole for 3 yearsD. letrozole for 2 years followed by tamoxifen for 3 years

ACCRUAL Randomisation to arms A and B: 1,835 patientsRandomisation to arms A, B, C, and D: 6,193 patients

RESULTS The first results are based on the comparison of the initial treatment assignment toletrozole in arms B and D with assignment to tamoxifen in arms A and C, butexcluding events occurring more than 30 days after therapy switch in arms C and D.

After a median follow-up of 25.8 months, we found a statistically significant differencein disease-free survival (DFS) in favour of letrozole:

• DFS hazard ratio 0.81, p = .003, absolute difference: 2.6% at 5 years.• The absolute difference in cumulative breast cancer relapse is 3.4% at 5 years.• Letrozole was particularly effective in preventing relapse at distant sites.

PROTOCOL TARGETED • Similar in both treatment arms except for an excess of thromboembolic events and vaginal bleeding on tamoxifen.

• Endometrial biopsies were more frequent with tamoxifen.• Bone fractures were more frequent with letrozole.• Mild cholesterol elevation was more common with letrozole.• Deaths without recurrence (particularly cardiovascular), although rare, were more

frequent with letrozole.

These results were presented during the 9th International “Primary Therapy of EarlyBreast Cancer” in St. Gallen, Switzerland, on January 26, 2005.

Information on sequential therapy will require further follow-up.

BIG 1-98 Trial: First ResultsNadia Munarini, PhD, IBCSG Coordinating Center

ADVERSE EVENTS:


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STATISTICAL Primary Core Analysis: comparing letrozole and tamoxifen as monotherapy (DFS-events in arms A and B + DFS-events in arms C and D occurring before the switchplus 30 days). 647 events required allowing the detection of a 20% relative riskreduction with 80% probability. Actual number of DFS events for the present analy-sis: 779. An intent-to-treat analysis was performed, excluding only the 18 patientswho withdrew consent and had neither treatment nor follow-up.

PRIMARY ENDPOINT DFS is defined as time from randomisation to first instance of invasive breast cancerrecurrence, including contralateral invasive breast cancer or new second malignancyor death without recurrence.

SECONDARY • Systemic DFS is defined as the time from randomisation to first instance ofinvasive regional or distant recurrence, second non-breast malignancy or death without recurrence.

• Overall survival (the time from randomisation to death from any cause).• Safety and tolerability.

SAFETY • Continuous medical surveillance of severe adverse events.• 6-monthly review by the Independent Data Safety and Monitoring Committee

(DSMC).• Interim efficacy analyses blinded as to treatment assignment after 261 and 430

events presented to the DSMC.

TRIAL RESPONSIBILITIES • IBCSG: study design, database, and data management, medical review, statistical analysis, coordination, and communication, ethics committee, independent data safety, and monitoring committee.

• Novartis: drug distribution, financial support.

PARTICIPATING

Additional information regarding IBCSG, BIG 1-98 can be found on the Web site.

CONSIDERATIONS

ENDPOINTS

COUNTRIESArgentinaAustraliaBelgiumBrazilCanadaChileCzech Republic

DenmarkFranceGermanyGreat BritainHungaryIcelandItaly

NetherlandsNew ZealandPeruPolandPortugalRussiaSlovenia

South AfricaSpainSwedenSwitzerlandTurkeyUruguay


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PPAATTIIEENNTT PPOOPPUULLAATTIIOONN::

This trial is for older women (66 years of age or older) withhistologically proven, resected breast cancer. The diseasemust be classified as endocrine nonresponsive and patientsmust not be candidates for endocrine therapy or for anadjuvant chemotherapy program that includes a “standard”anthracycline-containing chemotherapy regimen.

RRAATTIIOONNAALLEE::

Efficacy data in women aged > 70 years are scarce, resultingin a lack of clear guidelines for patients in this age group.Thus, a therapeutic dilemma exists when a woman atadvanced age presents with an endocrine nonresponsiveearly breast cancer. Relapses of breast cancer may occur ear-lier in patients with endocrine nonresponsive disease com-pared to those with hormone receptor-expressing tumours,even when axillary nodes are negative at presentation. Thisprovides a rationale for reducing the risk of relapse evenwhen life expectancy is less than decades.

Such a dilemma does not exist if the patient is biologi-cally (and functionally) young, and a “standard” chemother-apy regimen may be offered with no concern.

The physician may decide not to offer a relatively frailpatient any treatment, for fear of possible subjective orsevere toxic effects of chemotherapy. Typically, however,these patients are treated in a rather heterogeneous way byarbitrarily reducing doses or modifying schedules of adju-vant chemotherapy regimens that were studied in youngerwomen. This trial is therefore important because it isdesigned to test a reasonably tolerated cytotoxic regimen fora patient subpopulation uniformly treated within a ran-domized trial.

The choice of the population (endocrine nonresponsive)is advantageous because the magnitude of chemotherapyeffect for this postmenopausal cohort is likely to be quite

large, similar to the effect observed for premenopausalpatients with similar biological tumour characteristics.Avoiding dilution with patients having endocrine responsivetumours (even those with high number of axillary lymphnodes involved) maximizes the chance to observe a benefit inthe shortest time with the lowest number of patients.

TTAAIILLOORREEDD TTRREEAATTMMEENNTT IINNVVEESSTTIIGGAATTIIOONNSS::

Some of the investigators are likely to choose no adjuvantcytotoxic therapy as a standard for frail patients at advancedage, while others will prefer to offer some treatment for allpatients with endocrine nonresponsive disease. The CASAstudies are therefore aimed at investigating the role of adju-vant cytotoxic chemotherapy for postmenopausal women atadvanced age with endocrine nonresponsive early breastcancer. A PLD (Caelyx®), was chosen as the experimentaltreatment (Figure 1).

These two complementary randomization options aretailored to the investigator’s decision and/or the patient’spreference about what would constitute an appropriate con-trol treatment group for the individual patient, thusenabling the physician to express his or her own attitudeand/or belief towards adjuvant treatments in this subpopu-lation. Because of the separate designs, at the time of ran-domization the investigator will be asked to select one of thetwo randomization options:

• Option 1: PLD versus nil, is designed for patients who,according to the treating physician and/or to thepatient’s preferences, are candidates to receive no adju-vant therapy.

• Option 2: PLD versus low dose, metronomic CM, isdesigned for patients who, according to the treatingphysician and/or to the patient’s preferences, shouldreceive some adjuvant treatment.

BIG 1-05/IBCSG 32-05: Chemotherapy AdjuvantStudies for Women at Advanced Age (CASA)Phase III Trial Evaluating the Role of Adjuvant Pegylated Liposomal Doxorubicin(PLD, Caelyx®) for Women (age 66 years or older) with Endocrine NonresponsiveBreast Cancer who are NOT Suitable for Being Offered a “StandardChemotherapy Regimen”

Coordinating Group: International Breast Cancer Study Group (IBCSG)

BIG Studies for Older Patients


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These trials require a rather large number of patientsfrom a rather small subpopulation of breast cancer patients.Although the incidence of breast cancer in elderly women isquite high, it is estimated that only 15% will have a receptornegative (no expression of estrogen receptor and prandialglucose regulation) disease. Thus, a satisfactory accrual canonly be reached with an international collaboration andparticipation around the world.

AAIIMM::

The overall aim of the CASA study is to investigate the roleof PLD as adjuvant chemotherapy for older post-menopausal women for whom chemotherapy is indicated,but standard regimens, derived from trials in youngerwomen, are assumed to be too toxic or inconvenient. Thestratified analysis combining the results of both randomiza-tion options will provide the primary evidence on the effec-tiveness of PLD. This analysis will assess PLD versus non-PLD-containing control groups (either nil or CM). In addi-tion, analyses will be conducted separately for each of thetwo randomization options (adjusted for multiple compar-isons) to assess each of the individual pair-wise contribu-tions to the overall result.

PPAATTIIEENNTT EENNTTRRYY::

Patients should be randomized within 6 weeks after sur-gery. Patient-related baseline quality of life assessments, aswell as physician-documented baseline cognitive and phys-

ical functioning assessments, must also be obtained beforerandomization.

SSTTRRAATTIIFFIICCAATTIIOONN FFAACCTTOORRSS::

Institution is the only stratification factor.

EENNDDPPOOIINNTTSS::

Primary:

• Breast cancer free survival (events are reappearance ofinvasive breast cancer at any site including contralateraldisease)

Secondary:

• Tolerability (treatment completion)• Adverse events• Quality of life• Disease-free survival (includes second malignancies and

deaths)• Sites of failure• Overall survival• Causes of death

SSAAMMPPLLEE SSIIZZEE AANNDD AANNTTIICCIIPPAATTEEDD SSTTUUDDYYDDUURRAATTIIOONN::

The trial is designed to include 1,296 patients (432 per yearfor 3 years with 1.76 years of additional follow-up—totalstudy duration of 4.76 years).

Primary Surgery

Stratify

• Institution

RANDOM

PLD

No adjuvant therapy (nil)

Primary Surgery

Stratify

• Institution

RANDOM

PLD

Low-dose, metronomic CM

Option 2: CASA-CM

Option 1: CASA-Nil

Figure 1: CM = cyclophosphamide plus methotrexate; PLD = pegylated liposomal doxorubicin.


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PROTOCOL SUMMARY AND RATIONALE

Approximately 50% of new diagnoses of early breast cancerare made in patients above the age of 65. In 1998, for exam-ple, approximately 27,415 women in Germany had theirdiagnosis of breast cancer at an age above 60, which repre-sents approximately 60% of all newly diagnosed early breastcancers for that year.1 Because this age group has not beeneligible to participate in most trials in the past, the effect ofadjuvant therapy is still unclear in elderly patients. The pri-mary aim of the BIG 4-04/GBG 32 ICE (Ibandronate withor without Capecitabine in Elderly patients with early breastcancer) trial will be to determine, in the presence of a bis-phosphonate, the role of adjuvant chemotherapy withcapecitabine in elderly patients. The high activity, acceptabletoxicity, and oral formulation of capecitabine meet therequirements of elderly patients. In a recent analysis of theEarly Breast Cancer Trialists’ Collaborative Group database,presented in St. Gallen by R. Gelber2 it could be shown thatthe chemotherapy effect across age is highly affected by thefrequency of hormone-sensitive tumours and that the post-correction chemotherapy effect is similar in all age groups.The only adjuvant phase III study available so far is a smallFrench trial3 that demonstrated a significant contribution of

BIG 4-04/GBG 32 Ibandronate with or withoutCapecitabine in Elderly Patients with EarlyBreast Cancer/ICE—StudyAn Intergroup Study—The German Experience

Collaborating Groups: German Breast Group (GBG) (coordinator) WestdeutscheStudiengruppe (WSG), Arbeitsgemeinschaft Gynäkologische Onkologie (AGO),Nordostdeutsche Gesellschaft für Gynäkologische Onkologie (NOGGO)

Principal Investigators: Ulrike Nitz, University of Düsseldorf (WSG), and Gunter von Minckwitz (GBG)

weekly epirubicin to tamoxifen alone in 338 patients withmainly hormone-sensitive tumours. Therefore, the ICEstudy includes patients with both hormone-sensitive andinsensitive tumours.

The efficacy of bisphosphonates has been established inthe treatment and prevention of osteoporosis. Two studieshave recently shown that adjuvant long-term use of clo-dronate can reduce the risk of recurrence in breast cancer.4,5

A third trial, which did not find a positive result, sufferedfrom severe methodological inadequacies.6 The third-generation bisphosphonate ibandronate will be given in thistrial to all patients to prevent osteoporosis and, potentially,a recurrence of breast cancer—these patients are at risk forboth. Because the preference of elderly patients for intra-venous or oral administration is not known, the mode ofadministration for ibandronate will be according to patientchoice. Patient preference and compliance will be secondaryendpoints.

As another one of the secondary endpoints, geriatricassessment with the Charlson Scale will be compared withthe VES 13 Score.7,8 Both will be included together with age,serum albumin, hemoglobin level, and creatinine clearancein a multivariate analysis to assess their prognostic impactfor outcome and toxicities.

TTRREEAATTMMEENNTT SSCCHHEEDDUULLEESS::

Chemotherapy:All regimens are 16 weeks duration.

• PLD: Caelyx 20 mg/m2 IV × 8 doses (delivered every 2 weeks).

• CM Regimen: Low-dose, metronomic CM administeredfor 16 weeks; cyclophosphamide 50 mg/day orally con-

tinuously for 16 weeks; methotrexate 2.5 mg/twice a dayorally days 1 and 4 of every week for 16 weeks.

Radiotherapy:Radiation therapy to the conserved breast is recommended.Radiation therapy to the chest wall following mastectomy isoptional. Radiation therapy may be given either duringoperation or after all chemotherapy.


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STUDY DESIGN STATUS OF STUDY

The combining of the initiatives and sites of the four majorGerman breast cancer study groups (ie, AGO, GBG,NOGGO, and WSG) is definitely paying off. After receivingall the IRB approvals for the participating states or universi-ties, the ICE trial succeeded in already recruiting 147patients by March 2005. The following Serious AdverseEffects have been registered: hand foot syndrome (3),thrombosis (2), thromboembolism, myocardial infarction(not related to the study medication), angina pectoris (notrelated to the study medication), gingivitis, and hospitalisa-tion due to a gastrointestinal infection with diabetes. Onedrop-out and 1 interruption of the capecitabine treatmentdue to toxicity have also been registered.

So far, there are 150 sites registered, with about 70 active.Patient recruitment for this trial was expected to be difficult,yet the recruitment of well over 20 patients per month sincethe end of last year has demonstrated that women over 65 areopen to and interested in taking part in breast cancer trials.However, it may take quite an effort to address this patientgroup in general because one has to involve the family morecarefully and take social background into considerationwhen talking to patients about participation in this trial.

BIG groups interested in participating in the trial shouldnotify the BIG Secretariat as soon as possible by e-mail:[email protected]. For further scientific informationabout the study, please contact Dr. Cecilia Hanne of theGerman Breast Group: [email protected]

REFERENCES

1. Robert-Koch-Institut. 2. Gelber, R. Session 7: Best use of adjuvant systemic therapies II;

Chemotherapy aspects S30: predicting response to systemic treat-ments: learning from the past to plan for the future; oral presen-tation during the 9th International Conference on PrimaryTherapy of Early Breast Cancer. 26–29 January 2005, St. Gallen,Switzerland.

3. Fargeot P, Bonneterre J, Roche H, et al. Disease-free survivaladvantage of weekly epirubicin plus tamoxifen versus tamoxifenalone as adjuvant treatment of operable, node-positive, elderlybreast cancer patients: 6-year follow-up results of the FrenchAdjuvant Study Group 08 trial. J Clin Oncol 2004;22:4622–30.

4. Diel IJ, Solomayer EF, Costa SD, et al. Reduction in new metas-tases in breast cancer with adjuvant clodronate treatment. N EnglJ Med 1998;339:357–63.

5. Powles T, Paterson S, Kanis JA, et al. Randomized, placebo-controlled trial of clodronate in patients with primary operablebreast cancer. J Clin Oncol 2002;20:3219–24.

6. Saarto T, Blomqvist C, Virddunen P, Elomaa I. Adjuvant clo-dronate treatment does not reduce the frequency of skeletalmetastases in node-positive breast cancer patients: 5-year resultsof a randomised controlled trial. J Clin Oncol 2001;19:10–7.

7. Charlson ME, Pompei P, Ales KL, MacKenzie R. A new method ofclassifying prognostic comorbidity in longitudinal studies: devel-opment and validation. J Chron Dis 1987;40:373–83.

8. Saliba D, Elliot M, Rubinstein LZ, et al. The vulnerable elders sur-vey: a tool for identifying vulnerable older people in the commu-nity. J Am Geriatr Soc 2001;49:1691–9.

Age ≥ 65 yrs, N+ or N– (high risk: T ≥ 2 cm or G II/IIIor Receptor negative)

Randomization

Ibandronate 50 mg po dailyor 6 mg iv, q4W, 2 yr*

Ibandronate 50 mg po dailyor 6 mg iv, q4W, 2 yr* +Capecitabine 2000 mg/m2

days 1–14 q d22 × 6

If ER and/or PR positive: Anastrozole 1 mg po daily for 5 yr(in sequence to capecitabine).N = node, T = tumor size, G = grade.*according to patient choice

PATIENT DEFINITION

Patients should be randomized within 3 months after axil-lary dissection, have a Charlson Scale score of ≤ 2, and a cre-atinine clearance calculated by the Cockroft-Gold formulaof above 50 ml/minute.Radiotherapy should be given after chemotherapy if the patientis randomized to the capecitabine arm. In the ibandronate onlyarm, radiotherapy can start directly after randomization.

STRATIFICATION FACTORS

• participating centre• nodal status• age (65–69, 70–74, 75–79, 80+ years)• receptor status

END POINTS

Primary endpoint: any local or distant relapse of breast cancer,any second malignancy, and any death irrespective of its cause.

Secondary endpoints: any death related and unrelated tobreast cancer, any premature treatment discontinuation ofcapecitabine or ibandronate, any grade II to grade IV adverseevent specified as “serious” or “nonserious;” every bone frac-ture, bone surgery, new diagnosis of osteoporosis; number ofcompleted months of iv or po treatment with ibandronate, andfrequency of changes of administration preference; evaluationaccording to EORTC Q 30, Charlson Scale and VES–13 points.

Tertiary endpoints: expression of prognostic factors (willbe determined at a later stage): age, serum albumin level,hemoglobin, creatinine clearance, Charlson Scale, VES score.

SAMPLE SIZE AND STUDY DURATION

The trial is designed to include 1,394 patients in 3.5 years;the study duration including follow up: 8.5 years; firstpatient: July 2004.


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BIG 0-01/EORTC 10994: Sharing Some GoodNews about the p53 StudyBy Hervé Bonnefoi, MD, (Study Chairman), HôpitauxUniversitaires de Genève, Geneva, Switzerland

Updates on Other Big Trials

The first BIG study of the third millennium is not sobig in size with an initial target accrual of 1,440patients, but it does ask a big question: which patients

will benefit from taxanes? The aim of this trial is to identifypredictive factors of response to chemotherapy. Specifically,the p53 gene will be analysed as a primary endpoint, thequestion being whether p53 mutated tumours respond bet-ter to taxanes than p53 wild type tumours. Importantly,besides the p53 gene, other predictive factors will beanalysed in substudies.

The study design is summarized in Figure 1. In brief,patients with large operable breast cancer or locallyadvanced/inflammatory disease are randomised to receiveas a neoadjuvant treatment either a non-taxane (arm A)or a taxane regimen with docetaxel (arm B). p53 isassessed using a functional assay in yeast, which detectsbiologically important mutations and is more sensitivethan sequencing (it is insensitive to contamination ofsamples with normal tissue). There are two primary end-points. The first will make separate comparisons of thenormal p53 subgroup and the p53 mutated group withrespect to progression-free survival (PFS) in patients whoreceived a chemotherapy without taxanes (treatment A)versus those who received a chemotherapy with taxanes(treatment B). The second will be a comparison of PFSbetween patients who received treatment A versus thosewho received treatment B, independently of p53 status.

The secondary endpoints are distant metastasis free sur-vival, overall survival, and toxicity.

We would like to share some good news with you:

1. As shown in Figure 2, the achieved accrual is excellentdespite the requirement for a frozen tumour sample (2trucuts) before inclusion in this trial. This requirementwas a real concern when developing the trial, but doesnot seem to be an obstacle in our experience. The p53study is an intergroup trial (European Organization forthe Research and Treatment of Cancer [EORTC], Anglo-Celtic [ACCOG], Swiss [SAKK] and Swedish [SBCG]groups) and the accrual per group is shown in Figure 3.

2. The quality of the samples collected and analysed cen-trally is very good:

• 86% of tumours (or patients) are eligible for p53analysis with more than 20% tumour cells in at leastone trucut.

• The p53 functional test in yeast has succeeded in99% of the tumours.

• The quality and quantity of ribonucleic acidanalysed with the Agilent bioanalyser (AgilentTechnologies Inc., Palo Alto, CA) (with a picochip) isexcellent in 65% of the cases and therefore can beused for cDNA microarray analysis.Figure 1: Study design.

Figure 2: Accrual N = 1207. Cut-off date 15/01/2005.

Updates on Other BIG Trials

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3. In addition, several translational research substudies(TGIF studies) have been performed or are ongoingusing

adjuvant breast cancer treatment: evolution or revolution?...sistent with the atac (arimidex,...

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