Crafting a Strategy for New Drug Discovery and Development ...€¦ · Eli Lilly, F. Hoffman-La Roche, and Bristol-Myers Squibb, for supporting ... known SWOT analysis (strengths,

Volume 7 Number 1Winter 2005

According to the Merriam-Webster dictionary, besidesthe military definition, “strategy” can be defined asthe “art of devising or employing plans or stratagems

toward a goal” or the “adaptation or complex of adaptations(as of behaviour, metabolism, or structure) that serves orappears to serve an important function in achieving evolu-tionary success.” In the business and political worlds as well,

strategy can be seen as a collection of actions or a plan toreach a certain objective. A simple, operational definition ofstrategy could be the plan to go from business point A todayto business point B at a specified time point in the future.This concept may be applied to a pharmaceutical company;a strategy could be to increase the number of approveddrugs from number 1 to number 2. The concept may actu-

Crafting a Strategy for New Drug Discovery and Development: the Case for Collaborationbetween Academic Institutions, thePharmaceutical Industry, and Other Partners Pierre Dodion, MD, Executive Director, Global Strategy, Novartis Oncology

CONTENTS

International collaboration as sound .................. 1strategy making for breast cancer research

Editorial - Note from the editors ........................ 2News on BIG Studies .......................................... 9News from BIG Groups ...................................... 17TRANSBIG News ................................................ 19In the Pipeline / Upcoming Events ...................... 21

This issue was madepossible through thegenerous support in theform of an unrestrictededucational grant from SP Oncology.

International collaboration as sound strategy making for breast cancer research

(continued on page 3)

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This issue focuses on developing strategies and col-laborations, specifically those that will lead toimprovements in the way in which cancer is treat-

ed, and possibly prevented and cured. This, in essence, iswhat BIG is all about.

Our lead article by Pierre Dodion takes on the exampleof drug discovery and development and reflects on the fac-tors that need to be considered and the challenges onefaces when trying to formulate the soundest possiblestrategies. The conclusion is that ultimately “no singleorganization will devise a uniquely perfect strategy” andthat strategy making is a dynamic, iterative process inwhich “analysis, positioning, vision, and learning are com-plementary to each other.”

The article on the HERA (BIG 1-01/HERA BO 16348)trial nicely demonstrates the dynamic, iterative process ofstrategy development involved in large-scale, multinational,and multicultural collaborations—in this case one in whichwell over 20 academic collaborative groups, independentcentres, and the pharmaceutical industry (PI) participate.The very early strategies for this particular collaborationbetween academia and the PI were not always the best ones,but the parties learned from their difficulties and were ableto move forward to develop a trials model that is now ableto deal constructively with new challenges as they arise andthat has ultimately proved successful. The BIG 1-02/IBCSG27-02 and BIG 1-04/AZURE trials are also cases in point forthe argument that the most successful strategies in breastcancer research will be those that are collaborative andinternational in nature, despite the demanding complexitiesthey bring.

All of this should underscore the importance of our col-laborations—whether between academia and industry oracademic groups alone—and our need to learn continuallyfrom them. Now facing a particularly challenging time withrespect to the new European Union Clinical TrialsDirective, the need for us to continue to put our headstogether to develop creative research strategies is more per-tinent than ever.

Martine PiccartCarolyn Straehle

Breast International Group (BIG) Newsletter ~ Volume 7 Number 1, Winter 2005

22

Volume 7 Number 1 Winter 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

121 Blvd de Waterloo, 7th Floor

B-1000 Brussels, Belgium

Tel: +32 2 541 3146

Fax: +32 2 541 3199

Email: [email protected]

© BC Decker Inc 2004 All rights reserved. No part of this publication may be

reproduced in any form without written permission of the publisher.

We are grateful to the following compa-

nies for their generous support to the

Secretariat in the form of unrestricted

educational grants: SP Oncology, in par-

ticular for making this newsletter possi-

ble; and Novartis, AstraZeneca, Johnson

& Johnson, Amgen Europe, Aventis,

Eli Lilly, F. Hoffman-La Roche, and

Bristol-Myers Squibb, for supporting

many of our other activities.

EDITORIAL

Note From the Editors

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ally be applied to any other entity. For example, the strategyof a cooperative group may be to expand its activities fromrunning studies in the metastatic stages of cancer to trials inthe adjuvant setting. Or the strategy of a hospital with noclinical research program may be to develop one.

Although the definition of strategy appears to be relative-ly simple, how to develop one is quite a complex exercise;many papers and books have been written on this topic, andtheories and schools of thought on strategy have been devel-oped. The “design school” developed from extensive analysisof internal weaknesses and strengths as well as of externalthreats and opportunities,1 making the basis for the wellknown SWOT analysis (strengths, weaknesses, opportunities,and threats). The “planning school” takes SWOT as a startingpoint, identifies the various steps to reach a given objectiveand integrates them into a plan.2 The “position school” hassimilarities with the design and planning schools, but statesthat there are a limited number of successful strategies (orstrategic positions) available for each company.3

While the design, planning, and position schools rely onextensive analyses, the “entrepreneur school” is based on thevision, intuition, judgment, and insight of a single leader.4

According to the “learning school,” a strategy emerges whenan individual or an organization learns about a situationand how to deal with it.5 There are many other schools ofthought on strategy, but their review is beyond the scope ofthis article.

More modern theories tend to integrate the variousschools of thought on strategy into a more continuousstrategic process. Every strategy must start with a detailedanalysis of the current internal weaknesses and strengths ofthe business as well as of external threats and opportunities.The next step is to define an objective and a plan to reach it.This phase may well integrate the vision of a leader or asmall leading group. During the execution of the strategy,new elements will become available. The individuals andorganization will have to learn from these new elements andto adjust the strategy. New strategies may emerge and othersmay become obsolete. The modern vision of strategy istherefore a very dynamic process where analysis, position-ing, vision, and learning are complementary to each other.

The strategy of drug discovery and development is nomore than a particular case of strategy in general, and itscomplexity has been recognized by other authors.6,7 Theanalysis phase will define the target disease, disease stages,treatment options, the currently available drugs, their limi-tations (“weaknesses”) and the unmet medical needs(“opportunities”). From there, the objective to develop anew drug with specific properties may be formulated. Thedrug properties and requirements (in terms of efficacy, safe-ty, comparison with available drugs, route of administra-tion, and other attributes) are defined in a “target productprofile.” During drug development, new elements maybecome available and have an impact on the strategy. Inother words, the development group will learn during thedevelopment phase. A drug developed for one indication

may suddenly be developed for another indication (“emer-gent strategy”). And, of course, it is not unusual to terminatea drug development plan for lack of efficacy or an unsatis-factory risk-benefit ratio.

It is apparent from the above considerations that strate-gy is much about learning and gathering information—atthe time of analysis and continuously during the implemen-tation of the strategy. With that in mind, it is not surprisingthat there is little point for any organization to try to devel-op a strategy in isolation. Instead, developing a strategy isoften a matter of collecting information from multiplesources and of integrating vast amounts of data in a synthet-ic way. In the particular case of drug development, informa-tion has to be collected on an ongoing basis from the med-ical community, academic centres, cooperative groups, gov-ernmental bodies such as regulatory agencies, pharmaceuti-cal companies, policy makers, patients, and many otherstakeholders.

Drug development history contains several examples ofvery active collaboration between industry and other part-ners. Back in the 1970s, new platinum analogs were devel-oped in an attempt to identify agents retaining the activityof cisplatin but without the nephrotoxicity of the drug.Initial efforts were largely made by the academic world, inparticular by the group of Harrap and Calvert in the UK.8,9

Later, large cooperative groups, academic and nonacademicinstitutions (in particular smaller or “community” hospi-tals) and the pharmaceutical industry played key roles, inparticular in terms of the development and approval of suchagents in ovarian and lung cancer.10–13

The development of trastuzumab provides another, morerecent example of a successful collaboration between themedico-scientific community and the pharmaceutical indus-try. Following the identification in rat neuroblastoma of theHER2 gene, also known as c-erb-B2 (erbB2), or HER2/neu,the HER2 receptor was found to be present in normal humantissues but also to be overexpressed, or amplified, in certaincancer cells, including 25 to 30% of breast cancers;14,15

HER2/neu overexpression was found to be associated with aclinically aggressive tumor and a poor prognosis.16,17 Theamplification of the gene plays a direct role in tumorigenicityand thereby provides an opportunity to target therapiesdirectly at the gene. Quite extensive preclinical research wasperformed by both academic institutions and the pharmaceu-tical industry18,19 and laid the foundation for the successfulpivotal trial of trastuzumab in metastatic breast cancer. Again,the medical community and the pharmaceutical industry col-laborated closely in the clinical effort.20,21

Breast cancer may be taken as a good example of thecomplexity of establishing a sound strategy of drug develop-ment. If one focuses specifically on chemotherapy ofadvanced breast cancer and ignores for a moment the ques-tion of administering trastuzumab, it is widely recognizedthat anthracycline antibiotics and taxanes are the mostactive agents in this setting.22–25 Trials have demonstratedthat regimens combining a taxane and an anthracycline

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antibiotic are superior to regimens containing only anthra-cycline antibiotic combinations. However, there are stillmany open questions, such as which are the best agents, thebest combinations, and the optimal schedules. In addition,it is neither proven nor accepted by everyone that allpatients should receive a taxane plus an anthracyclineantibiotic combination up-front; similar overall resultsmight be achieved with a sequential approach, ie, using ananthracycline antibiotic-based regimen first, followed by ataxane-based regimen upon failure of the first line treat-ment or alternating multiple chemotherapy regimens. Thereare actually some data suggesting that this approach mightindeed be quite effective.26 How to integrate active agentsother than the anthracycline antibiotics and taxanes intopatient treatment plans is equally debated. For example, in astudy comparing docetaxel + capecitabine versus docetaxelin patients with advanced disease previously treated withanthracycline antibiotics, better results were reported in thepatients treated with capecitabine.27 However, how shouldthe clinician integrate those data into a treatment paradigmwhen taxanes are perceived by some as an “obligatory com-ponent” of first line therapy? If not used in first line thera-py, should anthracycline antibiotics be relegated to secondline therapy?

In this brief overview, the optimal treatment ofadvanced breast cancer has been discussed in isolation,without taking into account prior adjuvant therapy. If apatient has received no prior adjuvant therapy or has beenoff such therapy for a sufficient period of time (usuallymore than 6 to 12 months), that patient may be consideredto be sensitive to chemotherapy and the above strategy maybe applicable. However, another treatment strategy will haveto be developed for patients with resistant disease. In thissetting the adjuvant treatment may be considered as a “firstline treatment” and the first treatment given for advanceddisease, rather than as a second line treatment. The overallconclusion here is that treatments in the adjuvant, neoadju-vant, and advanced settings are intertwined, making theoverall treatment strategy extremely complex.

The same concepts apply to hormonal therapy of breastcancer and to combined or sequential hormonal therapyand chemotherapy. Soon, with the advances of targetedtherapy, the complexity will be even greater. Already today,after the demonstration of the activity of trastuzumab inpatients receiving first line chemotherapy with anthracy-cline antibiotics + cyclophosphamide or paclitaxel, newtreatment paradigms have been developed to include thisagent in the treatment strategy.21 A similar level of complex-ity exists for many other tumor types, including lung, col-orectal, ovarian, haematological, and other cancers.

Given that background, how should the development of anew drug be pursued, for example, in breast cancer? Shouldthe emphasis be on the discovery of new agents active inpatients with end stage disease? Or the development of agentsthat allow incremental progress in patients with earlier dis-

ease? Assuming that a new drug A is identified, should it beadded to existing combinations and given in sequence afterknown combinations? Thus, even if the developer can figureout an optimal mapping of the existing treatment strategy ina given disease, he or she will still be confronted with unlim-ited strategic choices in terms of new drug development.

So far, we have concentrated on the medico-scientificaspects of drug discovery and development. However, drugdiscovery and development cannot take place without prop-er funding. The pharmaceutical industry contributes, to alarge extent, to the funding of these activities. Other sourcesof funding include governmental agencies and charitableorganizations. As resources are ultimately limited, the crite-ria used to prioritize research activities are important toconsider and constitute an additional source of complexityfor the strategy of new drug development. A project of highimportance from the scientific perspective may or may notbe viewed as a priority by the partners who may potentiallyfund such projects. It was no secret, back in the early 1990s,that Ronald Reagan’s colorectal cancer had an impact on theinterest of policy makers in this disease.28 Pharmaceuticalcompanies need to take a wide range of business considera-tions (including unmet medical needs, availability of othertreatments, target populations, regulatory constraints, andother factors, as well as ability to achieve a return on itsinvestment) into account with their strategic planning, andthat clearly creates another level of complexity in the drugdevelopment strategy.29,30

One can very quickly draw the logical conclusion that nosingle organization or individual will come up with auniquely perfect strategy. In contrast, the probability is veryhigh that multiple partners will collaborate to come up withan initial best guess. Within that first approach, new datawill be generated and will be integrated into a second step ofthe strategy. This iterative process may have to be repeatedseveral times. It is equally probable that several best guessesmay be produced either by different groups or even within agiven organization. These strategic ideas and plans will becompared and confronted; in that context of competitiveanalysis and challenge, some of the plans will be improved,others will be abandoned, and new ones will emerge. Inother words, drug development strategy, like any other strat-egy, is a dynamic process where analysis, positioning, vision,and learning are complementary to each other.

REFERENCES

1. Christensen CR, Andrews KR, Bower JL, et al. Business policy:text and cases. 5th ed. Homewood: Irvin; 1982.

2. Steiner GA. Strategic planning: what every manager must know.New York: Free Press; 1979.

3. Porter ME. Competitive strategy: techniques for analyzing indus-tries and competitors. New York: Free Press; 1980.

4. Pinchot G. Intrapreneuring. New York: Harper and Row; 1985.5. Quinn JB. Strategies for changes: logical incrementalism.

Homewood,: Irvin; 1980.


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6. Robert TG, Lynch TJ, Chabner BA. The phase III trial in the eraof targeted therapy: unraveling the “go or no go” decision. J ClinOncol 2003;21:3683–95.

7. Eckhardt SG, Eisenhauer E, Parulekar WR, et al. Developmenttherapeutics: successes and failures of clinical trial designs of tar-geted compounds. Educational Book, 2003 Annual Meeting ofthe American Society of Clinical Oncology 2003;209–19.

8. Harrap K. Preclinical studies identifying carboplatin as a viablecisplatin alternative. Cancer Treat Rev 1985;12:21–33.

9. O’Dwyer P, Stevenson JP, Johnson SW. Clinical pharmacokineticsand administration of established platinum drugs. Drugs 2000;59(suppl 4):19–27.

10. Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatinand paclitaxel compared with cisplatin and paclitaxel in patientswith optimally resected stage III ovarian cancer: a GynecologicOncology Group study. J Clin Oncol 2003;21:3194–200.

11. Neijt JP, Engelholm SA, Tuxen MK, et al. Exploratory phase IIIstudy of paclitaxel and cisplatin versus paclitaxel and carboplatinin advanced ovarian cancer. J Clin Oncol 2000;18:3084–92.

12. Sculier JP, Paesmans M, Thiriaux J, et al. Phase III randomized trialcomparing cisplatin and carboplatin with or without ifosfamide inpatients with advanced non–small-cell lung cancer. European LungCancer Working Party. J Clin Oncol 2003; 16:3194–200.

13. Kelly K, Crowley J, Bunn PA, et al. Randomized phase III trial ofpaclitaxel plus carboplatin versus vinorelbine plus cisplatin in thetreatment of patients with advanced non–small-cell lung cancer: aSouthwest Oncology Group trial. J Clin Oncol 2001;19:3210–18.

14. Park JW, Tripathy D, Campbell MJ, et al. Biological therapy ofbreast cancer. Biodrugs 2000;14:221–46.

15. Schechter AL, Stern DF, Vaidyanathan L, et al. The neu oncogene:an erb-B-related gene encoding a 185,000-Mr tumor antigen.Nature 1984;312:513–6.

16. Albanell J, Baselga J. Trastuzumab, a humanized anti-HER2 mon-oclonal antibody, for the treatment of breast cancer. Drugs Today1999;35:931–46.

17. Press MF, Bernstein L, Thomas PA, et al. HER-2/neu gene ampli-fication characterized by fluorescence in situ hybridization: poorprognosis in node-negative breast carcinomas. J Clin Oncol1997;15:2894–904.

18. Baselga J, Norton L, Albanell J, et al. Recombinant humanized

anti-HER2 antibody (Herceptin®) enhances the antitumor activi-ty of paclitaxel and doxorubicin against HER2/neu overexpressinghuman breast cancer xenografts. Cancer Res 1998; 58:2825–31.

19. Pegram M, Hsu S, Lewis G, et al. Inhibitory effects of combina-tions of HER-2/neu antibody and chemotherapeutic agents usedfor treatment of human breast cancers. Oncogene 1999;18:2241–51.

20. McKeage K, Perry CM. Trastuzumab: a review of its use in thetreatment of metastatic breast cancer overexpressing HER2.Drugs 2002;62:209–43.

21. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapyplus a monoclonal antibody against HER2 for metastatic breastcancer that overexpresses HER2. N Engl J Med 2001;344:783–92.

22. Eisenhauer EA, Vermorken JB. The taxoids: comparative pharma-cology and therapeutic potential. Drugs 1998;55:5–30.

23. Fossati R, Confalonieri C, Torri A, et al. Cytotoxic and hormonaltreatment for metastatic breast cancer: a systematic review ofpublished randomized trials involving 31,510 women. J ClinOncol 1998;16:3439–60.

24. Figgitt DP, Wiseman LR. Docetaxel: an update of its use inadvanced breast cancer. Drugs 2000;59:621–51.

25. Nabholtz J-M, Falkson C, Campos D, et al. Docetaxel and doxoru-bicin compared with doxorubicin and cyclophosphamide as firstline chemotherapy for metastatic breast cancer: results of a ran-domized, multicenter, phase III trial. J Clin Oncol 2003;21:968–75.

26. Paridaens R, Van Aelst F, Gerogoulias V, et al. A randomized phaseII study of alternating and sequential regimens of docetaxel anddoxorubicin as first-line chemotherapy for metastatic breast can-cer. Ann Oncol 2003;14:433–40.

27. O’Slaughnessy J, Miles D, Vukelja S, et al. Superior survival withcapecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trialresults. J Clin Oncol 2002;20:2812–23.

28. Brown ML, Potosky AL. The presidential effect: the public healthresponse to media coverage about Ronald Reagan’s colon cancerepisode. Public Opin Q 1990;54:317–29.

29. Fitzgerald JD. Drug discovery and strategic marketing: the needto improve the connection. Drug Dev Res 1998;43:143–8.

30. York JM. Marketing and the drug development process. Clin ResPractices and Drug Reg Affairs 1988;6:159–71.


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The HERA experience, BIG 1-01/BO 16348 Victoria Greatorex and Holly Kania on behalf of the HERA Joint StudyManagement Team

Successful clinical trial collaboration between partiesfrom differing research cultures depends critically onseveral factors. As well as a legal framework, it needs to

establish processes and procedures and define commonobjectives requiring mutual support, trust, and a willingnessto collaborate.

The implementation of the European Union (EU)Directive in Europe has resulted in a changed environment

for the conduct of clinical trials in Europe. Within the scopeof this directive, the definition of what or who a sponsor ofa clinical trial is has been refined. Many perceive this as amajor limitation for the future conduct of “investigatordriven” or “academic clinical research,” and numerous ini-tiatives have been undertaken, or are underway, to find waysto work within the new legislative environment. While theimpact of the directive and its implementation—as well as

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future potential revisions—remains to be seen, the currentframework of the EU Directive may well present an oppor-tunity for greater, more involved collaboration between aca-demia and industry (Figure 1). Academia has the potentialto shape future clinical research that is focused on evidence-based therapies, and it is offered the opportunity to gainearly access to new treatments. In turn, industry benefitsfrom the additional patient pools that may not otherwise beavailable to them. It also gains more credibility for produc-ing study results that have been independently interpreted.Collectively a successful collaboration can only reflect posi-tively on all parties involved, including patients.

Accommodating the interests of both academia andindustry that collaborate on a clinical trial is a complex task.However, such working relationships can flourish if somebasic foundations are agreed upon up front. An example ofhow this can work is the HERA study, a large, phase III reg-istration study for Herceptin in HER2-positive early breastcancer, which is a collaboration between The BreastInternational Group (BIG) and its affiliated collaborativegroups, plus nonaffiliated collaborative groups, independ-ent sites, and Roche, as the industry partner.

INTERESTS AND GOALS

It was vital to determine up front that all parties had enoughcommon interests and goals to establish a functional collab-oration and working relationship. Ultimately, all partieswanted to explore survival benefit. However, the underlyingrationale for conducting the HERA trial for Roche was to actas a registration study for expanding the use of Herceptin inHER2-positive, early breast cancer patients, while for BIGand the other groups, it was to explore a range of scientificquestions, including those that are exploratory in nature orthat are based in translational research. Additionally, eachparty had to identify, from its point of view, what was criti-cal for success and what issues or items could be negotiated.Flexibility was key, because all parties had areas of expertisethat needed to be respected.

OVERCOMING THE CHALLENGES

Early negotiations were lengthy and at times difficult, result-ing on one occasion in a breakdown in communication,nearly jeopardizing the collaboration. The complexity ofhaving so many groups work together, with sometimes con-flicting priorities and objectives, also resulted in poorlydefined roles and responsibilities, and ultimately delays insetting up sites.

Subsequently, there were cautious but fruitful discussionsand negotiation that allowed all parties to re-examine theirmotivation to restore the collaboration, by identifying criticalelements important to all. At this point, all realized that if oneparty failed within the relationship, the venture would fail andthere would be no HERA trial. Thus, to overcome these andfuture challenges, from an operational perspective, a “oneteam” approach to everything had to be adopted, particularlywith respect to internal and external communications anddecision-making processes (Figure 2).

Figure 1 Figure 2

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COMMUNICATIONS

A communications plan was initiated so that at times ofstress or conflict, open dialogue could be maintained toavoid any future obstacles. Whilst this was an extremelyuncomfortable and difficult process, it allowed all partiestime to re-evaluate their criteria for success, which resultedin a more focused and pragmatic approach to decision mak-ing. Successfully implementing the communications planrequired open, constant, direct contact with counterparts,via teleconferences, E-mail, and face-to-face meetings. Thisprocess was embraced by all parties and required the shar-ing of information, ongoing constructive and pragmaticfeedback, and collective troubleshooting when issues arose.

DECISION MAKING

Identifying the key roles and responsibilities of each partywas a time consuming step because all elements had to bediscussed, agreed upon, documented, and then communi-cated. These tasks, roles, and responsibilities included jointproject and data management. Details included defining the

access to the study data (statistician, independent data mon-itoring committee and sponsor), how the data would beanalyzed, ownership of the study data, publication plans,and the process for the preparation of the final study report.These negotiations were complex and extremely detailed,and as study milestones were reached, circumstances arosethat required ongoing refinement and flexibility. The one-team approach facilitated this ongoing process by makinguse of shared expertise and knowledge. Figure 3 gives anoverview of the task, roles, and responsibilities defined upfront between all parties.

CONCLUSIONS

Despite the different cultures and level of detail necessary atthe operational level to establish and maintain the HERAcollaboration, this partnership has ultimately been a successfor all parties involved. For academia, and BIG in particular,the HERA study has provided the opportunity to further itsexperience working with industry to conduct a registrationstudy. For industry, HERA has offered a platform for com-munication with academic collaborative groups and it hasbeen instrumental in facilitating the acceptance of Roche asa study partner. For both academia and industry, HERAprovides a solid example of collaboration that can be builtupon, especially during a time of legislative transition.

Facts About the HERA Study:• 39 countries are taking part across Europe, North,

Central and South America, Africa, and the AsiaPacific region.

• As of the end of November 2004, 4,924 patientswere enrolled in the study, with enrolment to becompleted by the end of February 2005.

• Screening for entry into the study was closed onthe 21 May 2004. Patients who have not yet beenscreened are no longer able to enter the study.

• 477 sites have been actively recruiting patients.

Figure 3

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Translational Research and HERA Soheyl Babana, MS, MBA, Brian Leyland-Jonesa MD,and Mitch Dowsettb PhD

aDepartment of Oncology, McGill University, Canada; bDepartment of Academic Biochemistry, Royal Marsden NHS Trust, UK

The TransHERA translational research substudyinvolves sample collection in association with theHERA trial (BIG 1-01/BO 16348). The objectives of

TransHERA are to collect, store, and analyze breast cancertissue and serum from patients in the HERA trial to allowthe identification of molecular characteristics that are asso-ciated with the differential likelihood of response or thatallow detection of residual or relapsing disease.

TRANSHERA PLATFORMS

1. Tissue Micro Array PlatformParticipating centres will provide fixed tissue from allpatients. Sera samples from 1,154 patients will be availableto TransHERA for parallel analysis. Professor Mitch Dowsettat Royal Marsden Hospital will be responsible for storingand preparing Tissue Micro Arrays. Tissue sections takenfrom the arrays will be analyzed for molecular componentsusing immunohistochemical techniques. This is expected toinclude analyses of total and phosphorylated forms of HER-1, HER-3, HER-4, ERK 1/ 2, AKT, AIB1, p38MAPK, andIGF1R as well as ligands for the type growth factor receptors(eg, heregulin, TGFalpha) and phosphorylated forms of thereceptors, ERK 1/2 (total and phosphorylated), and AKT.

2. Ribonucleic Acid (RNA) PlatformWe also expect to assess RNA in these fixed tissues.However, fixed paraffin-embedded (FPE) samples intro-duce unique challenges for microarray analysis, includingpotential fragmentation and chemical modification of RNAmolecules. To overcome this limitation and to be able totake advantage of one of the largest tissue banks available(TransHERA), we intend to exploit the very recent techno-logical advances that are commercially available for RNAextraction and labelling. Such technologies will includearrays that are designed to focus on interrogating sequenceslocated closer to the 3' end of the transcripts comparedwith standard arrays. The majority of the probe sets onsuch arrays are selected from the 300 bases at the most 3'end of the transcripts. This is different from the standard

design strategy, which selects probe sets within the regionof 600 bases proximal to the 3' ends. Together, the reagentsand array accommodate the characteristics of these tran-scripts, typical of FPE RNA samples, enabling genome-wideprofiling. We plan to validate our findings with large-scalevalidation using real-time reverse transcription-poly-merase chain reaction (RT-PCR) in a similar approach tothat developed by the National Surgical Adjuvant Breastand Bowel Project (NSABP) and Genomic Health.Messenger RNA (mRNA) levels in FPE tissue specimenscan be quantified by Real-Time RT-PCR techniques despitethe extensive RNA fragmentation that occurs in tissues.Probe and primer sets for RT-PCR assays are based onamplicons that are both short and homogeneous in lengthand that enable effective reference data normalization.

3. Proteomics PlatformIn addition, we intend to conduct proteomic analyses onTransHERA tissue and sera. Proteomic analyses for markerdiscovery and validation will be conducted on a large num-ber of paraffin-embedded blocks and their matching sera.This will pave the way for establishing detectable prognosticmarkers in blood for diagnostic and treatment purposes.Experiments for establishing a proteomic signature willinclude gel electrophoresis followed by liquid chromatogra-phy coupled with quadrapole time-of-flight (LC-QTOF)mass spectroscopy. In the validation phase, we will turn to ahigh-throughput, gel-free approach (in solution proteindigestion) using a Fourier Transform Mass Spectrometer(FTMS) to analyze a large set of samples. The high sensitiv-ity and high resolving power of this cutting-edge mass spec-trometer will allow us to follow the fate of proteins previ-ously identified by LC-QTOF, in protein mass fingerprintmode. Both approaches (LC-QTOF and FTMS) will takeadvantage of bioinformatics tools for the study ofdynamic/functional proteomics.

Contact: S. Baban, Global TransHERA Project Manager, Tel: +1 514398 8741; Cell: +1 514 573 0480; E-mail: [email protected]

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News on BIG Studies

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Name Specialty Function/Region

Mitch Dowsett Pathology TransHERA Co-chairBrian Leyland-Jones Oncology TransHERA Co-chairNadia Harbeck Oncology GermanyAnnette Lebeau Pathology GermanyKathy Pritchard Oncology NCICWedad Hanna Pathology NCICRaimund Jakesz Oncology ABCSGMichael Gnant Oncology ABCSGDenis Larismont Pathology BrEASTBirgitte Rasmussen Pathology DBCGLuigi Serra Pathology GOIRCMarten Ferno Oncology SBCGMasakazu Toi Oncology JapanBarry Gusterson Pathology IBCSG/SAKKRobert Sutherland Molecular Biology ANZ BCTGSoheyl Baban Molecular Biology, Management TransHERA Project ManagerStella Dolci Data Management BrEAST Data CentreSebastien Guillaume Data Management BrEAST Data CentreChantal Bernard Data Management BrEAST Data CentreCarolyn Straehle Management BIG SecretariatRichard Gelber Biostatistics HERA StatisticianThorston Gutjahr Roche Herceptin Team

News on BIG Studies

BIG 1-05 / IBCSG 32-05: Chemotherapy AdjuvantStudies for Women at Advanced Age (CASA)Phase III Trial Evaluating the Role of Adjuvant Caelyx for Women (Aged 66 Yearsor Older) with Endocrine-Nonresponsive Breast Cancer Who Are NOT Suitablefor Being Offered a “Standard Chemotherapy Regimen”Coordinating Group: International Breast Cancer Study Group (IBCSG)Disclaimer: This trial has not yet been activated and details are still in the final negotiation stages, so some changes may yet occur.

PROTOCOL SUMMARY AND SCHEMA

PATIENT POPULATION

Women (66 years of age or older) with resected breastcancer. They should be candidates neither for endocrinetherapy (owing to endocrine-nonresponsive disease) norfor “standard” anthracycline-containing chemotherapy(because they are considered too frail for such a propos-al). The disease must be classified as endocrine nonre-sponsive, and patients must not be candidates forendocrine therapy or for an adjuvant chemotherapy pro-

gram that includes a “standard” anthracycline-containingchemotherapy regimen.

RATIONALE

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 at anadvanced age presents with an endocrine-nonresponsiveearly breast cancer. Relapses of breast cancer may occur ear-lier in patients with endocrine-nonresponsive disease com-pared with those with hormone receptor–expressing

TRANSHERA Committee

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tumors, even when axillary nodes are negative at presenta-tion. This provides a rationale for reducing the risk ofrelapse even when 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 nonrespon-sive) is advantageous because the magnitude ofchemotherapy effect for this postmenopausal cohort islikely to be quite large, similar to the effect observed forpremenopausal patients with similar biologic tumor char-acteristics. Avoiding dilution with patients withendocrine-responsive tumors (even those with a highnumber of axillary lymph nodes involved) maximizes thechance to observe a benefit in the shortest time with thelowest number of patients.

TAILORED TREATMENT INVESTIGATIONS

Some of the investigators are likely to choose no adjuvantcytotoxic therapy as a standard for frail patients at advancedage, whereas others will prefer to offer SOME treatment forall patients with endocrine-nonresponsive disease. TheChemotherapy Adjuvant Studies for Women at AdvancedAge (CASA) are therefore aimed at investigating the role ofadjuvant cytotoxic chemotherapy for postmenopausalwomen at advanced age with endocrine-nonresponsiveearly breast cancer. A pegylated liposomal doxorubicin(Caelyx) was chosen as the experimental treatment.

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 toward adjuvant treatments in this subpopula-tion. Because of the separate designs, at the time of random-ization, the investigator will be asked to select one of tworandomization options:

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

• Option 2, Caelyx versus low-dose, metronomiccyclophosphamide and methotrexate (CM), is designed

for patients who, according to the treating physicianand/or the patient’s preferences, should receive someadjuvant treatment.

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 receptor-negative (no expression of estrogen receptor and proges-terone receptor) disease. Thus, a satisfactory accrual can bereached only with an international collaboration and partic-ipation around the world.

PATIENT ENTRY

Patients should be randomized within 6 weeks after surgery. TheVES-13 questionnaire must be completed prior to randomiza-tion to determine the general health of the patient. Baseline QLassessments must also be obtained before randomization.

STRATIFICATION FACTORS

Institution

END POINTS

Primary: Breast cancer–free survival (events are reap-pearance of invasive breast cancer at any siteincluding contralateral disease)

Secondary: Tolerability (treatment completion)Adverse eventsQuality of lifeDisease-free survival (includes second malignancies and deaths)Sites of failureOverall survivalCompeting causes of death

SAMPLE SIZE AND ANTICIPATED STUDYDURATION

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).

BIG groups interested in participating in the trial shouldnotify the BIG Secretariat (<[email protected]>or <[email protected]>).

TREATMENT SCHEDULES

Chemotherapy: All regimens are 16 weeks duration.

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

CM regimen: Low-dose, metronomic CM administeredfor 16 weeks. C = cyclophosphamide

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Primary Surgery

Stratify

• Institution

RANDOM

Caelyx

No adjuvant therapy (nil)

Primary Surgery

Stratify

• Institution

RANDOM

Caelyx

Low-dose, metronomiccyclophosphamide andmethotrexate (CM)

Option 2: C-CM

Option 1: C-Nil

50 mg/d orally continuously for 16 weeks;M = methotrexate 2.5 mg/twice a day oral-ly days 1 and 4 of every week for 16 weeks.

Radiotherapy: Radiation therapy to the conserved breast isrecommended, but institutional choice

must be clarified for each patient prior torandomization. Radiation therapy to thechest wall following mastectomy is optional(if given, it may also include nodal fields).Radiation therapy may be given either dur-ing operation or after all chemotherapy.

Patients with isolated local or regional recurrence of breastcancer are at high risk of further dissemination of disease.So far, no randomized trial has been completed that inves-

tigates the value of chemotherapy after the radical local therapyof an isolated loco-regional recurrence. The International BreastCancer Study Group (IBCSG)-coordinated BIG 01-02 trial offersa unique chance to answer this question with a highly pragmat-ic, randomized, controlled design (Figure 1).

The type and duration of chemotherapy can be chosenby the investigator according to his or her personal prefer-ence and a patient’s prior therapy. The target accrual goal is977 patients to detect an improvement of the disease-freesurvival rate, from 50 to 60%, at 5 years after the recurrence.

The bad news: This trial continues to be slow to start. So far,more than 10 centres from the IBCSG and the Spanish GrupoEspañol de Investigación en Cáncer de Mama (GEICAM) inSpain, Switzerland, Hungary, Peru, and South Africa have joinedthe trial, and 14 patients have been randomized.

The good news: This trial is expected to accelerateconsiderably:

• The National Surgical Adjuvant Breast and BowelProject (NSABP) is in the final phases of activating itand making it available for North American centres viathe Cancer Trials Support Unit (CTSU). This trial will becalled NSABP B-37 in the USA and MAC.8 in Canada.

BIG 1-02 / IBCSG 27-02: Chemotherapy forRadically Resected Loco-Regional Relapse Stefan Aebi MD, University of Bern, Inselspital, Bern, Switzerland

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Figure 1 CT = chemotherapy; ER = estrogen receptor; PgR =progesterone receptor.

The AZURE trial has been open for recruitment forone year and is progressing well. The first patient wasentered in September 2003, and 744 patients were

enrolled by the end of October 2004. Recruitment reached110 patients per month in October, with 97 centres activelyrecruiting in the UK, Australia (Victorian CooperativeOncology Group [VCOG]), and Eire (Irish ClinicalOncology Research Group).

An early decision to run AZURE on a collaborativegroups model and, where possible, to work with the BreastInternational Group (BIG) groups in each country, hasproved instrumental in the success so far. Several BIGgroups in the UK are involved, and the expertise of localgroups in setting up the trial in their own countries has beeninvaluable, particularly in meeting the requirements of theEuropean Union Clinical Trials Directive. Also, their creativ-ity has to be applauded for the way the groups haveaddressed the logistical challenges of setting up AZURE,

which is a “BIG trial” in more ways than one!More sites are joining continually, with 129 having

received initiation visits. Initiation meetings took place withBelgian centres in August, and Spanish and Portuguese cen-tres (Grupo Español de Estudio and Tratamiento y otrasEstrategias Expirementales en Tumores Sólidos) inSeptember. The latter commenced recruitment inNovember. More Australian sites are interested in takingpart and will be coordinated by VCOG. Sites in France aremoving towards approval, the Italian group (GruppoOncologico di Recerca Clinica) is taking the first steps tojoin the study, and negotiations are ongoing to facilitateGerman participation. It is hoped that centres in the FarEast may join under the direction of VCOG.

It is planned that 3,300 women with stage II/III breastcancer will be enrolled, and with these new sites eager totake part, we are confident that we will complete recruit-ment on target in September 2006.

BIG 1-04 / AZURE: Does Adjuvant ZoledronicAcid RedUce REcurrence in Patients with High-Risk, Localised Breast Cancer?

• The Australian New Zealand Breast Cancer Trials Group(ANZBCTG) has almost completed the activation of 5centres.

The IBCSG has set up an insurance solution to enablethe Dutch Borstkanker Onderzoeksgroup Nederland(BOOG) to participate.

The participation of the North American groupsrequires an amendment to the protocol that will allow theuse of trastuzumab and clarify radiation therapy proce-dures. This amendment will be distributed as soon as thetrial is accepted by the CTSU.

This trial remains ambitious, and we welcome the sup-port of additional groups and single centres.

For further information about BIG 01-02 / IBCSG 27-02Chemotherapy for Radically Resected Loco-RegionalRelapse, please contact

IBCSG Coordinating CenterEffingerstrasse 40CH-3008 Bern, SwitzerlandPhone: +41 31 389 93 91Fax: +41 31 389 93 92E-mail: [email protected]

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Chile (Grupo Oncologíco Cooperativo Chileno deInvestigacion) and Peru (Sociedad Peruana de OncologiaMédica) were keen to participate, but we are very disap-pointed to report that local funding difficulties have meantthat this will not be possible.

AZURE also has an optional sub-study in which pro-teomics, tissue microarray, and other modern techniqueswill be used to identify specific prognostic indicators for thedevelopment of bone metastases and factors that are able topredict specific benefit from bisphosphonate treatment.Seventy-eight sites are now set up to take blood samples forthe sub-study, with samples being despatched from UK sitesevery two months to the central laboratories at SheffieldUniversity for long-term storage. The retrieval of tumourblocks and the production of tissue microarrays will com-mence early next year. It is hoped to expand the number of

countries taking part in the sub-study under the guidance ofthe collaborative groups.

The Data Monitoring and Ethics Committee reviewedall data from the AZURE trial as of August 2, 2004, andexpressed no concerns for the Serious Adverse Event fre-quencies reported thus far.

Many thanks to everyone in the BIG groups around theworld for their hard work in helping to set up AZURE inrecord time despite the ever-increasing burden of bureau-cracy that now confronts clinical research. We would alsolike to thank present and future patients for choosing to par-ticipate in this important study.

With best wishes,

The AZURE Team

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The main objective of the Locally AdvancedMastectomy NO Mastectomy (LAMANOMA) studywas to show that breast conserving treatment (radio-

therapy alone or tumorectomy followed or preceded byradiotherapy) is not inferior to mastectomy plus postopera-tive radiotherapy in terms of overall survival (primary end-point) and time to locoregional failure and quality of life(secondary endpoints) in locally advanced breast cancer(LABC) patients who first received induction chemothera-py. Major eligibility criteria in LAMANOMA includedLABC at presentation (T3-4, N0-N2, M0; any T, N2, M0;inflammatory breast cancer), prior induction chemotherapy(standard or investigational regimens), and eligibility forboth conservative local treatment and mastectomy plusradiotherapy at the time of randomization. Breast conserv-ing treatment (BCT) included a choice of one of the threetherapeutic options: radiotherapy alone, tumorectomy fol-lowed by radiotherapy, or tumorectomy preceded by radio-therapy. The type of local conserving management was tai-lored individually, but each institution had to describeupfront its policy for BCT. To show that breast conservingtreatment is not inferior to mastectomy plus postoperativeradiotherapy (a hazard ratio of less than 1.20), 1,210patients (605 per arm) were required to be randomized overa period of 5 years.

The study opened in October 2001. Despite a well-designed interest form and numerous institutions offeringtheir support, the study faced serious problems with patientaccrual. Initially 47 institutions from 21 countries represent-ing 4 international cooperative groups declared their inter-est in participating. Subsequently, 17 institutions werefound ineligible for various reasons, leaving 30 institutionsboth potentially interested and eligible. It was estimated thatthese 30 institutions together should be able to enter 242patients per year in the trial. Ultimately, however, only 11centres from 5 countries fulfilled all the requirements toopen accrual. Moreover, the total number of patientsenrolled over a period of 21 months was only 23, about oneper month instead of the estimated 20 per month. Hence,the study was closed due to insufficient accrual.

In order to determine the reasons for these problems, wedesigned a questionnaire including 20 specific questions, ofwhich 10 inquired about the causes of low patient accrual(more than one answer was allowed) and the remaining 10

asked about competing studies and the standard therapeuticstrategy used in the center for LABC. The results of this sur-vey were presented at the 4th European Breast CancerConference in Hamburg in March 2004.

In brief, the 30 institutions that initially declared theirinterest in the trial and were actually eligible received thequestionnaire, and 25 (83%) returned it. The most commonreason cited for the difficulties was that the institutiondecided to stand by its own current therapeutic strategy (7institutions), most frequently (6 institutions) depending ona patient’s response to primary chemotherapy. Otherresponses to the questions posed were the following: the lackof consensus on participation in a local team (6 institu-tions); large proportion of patient refusals (5 institutions);ethical and/or logistical problems (5 institutions); too fewpatients with LABC (5 institutions); another study in LABC(1 institution), and other causes (8 institutions).

Overall, we failed to detect any dominant reason for thisstudy’s failure. It is well known that physicians tend to over-estimate the potential accrual of their institutions to trials.Consequently, only a limited percentage of eligible patientsactually participate in a particular trial. This has variouscauses: for instance, not all eligible patients give informedconsent, or not all doctors involved in a patient’s treatmentmay be aware of the trial, and hence do not discuss it withtheir patients. If a patient is not offered participation in aphase III study during the first conversation about the dis-ease and its treatment, the chance of her or him participat-ing at a later point diminishes. This aspect of clinical trialmethodology is particularly difficult in diseases like breastcancer that are treated in a multidisciplinary fashion. Thedecision to participate in a trial must be made by the wholeteam, and all members should collaborate fully to make itwork. If a patient is informed by her surgeon about thetreatment plan, including chemotherapy followed by mas-tectomy (the “golden standard”), it may be difficult after-wards to offer her participation in a trial that has anotheroption, breast conservation. By the same token, if a patientis informed by her surgeon that primary chemotherapy mayresult in tumor regression and allow for breast conservation,she is likely to refuse participation in a trial where mastecto-my is still an option.

To decrease the risk of overestimating the number ofpatients in European Organization for Research and

BIG 2-00 / EORTC 10974 – LAMANOMA: Why did the LAMANOMA Study Fail? Jacek Jassem, MD,a Marcin Sinacki, MD,a Geertjan van Tienhoven, MDb

aDepartment of Oncology and Radiotherapy, Medical University of Gdansk;bDepartment of Radiation Oncology, Academic Medical Center, Amsterdam, The Netherlands

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Treatment of Cancer (EORTC) studies, all institutions report-ing interest in a given trial are now requested to make realis-tic estimates, not only based upon the opinion of one enthu-siastic investigator, but after discussion within their team.

Still, potential accrual estimates must be interpreted with cau-tion, and many of the current EORTC trials run somewhatmore slowly than originally estimated. In the LAMANOMAtrial, the estimate turned out to be far too optimistic.

Coordinating Participating Target Accrual as of 1 PharmaBIG Trial Group Groups Question Asked No. Pts Oct/Nov 2004 Partners

3-98/ EORTC IBCSG, GBG Attitude toward risk of loss of fertility related 385 80 NAYoung pts/ to adjuvant therapies in pts with earlyEORTC b.c. aged < 35? 10002

1-00/p53 EORTC SAKK, ACCOG, P53 status and response to 1,440 1,125 Grants from Aventis EORTC SBCG anthracyclines or taxanes? & Pharmacia; EORTC 10994 is sponsor

1-01/ BREAST 20 BIG groups, Comparison of 1 year vs 2 years vs no Herceptin® 4,482 4,924 RocheHERA/ BO 10 Roche affiliated in women with Her2 + primary breast cancer16348 groups, plus approx. who have completed adjuvant chemotherapy?

100 independent centres

1-02/ IBCSG GBG centres, Benefit of adjuvant chemotherapy for radically 977 16 NAIBCSG 27/ NCIC CTG, resected locoregional relapse of breast cancer?Loco–regional BOOG, GEICAM,Relapse ABCSG

2-02/ IBCSG ANZ BCTG, BOOG, Benefit of ovarian suppression given in addition 3,000 101 PfizerSOFT/ BREAST, CEEOG, to tamoxifen or aromatase inhibitor in ER+IBCSG 24-02 DBCG, EORTC, pts who receive CT and resume menses

GOCCHI, afterwards?US Intergroup

3-02/ IBCSG US Intergroup Benefit of tamoxifen vs. aromatase inhibitor for 1,845 206 PfizerTEXT/ ER+ pts receiving GnRH analogue?IBCSG 25-02

4-02/ IBCSG TBA Is CT necessary for low risk premenopausal 1,750 4 PfizerPERCHE/ endocrine responsive pts?IBCSG 26-02

5-02/ IBIS ANZ BCTG, Effectiveness of anastrozole vs. placebo in 10,000 357 Astra Zeneca, partial IBIS II DBCG, SAKK, preventing breast cancer in healthy, high-risk support (unrestricted

GBG, BOOG, post-menopausal women, and comparison educational grant)SBCG, NCRI between tamoxifen and anastrozole in

postmenopausal women with DCIS?

2-03/ GBG ABCSG, BOOG What can we learn about the diagnosis, treatment, 1,500 22 NAGBG 29 & maternal/foetal outcome of pts w/ breast

cancer during pregnancy? (prospective register study)

1-04/ NCRI ICR– CTSU, Benefit of zoledronic acid in (neo) adjuvant setting 3,300 886 Novartis; University ofAZURE ACCOG, WMBG, for improving bone metastasis and overall DFS Sheffield is sponsor

YBCRG, ICORG, in stage II/III b.c. patients?SOLTI, GOIRC,VCOG

4-04/ ICE GBG WSG What is the role of adjuvant chemotherapy: 1,394 41 Roche/ Astra Zenecaibandronate with or without capecitabine in elderly patients with early breast cancer?

1-03/ ICCG/GBG BOOG, CEEOG, Benefit of 2 yr adjuvant therapy with celecoxib 2,590 0 PfizerREACT/ DBCG, SPOM, compared with placebo in primary breast ICCG C/20/01 ICORG, GOCCHI cancer patients?GBG 27

Totals 32,663 7,762

Ongoing BIG Trials

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1616BIG Trial Coordinating Participating No. of Reason for Pharma

Group Groups Question Asked Patients Closure Partners

1-97/ NCIC CTG EORTC, IBCSG, Benefit from letrozole (5 yr) after 5,184 Reached target accrual; NovartisMA.17 (1) US Intergroup 5 yr of tamoxifen? study outcome positive

2-97/C/13/ ICCG ABCG, ANZ BCTG, Tamoxifen → exemestane: superior to 4,743 Reached target accrual; Pharmacia96(2) CEEOG, DBCG, tamoxifen alone? study outcome positive

EORTC, GEICAM,GONO, GOIRC,IBCSG, ICOG,ITMO, NWEG,NBCG, YBCRG, FBSG,GEAG, WCTN,US Oncology, SBCG

3-97/ SBCG IBCSG, Hormone replacement therapy: 447 Following IDMC NAHABITS GOCCHI, safe after radically treated in situ, recommendations

EORTC stage I or II breast cancer (individual (< 4 positive nodes?)centres)

1-98/IBCSG IBCSG DBCG, FBSG, Sequencing of tamoxifen/letrozole or 8,028 Reached target accrual Novartis18-98 Novartis group letrozole/tamoxifen superior to either

agent alone?

2-98/TAX BREAST IBCSG, SBCG, ABCSG, Incorporation of Taxotere® in sequence 2,887 Reached target accrual Aventis315 DBCG, GOCCHI, or combination with Adriamycin:

GEICAM, ICORG benefit to patients?

4-98/EORTC EORTC DBCG, YBCRG, ICCG Inhibitory effect of perioperative 20 Low accrual Astra Zeneca10963/PEAT Faslodex® on development of metastasis,

measured by DFS and OFS?

2-00/EORTC EORTC CEEOG, GOCCHI, Benefit of conservative local therapy 23 Low accrual NA10974/ ICCG (vs mastectomy) in locally advancedLamanoma breast cancer?

Total 21,332

ABCG = Argentine Breast Cancer Group; ABCSG = Austrian Breast and Colorectal Cancer Study Group; ANZ BCTG = Australian New Zealand Breast Cancer Trials Group; BIG = Breast International Group;BREAST = Breast European Adjuvant Studies Team; CEEOG = Central and East European Oncology Group; DBCG = Danish Breast Cancer Cooperative Group; DFS = disease-free survival; EORTC = EuropeanOrganization for the Research and Treatment of Cancer; FBSG = French Breast Study Group; GEAG = German Exemestane Adjuvant Group; GEICAM = Grupo Español de Investigacíon en Cancer de Mama;GOCCHI = Grupo Oncoloíico Cooperativo Chileno de Investigacíon; GOIRC = Italian Oncology Group for Clinical Research; GONO = Gruppo Oncologico Nord-Ovest; IBCSG = International Breast CancerStudy Group; ICCG = International Collaborative Cancer Group; ICOG = Israeli Clinical Oncology Group; ICORG = Irish Clinical Oncology Research Group; IDMC = Independent Data MonitoringCommittee; ITMO = Italian Trials in MedicalOncology; NBCG = Norwegian Breast Cancer Group; NCICTG= National Cancer Instituteof Canada, Clinical Trials Group; NWEG = North West England CancerGroup; SBCG = Swedish Breast Cancer Group; VCOG = Victorian Cooperative Oncology Group; WCTN = Wakes Cancer Trials Network; YBCRG = Yorkshire Breast Cancer Research Group.

Recently Closed BIG Trials

Coordinating Participating Potentially Interested Target No. Pharma BIG Trial Group Groups Groups Question Asked of Patients Partners

2-04/ ACCOG SPOM, ICORG ANZ BCTG What is the role of adjuvant chest wall 3,500 NASUPREMO EORTC irradiation in “intermdiate-risk” operable

breast cancer following mastectomy and axillary clearance?

3-04/ EORTC GOIRC, GOCCHI, IBCSG, SAKK, BOOG, Will gene profile signature be a better prognostic 5,000 UnderMINDACT SBCG YBCRG, CEEOG, tool to help in adjuvant decision-making negotiation

WSG, GBG than traditional clinical/pathological factors in node-negative breast cancer patients?

1-05 CASA/ IBCSG ANZ BCTG, BOOG, What is the role of adjuvant CT (with Caelyx®) 1296 Schering-IBCSG 32-05 GOCCHI, ITMO, for postmenopausal women at advanced age Plough

MOSG, SPOM, ( >66) with endocrine non-responsive early bc?SAKK

2-05 ACTION ICR-CTSU EORTC Chemotherapy versus no CT for older ER 1000 Under negative/poor patients negotiation(aged ≥70)?

Total 10,796

ABCSG = Austrian Breast and Colorectal Cancer Study Group; ACCOG = Anglo Celtic Cooperative Oncology Group; ANZ BCTG = Australian New Zealand Breast Cancer Trials Group; BIG = BreastInternational Group; BOOG = Dutch Breast Cancer Trialists’ Cooperative Group; CEEOG = Central and East European Oncology Group; DBCG = Danish Breast Cancer Cooperative Group; EORTC= European Organization for the Research and Treatment of Cancer; GBG = German Breast Group; GOCCHI = Grupo Oncoloíico Cooperativo Chileno de Investigacíon; GOIRC = Italian OncologyGroup for Clinical Research; IBCSG = International Breast Cancer Study Group; ICCG = International Collaborative Cancer Group; ICORG = Irish Clinical Oncology Research Group; NA = not appli-cable; NCRI = National Cancer Research Institute Breast Clinical Studies Group; SAKK = Swiss Group for Clinical Cancer Research; SBCG = Swedish Breast Cancer Group; SPOM = Sociedad Peruanade Oncología Médica; TBA = To Be Arranged; WMBG = West Midlands Breast Group; WSG = Westdeutsche Studien Gruppe; YBCRG = Yorkshire Breast Cancer Research Group.

Soon-to-Start/Planned BIG Trials

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It hardly needs to be stressed that the role of neoadjuvantchemotherapy (NAC) in the treatment of operablebreast cancer is currently under intensive investigation

in the hope of allowing greater conservation of the breast.Emerging evidence suggests that induction of pathologiccomplete response (pCR) is at least, to some extent, predic-tive of survival. Recently, the JBCRG initiated a study ofNAC using fluorouracil, epirubicin (100 mg/m2), cyl-cophosphamide (FEC100) followed by 75 mg/m2 docetaxel,and 202 patients with operable breast cancer have alreadybeen enrolled. An interim analysis of this study was report-ed at the last International Congress on Anti-CancerTreatment and the Organisation for Oncology andTranslational Research. We are now conducting anotherstudy of NAC using FEC100 followed by 100 mg/m2 docetax-el. This study aims to investigate the feasibility and safety of100 mg/m2 docetaxel in a Japanese population (currently,the maximum dose of docetaxel allowed in Japan is 70mg/m2). In addition, we plan to investigate the efficacy ofdocetaxel followed by FEC, which is the type of conversionadministration used in the initial study. Appropriately, thesestudies include pCR rate as an endpoint.

The current problem, however, is that the term pCR hasnot been applied in a consistent, standardized manner, mak-ing interpretation and generalization of the results difficult;only limited information is available about the reliabilityand validity of these classifications. The definition of pCRused thus far can be summarized as follows:

• near pCR: only focal invasive tumour residues in theremoved breast tissue

• quasi pCR: total or near total disappearance of invasivetumour in the removed breast

• comprehensive (C) pCR: no evidence of residual inva-sive tumour in the removed breast

• strict (S) pCR: disappearance of all tumour cells in theremoved breast

• pCRinv: only in situ tumour residuals in the removedbreast

• CpCRbr+n: no evidence of residual invasive tumour inthe breast and axillary nodes

• SpCRbr+n: no malignant tumour cells in the removedbreast and axillary nodes

By definition, SpCR is the most rigorous response in thebreast, and SpCRbr+n represents the ultimate response toNAC. Most frequently, however, pathologic response is char-acterized as pCR when there is no evidence of residual inva-sive tumours in the breast, ie, CpCR, as there are no data toindicate that in situ tumour residuals confer a higher risk ofdistant metastasis or a different long-term outcome thantotal absence of tumour cells, ie, SpCR or SpCRbr+n. Furtherstudy is needed to clarify whether loco-regional recurrenceand ipsilateral breast tumour recurrence after breast con-serving therapy vary according to the definition of pCR.

An additional issue appears to be the lack of a standard-ized method for handling surgical specimens. Conceptually,the evaluation of pCR based on complete sectioning of thesurgical specimen is not of the same calibre as that derivedfrom a few sections taken from the representative site. As themain aim of NAC is total eradication of the tumour in boththe breast and axillary lymph nodes, and sites ofmicrometastasis, it is mandatory that the pathologist makeevery effort to find any residual tumour, and to carry out amore extensive examination to confirm pCR if no tumour isfound on initial sampling. In cases where there is residualtumour in the resected breast, the distribution pattern—forexample, concentric or honeycomb—or the extent of theresidual tumour should be documented.

Use of divergent classifications without verification of theirreliability or validity, and lack of a standardized method forhanding of surgical specimens, may cause large fluctuations ofresults between trials. To resolve these issues, we have estab-lished a central committee for review of pathology, and in thefirst study three pathologists are now independently assessingthe pathologic response according to the “General Rules forClinical and Pathological Recording of Breast Cancer:Histopathological Criteria for Assessment of TherapeuticResponse in Breast Cancer” of the Japanese Breast CancerSociety. This assessment employs a 5-grade scale, and residualdisease is graded according to the size of the tumour and theextent of the cytotoxic effect of chemotherapy. Also, intraduc-tal components and lymph node metastasis can be evaluatedand recorded separately using these criteria. Moreover, thepathologic response would be graded as near pCR when thereare only focal invasive tumour residues in the removed breasttissue. We hope that our approach is suitable for this purpose.

From the Japan Breast Cancer Research Group(JBCRG): How to define pCR: Our Challenge Katsumasa Kuroi, Masakazu Toi, Hitoshi Tsuda, Masafumi Kurosumi,Futoshi Akiyama

News from BIG Groups

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1818

BACKGROUND AND AIMS

DCIS has become an increasingly common diagnosissince the advent of mammographic screening. In theUK DCIS currently accounts for approximately 20%

of screen-detected cancers. It is generally agreed that adequatelocal treatment comprises either simple mastectomy alone orcomplete microscopic tumour excision plus radiotherapy.Although radiotherapy has been shown to reduce the risk ofrecurrence, many clinicians are reluctant to use it in allpatients due to the lack of evidence that it affects mortality. Inthe UK only 30% of patients with DCIS receive radiotherapy,whereas elsewhere in Europe and the US it is standard thera-py. Previous trials were not prospectively designed to identifylow- or high-risk subgroups of DCIS patients.

The purpose of the DCIS II study is to identify, withina trial using adjuvant endocrine therapy, the group ofpatients who can be spared radiotherapy. The trial’s pri-mary aims are to test the effects of withholding radiothera-py in terms of ipsilateral tumour relapse and quality of life.Its secondary aims are to identify the minimum surgicalmargins required to minimise local recurrence rate and toidentify molecular markers that predict for ipsilateraltumour recurrence.

PATIENT ELIGIBILITY SUMMARY

Females with completely locally excised oestrogen recep-tor (ER) positive DCIS (≥ 1 mm clear margin) with noinvasive component; breast conserving surgery; low-riskDCIS defined as grade 1 or 2 < 30 mm or grade 3 < 15mm; aged between 40 and 70. Postmenopausal womenaged ≥ 40 will also be eligible for the IBIS II (DCIS) Study.Premenopausal women aged ≥ 40 and postmenopausalwomen not in the IBIS II (DCIS) study will all be pre-scribed tamoxifen.

DATA COLLECTION

Data will be managed by ICR-CTSU in collaboration withthe IBIS II trial team. Follow-up outlining all recurrences,deaths, adverse effects, changes in therapy etc will be collect-ed, preferably electronically.

SAMPLE SIZE

A total of 2,000 patients will provide 90% power to excludean increase of ≥ 3% in 5-year recurrence rates in the groupreceiving no radiotherapy (assuming 3% recurrence rate at 5years in radiotherapy group). If 5-year recurrence rates are ashigh as 8% in the radiotherapy group, the sample size is suf-ficient to exclude an increase of ≥ 4%. Estimates assume a 1-sided p-value of .05.

ASSOCIATED STUDIES

Several additional studies will be developed in connectionwith DCIS II: biological, quality of life, and pathologicalassessment of margin status.

TRIAL SUPPORT

The DCIS II Trial has the full support of BASO (TheAssociation for Cancer Surgery) and the NCRI (NationalCancer Research Institute) Breast and Radiotherapy ClinicalStudies Groups. The Trial was presented at the most recentBIG meeting (ESMO, October 2004); BIG collaborativegroups, as well as individual centres, are encouraged to con-sider participating in this trial. BIG groups should contactthe BIG Secretariat <[email protected]> to register their inter-est and Dr. Simon Piggott (Trial Coordinator), <[email protected]>; Tel: +44 (0)20 8643 8901 x 4674 or Fax: +44(0)20 8770 7876 for more details about the study.

From the Institute of Cancer Research, ICR-CTSURandomised Trial Testing Observation (No Radiotherapy) against Radiotherapyin Women with Low-Risk Completely Excised ER Positive Ductal Carcinoma inSitu (DCIS) of the Breast on Adjuvant Endocrine Therapy: BASO DCIS II

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TRANSBIG News

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One of the European Commission’s requirements underthe European Union (EU) Framework Programme VIis for Networks of Excellence like TRANSBIG to devel-

op and execute a plan that will ensure the “spreading of excel-lence” (SoE), or the dissemination of knowledge and informa-tion generated from the consortium’s activities. TRANSBIG’sSoE Committee (SoEC) therefore functions as the network’seducational and public relations arm. In addition to developinga traineeship program for scientists and physicians in basic,clinical, and translational breast cancer research, the SoEC willensure that information about the TRANSBIG network and itsprojects is presented on an ongoing basis in a variety of media,including newsletters, Web sites, presentations and workshopsat scientific conferences, and press conferences. While much ofthis information will be aimed at scientific audiences, an essen-tial aspect of SoE will be to establish a dialogue with the non-scientific and patient communities. Here the aim is to help raise

awareness about developments in breast cancer research,including the clinical trial MINDACT, as well as the many com-plex issues—ethical and otherwise—that accompany progressin the breast cancer field.

Working closely with the BIG/TRANSBIG Secretariat, thekey consortium partners involved in TRANSBIG’s SoEC arethe Federation of European Cancer Societies (FECS) andEUROPA DONNA, the European Breast Cancer Coalition.FECS is an international nonprofit association that coordi-nates collaboration between European societies active in dif-

TRANSBIG1

Spreading of Excellence

TRANSBIG News

1TRANSBIG is a translational research network founded by BIG in2004. It is partially funded by the European Commission, theBreast Cancer Research Foundation and the Prix Mois du Cancerde Sein. The funding organizations are not to be held responsiblefor any of the views expressed by TRANSBIG. For further informa-tion about the network, contact [email protected].

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ferent fields of cancer research, including prevention and treat-ment, with the ultimate goal of providing the best possibletreatment and care for all European cancer patients<www.fecs.be>. EUROPA DONNA, also an independent,nonprofit organisation, is a coalition of groups from countriesthroughout Europe that works to raise awareness of breastcancer and to mobilise the support of European women inpressing for improved breast cancer education, appropriatescreening, optimal treatment and care, and increased fundingfor research. EUROPA DONNA represents the interests ofEuropean women regarding breast cancer to local and nation-al authorities as well as to institutions of the EU <ww.cancer-world.org/cancerworld/home>. A third party, a public affairsconsultant with expertise in medical journalism and commu-nications, is also a critical member of the SoEC.

What does all this mean in practical terms? To date theSoEC has, among other things,

• organized a press conference at the 4th European BreastCancer Conference in Hamburg to mark the launch ofTRANSBIG in March 2004;

• prepared a “public relations pack” on CD for consortiummembers. This tool includes summaries, Q&A, and slidepresentations about TRANSBIG that are suitable forvarious audiences;

• written articles for newsletters and made presentationsabout TRANSBIG at conferences such as the EuropeanSociety of Medical Oncology (ESMO) 2004 in Vienna(eg, presentation during a patient seminar) and the 4th

UICC World Conference for Cancer Organizations inDublin (poster);

• liaised with journalists reporting on the project, includ-ing the creators of a European Commission sponsoredfilm on TRANSBIG; and

• been posting TRANSBIG materials on Web sites such asthose of BIG, FECS, EUROPA DONNA, and others.

The SoEC will continue to develop and coordinate suchmaterials and activities, with immediate priorities being to takethe first steps necessary to be able to launch the traineeship pro-gram in 2006 and to plan for workshops (scientific/patient-ori-ented) to take place at conferences in the coming year.

Dr. Martine Piccart was recently awarded two grants,supported largely by the Estée Lauder group, forsome of the TRANSBIG network’s research on gene

expression profiling as a way to better determine whichwomen with node negative breast cancer need adjuvantchemotherapy. Dr Piccart received a grant of $225,000 fromthe Breast Cancer Research Foundation (BCRF) during itsAnnual Symposium and Awards Luncheon at the Waldorf-Astoria in New York on 13 October 2004. Founded byEvelyn H. Lauder just over 10 years ago, the BCRF is dedi-cated to supporting outstanding clinical and geneticresearch on breast cancer. To date, BCRF has raised morethan $95 million to support breast cancer in the US, and for2004/2005 has awarded grants of over $18 million to sup-port 97 researchers across the US and worldwide. For moreon this impressive organization, refer to its Web site<http://www.bcrfcure.org>.

The second grant received by Dr Piccart, during the samemonth at the Hôtel de Ville in Paris, was the Prix Mois duCancer de Sein of 50,000 Euros. This prize was created bythe French organization “Le cancer du sein, parlons-en!” toreward the work of individuals in basic and clinical breastcancer research.“Le cancer du sein, parlons-en!,” which aimsto raise awareness about and help combat breast cancer, wasitself founded about 10 years ago by the Estée Lauder group,the Marie Claire group, and NRB Vaincre le Cancer headedby Prof. Claude Jasmin.

Martine Piccart Awarded Two Grants

Photo 1: Martine J. Piccart and Evelyn H. Lauder at October2004 Awards Ceremony.

Photo 2: Martine J. Piccart receiving Prix Mois du Cancer deSein, together with the other laureates.

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In the Pipeline / Upcoming Events

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Study Study Safety/Tolerability Efficacy Drug(s) Population Design Results Results Reference

Doxorubicin plus Adjuvant Measurement of left Grade 2 LVEF Not evaluated Perez EA et al. J Clincyclophosphamide ventricular ejection toxicity in 6.6% Oncol 2004;22:(AC) effect on left fraction (LVEF) in 1,576 of patients 3700–4.ventricular patients treated with function AC for 4 cycles q 3 wks

Tamoxifen + Women > Radiation plus tamoxifen or Patients and physicians No differences Huges KS, et al. N Engl Jradiation versus age 70 with tamoxifen alone following rated radiation plus between two Med 2004;351:971–7.tamoxifen stage I, ER+ lumpectomy tamoxifen inferior groups in ratesalone disease to tamoxifen alone of mastectomy

for adverse events for localand cosmetic results recurrence,

distant metastases,of 5-year survival;only significant difference between groups in local/regional recurrence at 5 years

Gemcitabine and Advanced Gemcitabine 1,000 mg/m2 Grade 3/4 neutropenia ORR 28.6%, 34.3% Hausmaninger H, et al.epirubicin disease (stage followed by epirubicin in 51.5% of patients of patients had SD Am J Clin Oncol

IIIB or IV); 15 mg/m2 days 1, 8, and (without febrile OS 17.1 months 2004;27:429–35.40% received 15 of 28-day cycles neutropenia); grade 3prior chemo- thrombocytopenia intherapy 29.4% of patients (no

hemorrhage or platelet transfusions); grade 3 alopecia in 38.2% ofpatients and grade 3 nausea/vomiting in 11.4% of patients

Sequential versus Metastatic Phase III evaluation of Febrile neutropenia No significant Alba E, et al. J Clinconcomitant sequential A followed significantly less differences Oncol 2004;22:2587–93.doxorubicin (A) by T versus concomitant common in A to T between the 2 and docetaxel (T) doxorubicin and paclitaxel arm than the AT arm groups in ORR,

(AT) (29.3% of patients median durationversus 47.8% of patients, of response,p = .02) TTP, OS

Doxorubicin and Metastatic Comparison of health No significant Bottomley A, et al. J Clinpaclitaxel related quality of life of differences in health Oncol 2004;22:2576–86.(AT) versus AT versus AC first line related quality ofdoxorubicin and life between thecyclophosphamide 2 groups(AC)

Prediction of Metastatic Evaluation of circulating Not applicable Patients with 5 or Cristofanilli M et al.progression-free tumour cells before more circulating N Engl J Medsurvival and overall treatment and at first tumour cells per 2004;351:781–91.survival from follow-up visit 7.5 ml blood hadassessment of significantly shortercirculating tumour median progression-cells in peripheral free survival andblood OS than patients

with fewer than 5cells, both at baseline and first follow-up

ER=estrogen receptor; ORR=objective response rate; OS=overall survival; SD=stable disease; TTP=time to progression


New Therapeutics/Regimens for Breast Cancer: Sample of Recent Publications

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Perez and colleagues have evaluated the effect of 4cycles of doxorubicin plus cyclophosphamide (AC)on left ventricular ejection fraction (LVEF) of

patients with early breast cancer receiving this regimen aspart of the NCCTG N9831 Intergroup adjuvant trial treat-ment program (AC x 4 followed by paclitaxel +/-trastuzumab). Grade 2 LVEF toxicity was observed in 6.6%of the 1,458 patients evaluable for this analysis and,notably, 2.5% of the patients had LVEF that decreased to orfell below the lower limit of normal. These data are inter-esting because they report the “acute” effects on LVEF ofdoxorubicin given at the “low” cumulative dose of240 mg/m2. The long-term effects of anthracyclines onLVEF have been reported by two different groups; a LVEFdecrease below the lower limit of normal was observed in3% of the patients treated with 8 cycles of CMF followed by4 cycles of doxorubicin (NCI Milan; median follow-up 11 years) and in 7% of women treated with 6 cycles of

FEC100 (FASG; median follow-up 8.5 years). A longer fol-low-up of the NCCTG N9831 Intergroup trial will tell uswhether these “early” LVEF changes will remain asympto-matic or translate into cardiac changes in the long term,especially in patients receiving additional trastuzumab. Weare in an era in which trastuzumab might become a stan-dard adjuvant treatment in patients with HER2+ earlybreast cancer. Short- and long-term safety data from ongo-ing trials are awaited to evaluate whether the sequenceanthracycline → trastuzumab can be administered. In thenear future, molecular markers might help us to identify acohort of HER2+ patients in which anthracyclines areexpected to be highly effective. Other cytotoxics such astaxanes and/or platinum compounds might become pre-ferred options to be combined with trastuzumab in theother cohort of HER2+ patients in which, on the basis of agiven molecular marker profile, anthracyclines are consid-ered a suboptimal or undue treatment.

Commentary on Perez et al.Laura Biganzoli, MD, Hospital of Prato, Prato, Italy

Commentary on Bottomley et al.Kathleen Pritchard, MD, Toronto Sunnybrook Regional Cancer Center,Toronto, Canada

In the study by Bottomley et al, 275 women were randomlyassigned to receive AT (doxorubicin 60 mg/m2 of an intra-venous bolus plus paclitaxel 175 mg/m2 as a 3-hour infu-

sion) or AC (doxorubicin 60 mg/m2 plus cyclophosphamide600 mg/m2), every three weeks for a maximum of 6 cycles.Dose escalation of paclitaxel (to 200 mg/m2) or of cyclophos-phamide (to 750 mg/m2) was planned at cycle 2 to reach equiv-alent myelosuppression in each group. Health-related quality oflife was assessed using the European Organization for Researchand Treatment of Cancer (EORTC) Quality of Life (QoL)Questionnaire C30 and the EORTC Breast Module at baselineand at the start of cycles 2, 4, 6, and 3 months after the last cycle.

The clinical results of this trial had previously beenreported elsewhere.1 The relative dose intensity and cumu-lative dose of doxorubicin was lower in the AT arm. Medianprogression-free survival, response rate, and overall survivalwere not different between the two regimens. The AT regi-men however, showed a higher incidence of febrile neu-tropenia (32% versus 9%) and a greater decrease in left ven-tricular ejection fraction (27% versus 14%).

The current paper reported quality of life results. In botharms, fatigue increased by the second assessment, but

decreased in the AC arm to levels comparable with baselinewhile remaining moderately increased in the AT arm. In bothgroups, nausea and vomiting increased at cycle 2 to clinicallyworse levels, but returned to levels comparable with baselineat the next assessment. In both groups, moderate clinicallysignificant increases in systemic therapy side effects were seenoccurring at cycle 2, and continuing over subsequent assess-ments. This became a large, clinically meaningful effect in theAT arm by the last cycle. Despite this increase in at least sometreatment-related problems, global QoL was maintained inboth arms and showed little or no change during the entirestudy. In addition, both groups showed moderate improve-ment in emotional functioning over time, and improvementin pain over time. In both groups, however, a statistically sig-nificant worsening in role and physical functioning was seen.

These data provide interesting details about specificimprovements and decreases in various areas in quality oflife over time, which differed between these two treatmentarms. Although these effects did not adversely influenceglobal quality of life scores, they may provide additionalinformation for clinicians to use in explaining possible com-parative quality of life changes with these regimens.

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REFERENCES

1. Biganzoli L, Cufer T, Bruning P. Doxorubicin and paclitaxel ver-sus doxorubicin and cyclophosphamide as first-line chemothera-py in metastatic breast cancer: The European Organization forResearch and Treatment of Cancer 10961 multicenter phase IIItrial. J Clin Oncol 2002;20:3114–21.

Commentaries on the studies appearing in this section will be provid-ed when possible. If you are interested in writing future commentariesfor us, please contact <[email protected]> with a message and the areasof expertise for which you would be interested in being consulted.

MIAMI BREAST CANCER CONFERENCE

February 23–26, 2005Miami, Florida <http://www.allconferences.com>

BREAST DISEASES: DETECTION,INTERVENTION & THERAPY

February 27–March 3, 2005Quebec City, Canada <http://www.thebreastcourse.com>

SOCIETY OF SURGICAL ONCOLOGY CANCER

SYMPOSIUM

March 3–6, 2005Atlanta, Georgia<http://www.surgonc.org>

AMERICAN SOCIETY OF BREAST SURGEONS

March 16–20, 2005Los Angeles, California<http://www.breastsurgeons.org>

NATIONAL COMPREHENSIVE CANCER

NETWORK (NCCN)March 16–21, 2005Hollywood, Florida<http://www.nccn.org>

29TH ANNUAL SYMPOSIUM OF THE AMERICAN

SOCIETY OF BREAST DISEASE

April 14–16, 2005Las Vegas, Nevada<http://www.asbd.org>

AMERICAN ASSOCIATION FOR CANCER

RESEARCH April 16–20, 2005Anaheim, California<http://www.aacr.org>

AMERICAN SOCIETY OF CLINICAL ONCOLOGY

May 13–17, 2005Orlando, Florida<http://www.asco.org>

7TH MILAN BREAST CANCER CONFERENCE

June 15–17, 2005Milan Italy<www.breastmilan.com>

NOTTINGHAM BREAST CANCER 9TH

INTERNATIONAL CONFERENCE

September 13–16, 2005Nottingham UK<http://calendar.uicc.org>

ECCO 13—THE EUROPEAN

CANCER CONFERENCE

October 30–November 3, 2005Paris, France<http://www.fecs.be>

17TH AACR-NCI-EORTC MOLECULAR

TARGETS AND CANCER THERAPEUTICS

November 14–18, 2005Philadelphia, Pennsylvania<http://www.eortc.be>

SAN ANTONIO BREAST CANCER SYMPOSIUM

December 8–11, 2005San Antonio, Texas<http://www.sabcs.org>

Conference Calendar 2005

The next BIG/TRANSBIG meetings will take place as follows:

during ASCO, Orlando,Sunday 15 June 2005, 18:00–19:30, BIG General Assembly (for BIG members);

during ECCO 13, Paris,TRANSBIG meetings Thursday 28 October 2005 (for consortium members, by invitation),

BIG meeting Friday 29 October 2005, details TBA (for BIG members).

NOTICE TO MEMBERS: BIG AND TRANSBIG MEETINGS

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