European oncologists' preferences for the management of breast cancer: case presentations and expert commentary

The Breast (2008) 17(S2) S1–S11

www.elsevier.com/locate/breast

European oncologists’ preferences for the management of breast cancer: case presentations and expert commentary M. Anderssona , A. Awadab , P. Barrett-Leec , P. Ellisd , P. Hupperetse , uckh , C. Monnerati , U. Nitzj , C. Jackischf , E. Kubistag , H.-J. L¨ M. Untchl a

Rigshospitalet, Copenhagen, Denmark Institut Jules Bordet, Brussels, Belgium c Velindre Hospital, Whitchurch, Cardiff, United Kingdom d Guy’s Hospital, London, United Kingdom e University Hospital Maastricht, Maastricht, the Netherlands f Klinikum Offenbach, Offenbach, Germany g Universit¨ atsklinik f¨ ur Frauenheilkunde, Vienna, Austria h Medizinische Hochschule, Hannover, Germany i Service Cantonal d’Oncologie, La Chaux-de-Fonds, Switzerland j Bethesda Klinik, M¨ onchengladbach, Germany k Helios Klinikum Berlin-Buch Akademisches LK der Universit¨ at Charit´ e, Berlin, Germany b

KEYWORDS Breast cancer; HER2 overexpression; Inflammatory Breast Cancer; Oestrogen receptors; Progesterone receptors; Neoadjuvant; Adjuvant; Tamoxifen and Aromatase inhibitors; Trastuzumab; Lapatinib; Taxane; Docetaxel

Summary The development of new cytotoxic and biological agents has brought a welcome extension in the range of therapeutic options available to women with both early-stage and advanced breast cancer. Among the most significant recent developments has been the recognition of HER2 as a prognostic factor and target for treatment. In a series of meetings across Europe, 230 experienced oncologists and an expert faculty discussed and voted on how best to treat five women whose cases were chosen to bring out important issues in treatment. In most cases, a range of options were considered appropriate, and intriguing differences emerged between countries in the choices preferred. The following represents a very abbreviated outline of the cases and the management decisions made. Case 1, symptomatic, visceral, metastatic disease overexpressing HER2: most favoured option, trastuzumab plus docetaxel. Case 2, adjuvant chemotherapy in high-risk, hormone-negative, HER2-positive disease: favoured option, FEC-100 for three cycles, followed by three cycles of docetaxel (trastuzumab also given). Case 3, adjuvant endocrine therapy in a postmenopausal woman with hormone-positive, HER2-negative disease: favoured option, tamoxifen for two years followed by aromatase inhibitor (either exemestane or anastrozole). Case 4, inflammatory HER2-positive breast cancer progressing on FEC-100: favoured option, switch to a taxane plus trastuzumab. Case 5, a young woman with hormone-negative, HER2-positive disease who develops symptomatic visceral metastases a year after adjuvant FEC-100 and trastuzumab: favoured option, enrollment in a clinical trial of the HER2 tyrosine kinase inhibitor lapatinib alone or in combination with trastuzumab or chemotherapy. Together, the expression of

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M. Andersson et al. these preferences and the discussions that followed provide a valuable insight into current practice at a time of exceptionally rapid change in the management of breast cancer. © 2008 Elsevier Ltd. All rights reserved.

Introduction The treatment of breast cancer has seen steady and substantial advance over the past thirty years, to the extent that we now have a range of management options in many settings. These include endocrine agents (the archetypes of targeted therapy), cytotoxics, monoclonal antibodies (notably trastuzumab, Herceptin), and small molecule inhibitors of intracellular signaling. Increasingly, we will have the opportunity of tailoring therapy to the individual patient, based on clinical circumstances and the molecular characteristics of a specific tumour. However, many problems remain. In the adjuvant setting, despite our awareness of important prognostic factors, we are not yet able to attune treatment sufficiently precisely to risk of recurrence. Among patients with advanced and metastatic disease, the eventual development of resistance even to combination therapies means that valuable prolongation of disease-free and overall survival has yet to be translated into cure. In a series of interactive meetings held across Europe in late 2006 and 20071 , audiences of practising oncologists and an expert faculty discussed the management of five cases of breast cancer chosen to bring out important issues in treatment, either of advanced disease or in the adjuvant setting. Participants were self-selected. Therefore their views cannot be taken as formally representative of the individual countries in which meetings were held, nor of Europe as a whole. However, they do represent a valuable insight into the thinking and practice of oncologists routinely involved in the management of breast cancer during a period of exceptionally rapid change. The majority of the 230 clinicians participating were senior medical oncologists in hospital practice. Seventy-two percent had served at least six years since their oncology training, and 68% see at least seven new breast-cancer patients a month. Among important recent developments have been our increasing understanding of HER2 as a prognostic factor and target for treatment, and advances in our ability to classify tumours using immunohistochemistry (IHC) to establish overexpression of this protein and, more recently, 1

fluorescence in situ hybridisation (FISH) to measure HER2 gene amplification. As demonstrated in the case histories that follow, insight into this aspect of the molecular biology of individual tumours is helping to optimise use of the HER2 antibody trastuzumab and will play a similar role with the advent of second-generation agents such as the oral HER2 tyrosine kinase inhibitor lapatinib.

Case studies Case 1. Metastatic disease overexpressing HER2 Three years ago, a 63-year-old postmenopausal primary school teacher was diagnosed with an infiltrating ductal carcinoma of the left breast. The 1.7 cm tumour was poorly differentiated (grade 3), and ER- and PR-negative (0% of cells positive) but overexpressed HER2 (3+ on IHC). One of 15 axillary nodes was positive. The TNM classification was pT1c, pN1, M0. She was treated initially with a lumpectomy and axillary lymphadenectomy, followed by six cycles of adjuvant FEC-100 (5-fluorouracil plus epirubicin plus cyclophosphamide) and radiotherapy to the left breast. Two and a half years later, she has a nonproductive cough and shortness of breath. Her ECOG performance status is 1. A chest X-ray shows bilateral pulmonary nodules, and CT of the abdomen reveals three nodules in the liver. Liver biopsy has confirmed metastatic adenocarcinoma that is HER2-positive by FISH. Participants were asked to recommend a regimen from the ten listed in Table 1. They were subsequently asked whether their choice would be different if the patient harboured multiple brain metastases. Treatments recommended Trastuzumab monotherapy was not considered a credible option; and use of an anthracycline regimen without trastuzumab received no support at all. The favoured choice by far was trastuzumab plus docetaxel (57% of overall vote). This option was endorsed by 70% of participants in Amsterdam (the centre most wholehearted in this

Meetings were held in Athens, Frankfurt, Prague, London and Amsterdam. The voting of participants in the Prague meeting is included in this report. However, due to problems with audiorecording, the expert commentary is not.

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Table 1 Metastatic disease overexpressing HER2: percentage of participants recommending listed treatments a,b Option: Trastuzumab plus:

paclitaxel docetaxel vinorelbine liposomal doxorubicin liposomal doxorubicin + docetaxel a taxane + carboplatin capecitabine capecitabine + docetaxel a b

Recommended (%) Athens Frankfurt

Prague

London

Amsterdam

Mean across meetings

14 57 0 14 5 10 0 NA

24 52 0 0 7 17 0 NA

19 62 10 0 NA 0 5 5

4 70 13 0 4 4 0 NA

18 57 5 4 5 9 1 5

31 42 0 4 4 15 0 NA

There was no support for an anthracycline-containing regimen without trastuzumab, and virtually none for trastuzumab alone. NA, Not asked.

choice) but by 42% even at the least enthusiastic meeting (Frankfurt). The second most popular choice was trastuzumab plus paclitaxel, with 18% of the vote overall. In London and Amsterdam, there was some interest in the combination of trastuzumab and vinorelbine. Fourteen percent of the Athens audience voted for the combination of trastuzumab with liposomal doxorubicin, but this idea received little support elsewhere. There was no real interest in combining trastuzumab with docetaxel plus capecitabine (an option offered to delegates in London), or with docetaxel plus liposomal doxorubicin (an option offered elsewhere). However, use of trastuzumab with the chemotherapy doublet of taxane plus carboplatin was advocated by 10% of participants in Athens, 15% in Frankfurt, and 17% in Prague. Commentary Discussants: Christian Monnerat, Ernst Kubista, Paul Ellis, Michael Untch The median 3.4 month time to progression with trastuzumab monotherapy is unacceptably short in this first-line setting 1 . Except in patients who are frail or who do not wish to have chemotherapy, trastuzumab therefore needs to be combined with some form of cytotoxic treatment. Careful selection of patients and more effective monitoring mean that cardiac toxicity is now less of an issue with trastuzumab/chemotherapy combinations 2 . Several of the options suggested to participants would be appropriate and achieve a good rate of response 3,4 . This patient has visceral disease and is symptomatic and so needs a treatment that achieves a rapid response. Taxane combinations have been the most widely studied: adding trastuzumab to docetaxel (weekly or every three weeks) or paclitaxel (weekly) achieves objective

response rates (ORR) in the region of 60% and 9 12 months free of progression. Long-term follow up of the M77001 trial of trastuzumab plus docetaxel shows that around 22% of patients are alive at four years 5 . This represents a treatment effect extending well beyond the traditional aim of palliating metastatic disease. Importantly, trial patients who were initially randomised to a taxane alone and who then had trastuzumab added on progression did not do as well as patients randomised to the combination at the start of treatment: we should therefore not delay in giving HER2-targeted therapy. There is some consensus that paclitaxel given every three weeks is less effective than threeweekly docetaxel. However, weekly paclitaxel may have a benefit similar to that seen with threeweekly docetaxel. Vinorelbine is an alternative partner for trastuzumab, achieving results that match those obtained by combining the antibody with a taxane 6-8 . Vinorelbine plus trastuzumab is well tolerated and a less expensive option. A trial underway in the Nordic countries is directly comparing trastuzumab plus vinorelbine against trastuzumab plus docetaxel in this firstline setting. Relevant to the choice of drug in an individual patient are the toxicity profiles of the different agents and previous adjuvant therapy. This woman has already been treated with an anthracycline as part of the FEC regimen. Participants in general did not think doxorubicin was a good option, but some would consider that rechallenge with an anthracycline is not excluded in this patient since 2.5 years have elapsed since her treatment with adjuvant FEC. Liposomal doxorubicin is less cardiotoxic than the standard formulation

S4 and has useful activity in combination with trastuzumab 9 . This patient has had no prior exposure to trastuzumab, but, increasingly, patients with metastatic disease will already have seen this agent in the adjuvant setting, so presenting a new dilemma. The latest data from BCIRG Study 007 show that giving trastuzumab together with two cytotoxics (i.e. adding carboplatin to docetaxel) does not extend TTP and confers no survival advantage when compared with combining trastuzumab with one cytotoxic given at an adequate dose 2 . In both arms, TTP was over 10 months, and OS over 36 months. However, it may be tempting to try such triple therapy in a patient faced with life-threatening visceral metastases. The choice between giving trastuzumab once weekly or every three weeks is partly one of convenience for the patient. However, in a symptomatic patient with visceral metastases there is a case for starting trastuzumab weekly, to quickly achieve steady state. Taxane dose is also an issue. This patient has liver involvement, and, in the case of docetaxel, the appropriate dose (in the range of 75 to 100 mg/m2 ) should be guided by liver function. In some instances, poor liver function might suggest a preference for weekly paclitaxel. As a mark of what the future may hold, interim results from the phase II extension of a dosefinding trial of trastuzumab plus bevacizumab suggest an ORR of 54% 10 . This is arguably the first evidence that a combination of two targeted agents in metastatic breast cancer can achieve activity previously seen only with chemotherapy although there may be a high level of cardiotoxicity. Treatment in the case of brain metastases Around 70% of participants overall said that their choice of initial therapy in this case might have been different if the patient had had multiple brain metastases. This is an important consideration: brain involvement is found in more than 30% of HER2-positive breast cancer patients with metastatic disease, and the brain may become more frequent as a site of recurrence as patients survive longer. Data from the Danish Breast Cancer Group’s prospective adjuvant trial show that the incidence of cerebral metastases in HER2-positive patients is five times that in HER2-negative patients. It is not uncommon to find women who have been treated with trastuzumab presenting with symptomatic cerebral lesions while visceral disease is well controlled or absent.

M. Andersson et al. Brain metastases often progress rapidly, and prognosis at the moment is poor. Management is guided by symptoms. Radiotherapy is clearly a mainstay. In terms of targeting HER2, trastuzumab is a large molecule and may not penetrate the brain as effectively as a small molecule such as lapatinib. In the study of capecitabine with or without lapatinib, fewer patients treated with the combination developed brain metastases 11 . Although numbers are small, the difference between treatment arms (11 CNS relapses with capecitabine alone vs 4 among patients treated with capecitabine plus lapatinib) approached significance (p = 0.07, Fisher’s exact test). Case 2. Adjuvant chemotherapy in high-risk disease A 48 year old premenopausal woman diagnosed with cancer of the left breast has undergone lumpectomy and axillary lymphadenectomy. The tumour was an infiltrating ductal carcinoma, 2.6 cm in size, and grade 3. No cells were positive for ER or PR but the tumour was HER2positive by FISH. Fourteen percent of cells were in S phase. On axillary clearance, four of twenty nodes were positive. The patient has an ECOG performance status of 0 and no comorbidities. On completion of adjuvant chemotherapy, the patient will have radiotherapy. Trastuzumab will be administered. What is the optimum regimen of adjuvant chemotherapy? Treatments recommended Some form of sequential docetaxel-containing adjuvant regimen was the most frequent choice at all meetings: in Athens and Prague, the favoured option was four cycles of AC or EC followed by four of docetaxel, while Frankfurt and London favoured three cycles of FEC-100 followed by three of docetaxel. The next most popular choices were TAC for six cycles and AC or EC ×4 followed by paclitaxel ×4. Because of the perceived need for a taxane overall, FEC-100 ×6 and FAC ×6 were not thought good options. However, there was a 25% vote in London for “other” options. These included epirubicin plus CMF and high-dose chemotherapy. (See Table 2.) Commentary Discussants: Ahmad Awada, Hans-Joachim L¨ uck, Peter Barrett-Lee, Pierre Hupperets, Christian Monnerat Adjuvant Online, one of several tools for risk assessment, has yet to incorporate HER2 status into its risk estimation algorithm (https:// www.adjuvantonline.com Version 8). However,

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Table 2 Adjuvant chemotherapy in high-risk disease: percentage of participants recommending various treatments Regimen a

AC or EC ×4 followed by paclitaxel ×4 AC or EC ×4 followed by docetaxel ×4 FEC-100 ×6 FEC-100 ×3 followed by docetaxel ×3 TAC ×6 FAC ×6 Other a

Recommended (%) Athens Frankfurt

Prague

London

Amsterdam

Mean across meetings

24 38 0 14 24 0 0

19 26 4 15 21 0 15

5 20 5 45 0 0 25

23 18 5 32 23 0 0

16 22 5 29 18 1 9

9 9 13 39 22 4 4

AC = Adriamycin (doxorubicin) plus cyclophosphamide; EC = epirubicin plus cyclophosphamide; FEC = 5-fluorouracil plus epirubicin plus cyclophosphamide; TAC = Taxotere (docetaxel) plus Adriamycin (doxorubicin) plus cyclophosphamide; FAC = 5-fluorouracil plus Adriamycin (doxorubicin) plus cyclophosphamide.

based on the other information we have, the programme predicts that this patient in the absence of therapy would have a 66% chance of dying within ten years from her breast cancer, and only a 1% chance of dying from other causes. Two factors here are particularly relevant, and underlie the preference for a taxane-containing regimen to accompany the adjuvant trastuzumab: the patient has four positive lymph nodes, and a HER2-positive tumour. Both are indicative of aggressive disease. An overview of eight studies which have looked at the effect of adding paclitaxel or docetaxel to standard anthracycline-based chemotherapy shows that addition of the taxane significantly reduces risk of relapse and decreases five-year mortality by up to 6%. Of particular relevance to this case, subgroup analysis of the CALGB 9344 trial has recently suggested that HER2-positive patients benefit (irrespective of ER status) from the addition of paclitaxel to AC, while patients who are HER2-negative and ER-positive do not 12 . The trials do not allow us to decide whether giving the taxane following standard anthracyclinebased chemotherapy is superior to giving it at the same time, or vice versa. There is little evidence to support a choice of FEC ×3 followed by docetaxel ×3 over TAC ×6, for instance. In justifying any particular choice, much has to be made of subgroup analyses. What is undisputed is the differences between regimens in toxicity: with TAC ×6 there is, for example, a high rate of febrile neutropenia (occurring in around a third of patients, in the absence of prophylactic growth factors). There are also toxicity differences between the taxanes which may influence choice of agent in a particular patient. If adjuvant paclitaxel is to be used, it

is reasonably clear that this should be given on a weekly rather than three-weekly schedule 13 . As for the importance of also targeting HER2, it is clear that AC followed by taxane plus trastuzumab leads to significantly better diseasefree and overall survival than AC followed by taxane and no trastuzumab 14,15 . The combined analysis of the NSABP and NCCTG trials, for example, showed a DFS of 67% at four years in the arm without trastuzumab, and 85% in the arm which also received the HER2 antibody. There is level-1 evidence for using a year of adjuvant trastuzumab in women with HER2-positive breast cancer. However, provocative data from the FinHER study in Finland suggest that the same benefit can perhaps be derived from a course of trastuzumab as short as nine weeks 16 . In the US trials and the BCIRG 006 and FinHER studies, trastuzumab was begun at some stage during the period of chemotherapy. In the US B31 study, in which patients in the experimental arm received trastuzumab at the same time as they were given the taxane, the cumulative incidence of cardiac events was 4.1% among patients who had the antibody but less than 1% in the nontrastuzumab arm. (However, the only cardiac death was in the control arm.) In the HERA study, which also showed a significant survival advantage for patients given anti-HER2 therapy, trastuzumab was begun only after sequential chemotherapy had been completed. In this trial, around 2% of patients treated with trastuzumab (compared with 0.2% in the observation arm) developed symptomatic congestive heart failure: the rates of NYHA class III/IV CHF were 0.6% and 0%, respectively 17 . Such differences are relevant in deciding the timing of trastuzumab administration in relation to chemotherapy. A potentially helpful

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Table 3 Adjuvant endocrine therapy: percentage of participants recommending various treatments Regimen

Tamoxifen × 5 yrs Anastrozole × 5 yrs Letrozole × 5 yrs Tamoxifen × 2 yrs then exemestane × 3 yrs Tamoxifen × 2 yrs then anastrozole × 3 yrs Tamoxifen × 5 yrs then letrozole × 5 yrs Other

Recommended (%) Athens Frankfurt

Prague

London

Amsterdam

Mean across meetings

26 13 9 13 9 30 0

20 11 4 24 20 20 0

22 17 0 22 39 0 0

10 5 14 24 24 14 10

20 13 7 17 23 13 2

21 17 10 24 24 3 0

pragmatic policy based on the Intergroup analysis has been adopted by many clinicians. In adjuvant patients at high risk of tumour recurrence who are relatively young, trastuzumab and a taxane are given concomitantly, while in patients at high risk of cardiotoxicity and intermediate risk of tumour recurrence, chemotherapy and trastuzumab are given sequentially. There is now a reasonable consensus that careful selection of patients according to cardiovascular history and risk factors (such as age and treated hypertension), coupled with appropriate monitoring of heart function, has very much reduced the risk of symptomatic cardiac problems in patients treated with adjuvant trastuzumab and chemotherapy. Data from the HERA, B31 and N9831 studies are consistent in showing an incidence of brain metastases as first site of relapse that is higher in trastuzumab-treated women than in controls. This may point to a need for second-generation anti-HER2 agents that more readily cross the blood brain barrier. Also of possible relevance to optimizing future therapy are data from the AGO group and elsewhere suggesting a benefit from dose-dense, accelerated chemotherapy. However, the implications of these findings for combinations of chemotherapy with trastuzumab in HER2 positive disease are not yet clear. Case 3. Adjuvant endocrine therapy Following an abnormal screening mammogram in a 59-year-old postmenopausal general practitioner, an invasive ductal carcinoma of the right breast was diagnosed. The tumour was 1.7 cm, well differentiated (grade 1), and hormone-receptor positive (ER 80% and PR 60% positive cells). HER2 status by FISH was negative. None of the 15 axillary nodes sampled was positive. She was treated by lumpectomy and axillary

lymphadenectomy. Radiation to the right breast was planned. The patient had mild ostopenia (T score of 1.2) and was taking calcium and vitamin D. Three years ago, she was investigated for postmenopausal bleeding, but no pathology was found. The patient’s total cholesterol, at 250 mg/dL, was above the upper limit of normal (200 mg/dL). Her father died of a myocardial infarction at the age of 64. The patient’s ECOG performance status was 1. Participants were asked to choose the optimal adjuvant endocrine therapy from among the options listed in Table 3. Treatment recommended There was relatively little consensus among participants on the optimum endocrine treatment for this patient. (In part, this may reflect the opinion of some in the audience that “no see treatment” should have been an option commentary below.) Overall, opinion was fairly evenly divided between three options: tamoxifen for five years, and tamoxifen for two years followed by either exemestane or anastrozole for three years. Each of these proposals attracted the support of around one in five participants. There was about half this level of support for three further options: five years of anastrozole or letrozole, or five years of tamoxifen followed by five of letrozole. The preferences expressed show interesting diversity across the countries. Preference for two years of tamoxifen followed by anastrazole was strong in London, but nowhere else was the result as clear-cut; and in Athens, the idea of following tamoxifen by either exemestane or anastrozole was very much a minority view. Here the majority of participants voted either for five years’ adjuvant tamoxifen, or the extended ten-year treatment option of tamoxifen followed

European oncologists’ preferences for the management of breast cancer by letrozole. Extended treatment was also considered a possibility in Prague, but received little support in Amsterdam and Frankfurt, and none at all in London. Commentary Discussants: Paul Ellis, Ahmad Awada, Hans-Joachim L¨ uck The major choice presented here was between using an aromatase inhibitor (AI) up-front for five years on the one hand, and switching to an AI after 2 3 years of tamoxifen on the other. The trials of up-front AI versus tamoxifen have shown improved disease-free survival but no significant benefit on mortality 18,19 . However, studies in which patients are switched to an AI after a period on tamoxifen have shown evidence of survival benefit when compared with the full five years of tamoxifen 20,21 . The endocrine treatment most strongly endorsed by the recent expert meeting in St. Gallen is 2.5 years tamoxifen followed by an AI, either steroidal, like exemestane, or non-steroidal, like anastrozole. (In efficacy terms, there appears to be little difference in this setting between the AIs.) Just under half of the participants in the meetings reported here were in broad agreement with this “switch” approach. In St. Gallen, five years of anastrozole was regarded as an acceptable alternative, but this option was chosen by only one in ten in our series of meetings. A second question posed concerned the possible value of extending adjuvant treatment to ten years; and it is clear that there is a continued risk of recurrence (higher in ER+ than ER tumours) out to at least eleven years. While ten years of tamoxifen is associated with a poorer outcome than five years treatment (according to NSABP data), we do not yet have any evidence regarding a more extended period of treatment with an AI. In clinical practice, guidelines whatever their must be adapted to the circumstances origin of the individual patient. In this instance, family history, clinical history and laboratory findings show potential for a full set of adverse events associated with endocrine treatment. The patient’s degree of osteopenia, while mild, is sufficient to confer a 2 3-fold increased risk of osteoporotic fracture compared with the normal population 22 . Data from the ATAC study are clear in demonstrating that osteopenia at the start of adjuvant treatment predicts subsequent osteoporosis. This patient also has cardiovascular risk factors. Tamoxifen could benefit her bone health (or at least not worsen it), is well tolerated, and would be considered an option by many but at the cost

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of increasing risk of endometrial cancer, deep vein thrombosis and stroke. On the other hand, data from the ATAC and ITA trials show a lower rate of hypercholesterolaemia and lipid disorders with tamoxifen than with anastrozole 23 . Also relevant to this case are the findings of the IES trial showing an 18% incidence of gynaecological symptoms with tamoxifen, compared with a 14% incidence with exemestane 20 . But the broad issue is whether the potential cardiac benefits of a full five years’ tamoxifen outweigh the inferior efficacy when compared to the strategy of sequential tamoxifen and AI, or an AI up-front. The patient being considered is at relatively low risk of dying from her cancer. Adjuvant Online (version 8) predicts that this patient, even if untreated, has only a 2.8% risk of death from breast cancer over the next ten years (compared with a 10% risk of dying from other causes). Many centres do not give any kind of adjuvant endocrine treatment unless tumours are larger than 2 cm and at least grade 2. Given the circumstances of this case, i.e. a postmenopausal patient with a small, well differentiated and hormone-receptor positive tumour, five years of tamoxifen, or no adjuvant treatment at all, could be considered reasonable alternatives to two years’ tamoxifen followed by three of AI.

Case 4. Inflammatory breast cancer A 52-year-old shopkeeper diagnosed with stage IIIB inflammatory breast cancer (IBC) is undergoing induction chemotherapy with four cycles of FEC-100 prior to surgery and radiotherapy. While on chemotherapy, she experiences disease progression. Her ECOG PS is 1. Pathology showed a poorly differentiated (grade 3) ER- and PRnegative tumour that was HER2-positive by FISH. Participants were asked to choose between the options listed in Table 4. Recommended treatment Across all meetings where the question was posed (this case of IBC was not presented in London), the clear majority of participants recommended switching the patient from FEC to taxane plus trastuzumab. In Prague, there was some support (18% of participants) for enrolling the patient in a trial of lapatinib; and in Amsterdam there was a similar level of support for two other options: adding a taxane to FEC, and switching to a taxanebased chemotherapy without anthracyclines and without addition of trastuzumab.

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Table 4 Inflammatory breast cancer: percentage of participants recommending various treatments a Option

Recommended Athens Frankfurt

Add taxane to anthracycline-based regimen 0 Switch to taxane-based chemotherapy without anthracycline 5 Add trastuzumab to current chemotherapy 5 Switch to taxane plus trastuzumab 84 Include in trial of lapatinib 5 a

11 11 4 74 0

Prague

Amsterdam

Mean across meetings

0 0 8 72 18

14 14 10 57 5

6 8 7 72 7

This case was not presented in London.

Commentary Discussants: Christian Monnerat, Ulrike Nitz IBC is relatively rare, accounting for only 1 2% of breast cancers. It requires a multimodality approach to treatment. Several small series, including one from the Royal Marsden, suggest the frequency of HER2 positivity is greater than in non-inflammatory breast cancers, and may exceed 30% 24 . However, in contrast to the situation in other forms of breast cancer, HER2 positivity in IBC does not seem to have any prognostic significance. For IBC in general, median overall survival is a little under three years 25 . Several studies of single-agent neoadjuvant chemotherapy in locally advanced breast cancer (including IBC) have shown relatively low rates of pathological complete response (pCR). However, the chemotherapy given was typically of short duration. General principles suggest treatment should be dose-intense, maintained for at least 12 weeks, and combine several cytotoxic agents. There may be benefit from adding trastuzumab to neoadjuvant docetaxel and cisplatin given for four cycles over 12 weeks 26 . If not given in the neoadjuvant setting, trastuzumab should certainly be part of adjuvant therapy. The situation faced by this patient is unusual, since progression while undergoing FEC is relatively rare, but gives a clear indication that change in treatment is needed. Adding trastuzumab to the existing FEC regimen raises cardiotoxicity issues. So, based on the very limited data available, participants’ choice of switching to a taxane plus trastuzumab is entirely reasonable. There is not likely to be cross-resistance between FEC and a taxane, and these agents are arguably the most active we have in breast cancer. The preferred agent would probably be docetaxel. Lapatinib is active in HER2-positive breast cancer and its potential in neoadjuvant chemotherapy, including in patients with IBC, is being assessed. Spector et al. 27 have reported a phase II

of lapatinib monotherapy in IBC resistant or refractory to prior anthracyclines, i.e. very much the situation in which this patient finds herself. Among patients with HER2-overexpressing disease, the response rate was 62%. Case 5. Disease progression following adjuvant trastuzumab A 45-year-old premenopausal woman was diagnosed with a stage IIA (pT1c, pN1) cancer in her left breast. The tumour was grade 3, ER- and PR-negative, and HER2-positive by FISH. She had lumpectomy and axillary lymphadenectomy. Having agreed to participate in the HERA trial, she was randomized to receive trastuzumab for one year following anthracycline-containing chemotherapy (FEC-100 for six cycles) and radiotherapy. Five months after completion of trastuzumab, the patient developed persistent non-productive cough and mild dyspnoea on exertion. Thorough evaluation revealed small bilateral pulmonary nodules and moderate left pleural effusion. Cytology confirmed adenocarcinoma consistent with the breast primary. The patient has an ECOG performance status of 1. Participants were offered the treatment options listed in Table 5. This case was not presented in London. Recommended treatments At the Amsterdam meeting, the majority of participants (57%) recommended resumption of trastuzumab in combination with chemotherapy. However, a substantial minority (29%) opted for a clinical trial of lapatinib as a single agent or in combination (for example, with either trastuzumab or trastuzumab plus paclitaxel). Enrollment in a lapatinib trial was the most popular option in Prague and Athens (were it was chosen by just over 50% of participants) and was also strongly favoured in Frankfurt (where it was endorsed

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Table 5 Disease progression following adjuvant trastuzumab: percentage of participants recommending various treatments a Option

Resume trastuzumab and chemotherapy Chemotherapy alone, no trastuzumab Clinical trial of lapatinib alone or in combination Other a

Recommended (%) Athens Frankfurt

Prague

Amsterdam

Mean across meetings

34 10 52 3

20 27 51 2

57 10 29 5

33 12 43 13

20 0 40 40

This case was not presented in London.

by 40%). At this German meeting, the number opting for the “other” category was also 40%, in part because participants were thinking about the possibility of using bevacizumab. Chemotherapy alone was generally an unpopular choice, except in Prague, where it was chosen by 27%. Commentary Discussants: Michael Andersson, Christian Jackisch This patient was unfortunate. Available data from the HERA trial show that, compared with the observation arm, treatment with trastuzumab for one year is associated with a reduction of around one third in relative risk of disease progression and death at a median follow-up of two years 17 . This patient was among only 9% of trastuzumab-treated patients who experienced a distant recurrence. However, it is also worth pointing out that among women with ER- and PR-negative disease and 1 3 positive nodes, the cumulative incidence of relapse or metastasis was 25% at two years. In this setting of recurrent disease following adjuvant therapy including trastuzumab, there are no trial data to guide us, and little experience. We have no definition (in terms of the interval between the end of adjuvant therapy and the return of disease) of what constitutes resistance to trastuzumab. If we think there may still be benefit from the antibody in this metastatic setting, there are good reasons for combining it with chemotherapy. For example, this case meets three of the four criteria for chemotherapy developed by the German AGO group (disease negative for hormone receptors, visceral metastases and pain). The pivotal trial in first line metastatic patients with IHC 3+ HER overexpression showed that adding trastuzumab to paclitaxel resulted in a 39% prolongation of median survival 3 . A very similar benefit was seen in a second study in which trastuzumab was added to docetaxel 4 . If we think there is unlikely to be further benefit from trastuzumab, the patient should receive chemotherapy alone.

Many agents are active. A recent Cochrane analysis confirms that taxane-containing regimens are likely to be superior to non-taxane combinations 28 . Single-agent taxane may be as good as a combination: the latter increases RR and TTP but, in trials in which a large proportion of patients cross over, tends to show no survival advantage. However, trials of the combination of capecitabine with docetaxel and of gemcitabine plus paclitaxel have shown significant advantage in overall survival when compared with the single agent taxane 29,30 . Combinations increase adverse events such as neutropenia, neurotoxicity and hand foot syndrome; but there are data showing improved quality of life in breast-cancer patients with prior anthracycline treatment receiving 5 6 cycles of the combination of gemcitabine and taxane rather than taxane alone. Enrollment in a trial of lapatinib, a small molecule inhibitor of both HER2 and EGFR tyrosine kinase, would also be an appropriate option for this patient. Given the role of angiogenesis in tumour progression, the anti-VEGF monoclonal antibody bevacizumab (Avastin) plus paclitaxel would also be a possibility but note that the E2100 trial with weekly paclitaxel included only a very small number of patients with HER2-positive disease 31 . Clinical developments in this case This patient was in fact treated by resuming trastuzumab, along with chemotherapy. However, three months from the start of therapy, her symptoms had not improved. The cough persisted and the pulmonary nodules were stable. Participants’ choice of further treatment At this stage, enrollment in a clinical trial involving lapatinib became the most popular choice at each meeting (with 55% endorsement overall). The second most favoured option (21% endorsement) was to continue trastuzumab but in combination with a different regimen of chemotherapy.

S10 Further commentary Continuing with trastuzumab in this instance falls into the realm of treatment beyond progression. In the case of this agent there may be some validity in this approach since preclinical data suggest tumour repopulation if the agent is stopped 32 . In an extension to the pivotal study 3 of Slamon et al. 33 , pts were eligible to receive trastuzumab on progression. Among patients who had already had trastuzumab first line, this second exposure to the antibody produced an ORR of 11% and a clinical benefit rate of 22%. However, in the absence of data from randomised clinical trials, all the options presented would be reasonable. The most popular choice among participants was enrollment in a lapatinib trial, and there is a good basis for this suggestion in data from the comparison of lapatinib plus capecitabine vs capecitabine alone in women with refractory advanced or metastatic breast cancer 13 . In this study, adding the small molecule tyrosine kinase inhibitor to capecitabine led to a median TTP of 37 weeks, compared with the 20 weeks seen with capecitabine alone.

Discussion The realisation that HER2 is highly relevant to outcome in many patients with breast cancer, and the development of agents that change the natural history of HER2-positive disease has been described as having an impact analogous to the introduction of tamoxifen. Trastuzumab has extended the curative potential of adjuvant therapy, and helped shift the focus in metastatic disease from palliation to promoting long-term survival. In patients with HER2-positive metastatic disease, the case for using trastuzumab in first-line therapy is strong. It should probably be combined with a taxane, and the majority preference expressed in these meetings was for docetaxel, although many viewed vinorelbine as a similarly active and well-tolerated alternative. Whatever the details, the clear consensus was that, in advanced HER2-positive disease, use of an antiHER2 agent should begin earlier rather than later. This theme of course extends into the adjuvant setting, where use of trastuzumab has also clearly proved its worth. However, in both early and advanced disease, the benefits achieved so far, though highly significant, are only partial; and there remains a pressing need for alternative means of targeting the HER2 signaling pathway.

M. Andersson et al.

Acknowledgements The meetings were organized by the independent medical education provider prIME Oncology and made possible by an unrestricted educational grant from GlaxoSmithKline. Rob Stepney, medical writer, assisted in the preparation of the manuscript.

Conflict of interest statement Peter Barrett-Lee has received honoraria from Roche, sanofi-aventis, Novartis, AstraZeneca and GlaxoSmithKline. Michael Andersson has received honoraria from Roche, sanofi-aventis, GlaxoSmithKline, Topo-Target, Pharmexa, ScheringPlough, AstraZeneca and Lilly. Christian Jackisch has no financial or personal relationships conflicting with his position as a co-author of this manuscript. Ahmad Awada has received a honorarium from prIME Oncology for his participation, as expert, in meetings about clinical cases. Hans-Joachim L¨ uck has received honoraria from GlaxoSmithKline, AstraZeneca, Roche and Novartis. Michael Untch has received presentation honoraria from Roche, GlaxoSmithKline, Novartis and Schering-Plough. Ulrike Nitz received speaker honoraria from AstraZeneca, sanofi-aventis, Roche and Amgen. Ernst Kubista has none declared, Paul Ellis has none declared, Christian Monnerat has none declared, Pierre Hupperets has none declared.

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