Published Ahead of Print on September 28, 2009 as 10.1200/JCO.2009.23.3734 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2009.23.

3734

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Lapatinib Combined With Letrozole Versus Letrozole and Placebo As First-Line Therapy for Postmenopausal Hormone ReceptorPositive Metastatic Breast Cancer
From the Royal Marsden Hospital, London; GlaxoSmithKline, Middlesex, United Kingdom; Sammons Cancer Center, Dallas, TX; David Geffen School of Medicine; University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA; GlaxoSmithKline, Collegeville, PA; GlaxoSmithKline, Durham, NC; University of Miami Sylvester Comprehensive Cancer Center, Miami, FL; University Hospital J. Minjoz, LInstitut National de la Sante et de la Recherche Me dicale Unit 645, Besanc on; Institut Curie, Paris; Department of Medical Oncology, CRLC Val dAurelle, Montpellier, France; Cancer Research Center, Moscow; City Clinical Oncology Dispensary, St Petersburg, Russia; Instituto De Enfermedades Neoplasicas, Lima, Peru; and The All-Ireland Cooperative Oncology Research Group, Dublin, Ireland. Submitted April 16, 2009; accepted June 25, 2009; published online ahead of print at www.jco.org on September 28, 2009. Supported by GlaxoSmithKline and by National Health Service funding to the Royal Marsden National Institute for Health Research Biomedical Research Centre. Presented in part at the 31st Annual San Antonio Breast Cancer Symposium, December 10-14, 2008, San Antonio, TX. Authors disclosures of potential conicts of interest and author contributions are found at the end of this article. Clinical Trials repository link available on JCO.org. Corresponding author: Stephen Johnston, MA, PhD, FRCP, Royal Marsden National Health Service Foundation Trust & Institute of Cancer Research, Fulham Rd, Chelsea, London, SW3 6JJ, United Kingdom; e-mail: stephen .johnston@rmh.nhs.uk. 2009 by American Society of Clinical Oncology 0732-183X/09/2799-1/$20.00 DOI: 10.1200/JCO.2009.23.3734

Stephen Johnston, John Pippen Jr, Xavier Pivot, Mikhail Lichinitser, Saeed Sadeghi, Veronique Dieras, Henry Leonidas Gomez, Gilles Romieu, Alexey Manikhas, M. John Kennedy, Michael F. Press, Julie Maltzman, Allison Florance, Lisa ORourke, Cristina Oliva, Steven Stein, and Mark Pegram
A B S T R A C T

Purpose Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as rst-line treatment of hormone receptor (HR) positive metastatic breast cancer (MBC). Patients and Methods Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population. Results In HR-positive, HER2-positive patients (n 219), addition of lapatinib to letrozole signicantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] 0.71; 95% CI, 0.53 to 0.96; P .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benet (responsive or stable disease 6 months) was signicantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] 0.4; 95% CI, 0.2 to 0.8; P .003). Patients with centrally conrmed HR-positive, HER2-negative tumors (n 952) had no improvement in PFS. A preplanned Cox regression analysis identied prior antiestrogen therapy as a signicant factor in the HER2-negative population; a nonsignicant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR 0.78; 95% CI, 0.57 to 1.07; P .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable. Conclusion This trial demonstrated that a combined targeted strategy with letrozole and lapatinib signicantly enhances PFS and clinical benet rates in patients with MBC that coexpresses HR and HER2. J Clin Oncol 27. 2009 by American Society of Clinical Oncology

INTRODUCTION

Despite recent advances in the treatment of hormone receptor (HR)positive metastatic breast cancer (MBC), resistance to endocrine therapies limits their success. Cross-talk between pathways involving the epidermal growth factor family of receptors ErbB1 (epidermal growth factor receptor [EGFR]) and ErbB2 (human epidermal growth factor receptor 2 [HER2])and the estrogen receptor (ER) has been implicated in resistance to endocrine therapy.1-5 This has created a rationale for using targeted agents against EGFR pathways in combina-

tion with endocrine manipulation to overcome endocrine resistance. Overexpression of HER2 confers resistance to established endocrine therapies,2,6-8 and a randomized trial in HR-positive, HER2-positive MBC reported that trastuzumab combined with the aromatase inhibitor (AI) anastrozole doubled the median progression-free survival (PFS) compared with anastrozole alone from 2.4 to 4.8 months.9 Experimental models have shown that hormone-sensitive ER-positive breast cancer cells that initially lack EGFR or HER2 develop acquired resistance over time with enhanced expression of
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Johnston et al

receptors involved in cross-talk with ER.10-14 Two randomized trials in HR-positive MBC suggested that the EGFR tyrosine kinase inhibitor (TKI) getinib may improve PFS when added to endocrine therapy.15,16 Thus, for patients with HR-positive, HER2-positive tumors, a strategy of combined therapy might enhance endocrine effectiveness, whereas it could delay disease progression for those with HR-positive, HER2-negative tumors at risk of early relapse. Lapatinib, a potent, orally active, dual TKI against EGFR and HER2, has demonstrated activity in both trastuzumab-nave and pretreated HER2-positive MBC.17-25 Synergy between lapatinib and tamoxifen occurs in models of endocrine resistance.26,27 A phase I study conrmed that letrozole and lapatinib could be coadministered at their recommended doses without pharmacokinetic interaction.28 This phase III trial compared the combination of letrozole plus lapatinib with letrozole plus placebo as rst-line treatment of patients

with HR-positive MBC, including a population with known HER2positive tumors.

PATIENTS AND METHODS

Patients Eligible patients were postmenopausal women with histologically conrmed stage IIIB/IIIC or IV ER-positive and/or progesterone receptor (PgR) positive invasive breast cancer. No prior therapy for advanced or metastatic disease was allowed. Prior neoadjuvant/adjuvant antiestrogen therapy was allowed, as was adjuvant AI and/or trastuzumab, provided it was completed more than 1 year before study entry. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, normal organ function, and a left ventricular ejection fraction (LVEF) within the institutional range of normal. Patients with extensive symptomatic visceral disease were excluded.

Table 1. Baseline Patient Demographics and Clinical Characteristics HER2 Positive Letrozole Placebo (n 108) Demographic or Clinical Characteristic Age, years Median Range ECOG performance status 0 1 Hormone receptor status ER/PgR positive ER positive/PgR negative Disease stage IIIB or IIIC IV No. of metastatic sites Median Range Disease stage Bone only Visceral or soft tissue Liver Lung Lymph node Soft tissue Other Previous therapy Endocrine Tamoxifen or toremifene only Aromatase inhibitor only Chemotherapy Anthracycline only Anthracyclines and taxanes Other Biologic therapy (any) Interval since prior adjuvant antiestrogen therapy 6 months or no prior therapy 6 months No. of Patients 59 45-87 51 57 69 20 7 101 2 1-7 18 90 37 40 43 31 18 62 60 1 51 38 9 4 1 67 41 17 83 34 37 40 29 17 57 56 1 47 35 8 4 1 62 38 16 95 33 43 57 35 19 60 59 1 61 41 9 11 1 73 38 47 53 64 19 6 94 % Letrozole Lapatinib (n 111) No. of Patients 60 44-85 59 51 74 19 5 106 2 1-7 14 86 30 39 51 32 17 54 53 1 55 37 8 10 1 66 34 85 559 171 242 304 218 127 317 302 3 280 172 41 66 1 487 157 53 46 67 17 5 95 % Letrozole Placebo (n 644) No. of Patients 63 35-95 349 286 414 90 30 613 2 0-7 13 87 27 38 47 34 20 49 47 1 43 27 6 10 1 76 24 94 548 146 248 312 212 125 313 300 5 281 171 42 68 2 501 141 54 44 64 14 5 95 % ITT Letrozole Lapatinib (n 642) No. of Patients 62 31-94 370 268 420 91 25 616 2 0-7 15 85 23 39 49 33 19 49 47 1 44 27 7 11 1 78 22 58 42 65 14 4 96 %

Abbreviations: HER2, human epidermal growth factor receptor 2; ITT, intent to treat; ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; PgR, progesterone receptor. Indicates prespecied baseline prognostic factors used in predened stepwise Cox regression model. Additional factors included treatment, disease-free interval, and serum HER2 (extracellular domain) at baseline.

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First-Line Lapatinib Letrozole in Hormone ReceptorPositive MBC

Availability of archived tumor tissue was required for subsequent biomarker analyses. All patients provided signed informed consent, and the protocol was approved by institutional review boards. This study was funded by GlaxoSmithKline (Research Triangle Park, NC) and conducted in accordance with good clinical practice and all applicable regulatory requirements, including the 1996 version of the Declaration of Helsinki. Study Design This was a randomized, double-blind, controlled, parallel-group, multicenter, phase III study. Patients were stratied by sites of disease (soft tissue/ visceral or bone-only disease) and prior adjuvant antiestrogen therapy ( 6 months since discontinuation or 6 months since discontinuation or no prior endocrine therapy). The combination regimen consisted of lapatinib 1,500 mg orally and letrozole 2.5 mg orally daily. The control arm consisted of letrozole 2.5 mg daily with matching lapatinib placebo pill. Therapy on both arms was administered daily until disease progression or withdrawal from study. The protocol did not permit crossover of treatment at the time of progression. Women were assessed before each 4-week course of therapy, every 12 weeks starting at week 108, and at study conclusion or withdrawal. All patients were observed for survival information. Randomized therapy was permanently discontinued for unacceptable toxicity assessed according to the National Cancer Institute Common Terminology Criteria of Adverse Events (version 3.0) or for the development of grade 3 or 4 interstitial pneumonitis, hepatotoxicity, or cardiac dysfunction. Cardiac evaluations were performed at 8-week intervals before week 108 and at 12-week intervals thereafter. Recommendations for dose modications and toxicity management were provided in accordance with US Food and Drug Administrationapproved lapatinib prescribing information.29 The primary end point was investigator-assessed PFS, dened as time from random assignment until the earliest date of disease progression or death as a result of any cause in the HER2-positive population. Secondary end points included overall response rate (ORR); clinical benet rate (CBR), which was dened as complete response, partial response, or stable disease for 6 months; overall survival (OS); safety; and PFS for the intent-to-treat (ITT) HR-positive population. Disease progression and response evaluations were determined according to Response Evaluation Criteria in Solid Tumors (RECIST).30 Measurable disease was not required. The ITT population included all randomly assigned patients regardless of whether they received study medication. The HER2-positive population included all randomly assigned patients who had documented HER2 positivity in a commercial laboratory31 in primary or metastatic sites dened as either uorescence in situ hybridization positive, 3 staining intensity by immunohistochemistry, or 2 by immunohistochemistry and uorescence in situ hybridization positive. The safety population included all patients who received at least one dose of randomized therapy. Statistical Analysis Two sample size calculations were performed. A total of 1,280 HRpositive patients were required to ensure that 218 patients with HER2-positive tumors were enrolled to obtain 173 events with 80% power to detect a hazard ratio (HR) of 0.645 ( .05). Additionally, 612 events were needed in the ITT population to provide 90% power to detect an HR of 0.769. To ensure that the overall type I error rate was preserved, a closed hierarchical testing procedure was used, whereby PFS was initially tested in the HER2-positive population at an level of .05. Testing was performed in the ITT population at an level of .05 only if statistical signicance was achieved in the HER2-positive population. An Independent Data Monitoring Committee convened on an ongoing basis to monitor safety data. PFS and OS were summarized using the KaplanMeier method and compared between treatment arms using a stratied logrank test, stratifying for site of disease and prior adjuvant antiestrogen therapy. The date of documented disease progression was dened as the date of either radiologic or symptomatic disease progression. To further explore the impact of well-known prespecied baseline prognostic factors (Table 1) on PFS and OS, a predened stepwise Cox regression model was used.
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RESULTS

Patient Population Between December 9, 2003 and December 29, 2006, 1,286 patients with HR-positive MBC were randomly assigned to receive letrozole plus lapatinib (n 642) or letrozole plus placebo (n 644); of these, 17% of patients in each arm had tumors centrally conrmed in a commercial laboratory as HER2 positive (n 111 and n 108, respectively). The safety population consisted of 1,278 patients. Figure 1 outlines all treatment populations. Baseline patient and disease characteristics were well balanced between treatment arms for both the HER2-positive and ITT HRpositive populations (Table 1). Only three patients received prior adjuvant trastuzumab therapy. Clinical Efcacy After a median follow-up time of 1.8 years, median PFS for patients in the HER2-positive population increased from 3.0 months for letrozole-placebo to 8.2 months for letrozole-lapatinib, demonstrating a signicant reduction in the risk of progression for the combination (HR 0.71; 95% CI, 0.53 to 0.96; P .019; Fig 2A). In the HER2-positive population, the ORR was signicantly improved from 15% to 28% for patients treated with letrozole-lapatinib (odds ratio [OR] 0.4; 95% CI, 0.2 to 0.9; P .021). Including patients with stable disease for 6 months, the CBR was likewise signicantly improved (29% to 48%; OR 0.4; 95% CI, 0.2 to 0.8; P .003; Fig 2B). With less than 50% of OS events yet recorded, the median OS in the HER2-positive population was 32.3 months in the letrozoleplacebo arm compared with 33.3 months in the combination arm (HR 0.74; 95% CI, 0.5 to 1.1; P .113; Fig 2C). The signicant result for PFS in the HER2-positive population allowed for analysis of the ITT HR-positive population by hierarchical testing. After a median follow-up of 2 years, median PFS increased from 10.8 months with letrozole-placebo to 11.9 months with the combination (HR 0.86; 95% CI, 0.76 to 0.98; P .026; Fig 3A), and there was no statistical difference in ORR or CBR between treatment arms (Fig 3B). In the 952 patients with centrally conrmed HER2negative tumors, there was no improvement in PFS (HR 0.90; 95% CI, 0.77 to 1.05; P .188). The stepwise Cox regression analysis for PFS adjusting for known baseline prognostic factors conrmed the benet of combination therapy in the HER2-positive population (HR 0.65; 95% CI, 0.47 to 0.89; P .008). After retaining treatment and stratication factors, age (younger), performance status (0), and baseline serum soluble HER2 extracellular domain (measured by quantitative enzyme-linked immunosorbent assay) were identied as being signicant. In the HER2negative population, there was also an impact of combination therapy on PFS, and in addition to the signicant baseline factors mentioned earlier, the number of metastatic sites ( three sites) and prior adjuvant antiestrogen stratication were identied as being signicant in the HER2-negative population. In view of this nding and the relevance of prior tamoxifen exposure in the HER2-negative population on endocrine resistance, an exploratory analysis of predened prior antiestrogen therapy stratication was performed. In the 6 months since discontinuation/ none group (n 752), 33% of patients had received prior adjuvant
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Johnston et al

Patients randomly assigned as of 29-Dec-2006 (ITT Population)* (N = 1,286)

Patients with HER2-positive MBC (HER2-Positive Population) (n = 219) Did not receive therapy (n = 0) 0 erroneously received monotherapy Randomly assigned to therapy (n = 219) 2 erroneously received combination Did not receive therapy (n = 0)

Patients with HER2-negative MBC (HER2-Negative Population) (n = 952) Randomly assigned to therapy (n = 952) 11 erroneously received combination Did not receive therapy (n = 8)

Patients with HER2-Missing MBC (HER2-Missing Population) (n = 115) Randomly assigned to therapy (n = 115) 1 erroneously received combination

7 erroneously received monotherapy

2 erroneously received monotherapy

Randomly assigned to combination therapy with lapatinib 1,500 mg + letrozole 2.5 mg po daily (n = 111)

Randomly assigned to monotherapy with letrozole 2.5 mg po daily (n = 108)

Randomly assigned to combination therapy with lapatinib 1,500 mg + letrozole 2.5 mg po daily (n = 478)

Randomly assigned to monotherapy with letrozole 2.5 mg po daily (n = 474)

Randomly assigned to combination therapy with lapatinib 1,500 mg + letrozole 2.5 mg po daily (n = 53)

Randomly assigned to monotherapy with letrozole 2.5 mg po daily (n = 62)

Censored (8 on combo; n = 23)

Data lock for protocoldefined analysis as of 03-Jun-08 based on 177 investigator-reported PFS events||

Censored (10 on mono; n = 19)

Censored (89 on combo; n = 184)

Investigator-reported PFS events as of 03-Jun-08 (n = 636)

Censored (81 on mono; n = 132)

Censored (6 on combo; n = 22)

Investigator-reported PFS events in HER2-missing as of 03-Jun-08 (n = 76)

Censored (4 on mono; n = 17)

PFS events in the combination therapy (n = 88)

PFS events in the monotherapy (n = 89)

PFS events in the combination therapy (n = 294)

PFS events in the monotherapy (n = 342)

PFS events in the combination therapy (n = 31)

PFS events in the monotherapy (n = 45)

PD by radiological scans/ photos (n = 76)

PD by clinical PD (n = 9)

Died prior to PD (n = 3)

PD by radiological scans/ photos (n = 72)

PD by clinical PD (n = 15)

Died prior to PD (n = 2)

PD by radiological scans/ photos (n = 250)

PD by clinical PD (n = 37)

Died prior to PD (n = 7)

PD by radiological scans/ photos (n = 291)

PD by clinical PD (n = 37)

Died prior to PD (n = 14)

PD by radiological scans/ photos (n = 27)

PD by clinical PD (n = 3)

Died prior to PD (n = 1)

PD by radiological scans/ photos (n = 35)

PD by clinical PD (n = 8)

Died prior to PD (n = 2)

Fig 1. Study design, populations, random assignment, and assessment of events. (*) In the intent-to-treat (ITT) population, 1,088 patients discontinued treatment 64% for progression, 5% for consent withdrawal, 10% for an adverse event, 1% for a protocol violation, 1% for death, 1% lost to follow-up, and 3% for other reasons (including but not limited to radiation, surgery, scans misread/misinterpreted, and investigator discretion). () In the human epidermal growth factor receptor 2 (HER2) positive population, 201 patients discontinued treatment76% for progression, 6% for consent withdrawal, 5% for an adverse event, 1% for a protocol violation, 1% for death, and 3% for other reasons. () In the HER2-negative population, 782 patients discontinued treatment11% as a result of an adverse event, 4% as a result of consent withdrawn, 1% as a result of loss to follow-up, 1% as a result of protocol violation, 62% as a result of progression, 1% as a result of death, and 3% as a result of other reasons. () In the population with HER2 status unknown, 105 patients discontinued treatment 64% for progressive disease, 10% for consent withdrawal, 10% for an adverse event, 1% for protocol violation, 1% lost to follow-up, 1% for death, and 5% for other reasons. () The protocol-dened primary and secondary study analyses were to commence once approximately 173 events (disease progression or deaths on study) had occurred in the HER2-positive population. MBC, metastatic breast cancer; po, orally; combo, combination therapy; mono, monotherapy; PFS, progression-free survival; PD, progressive disease.

tamoxifen (median duration, 5.0 years); median time since discontinuation was 3.5 years. The remaining 67% of patients had no prior exposure to hormone therapy. The HR for PFS in this group was 0.94 (95% CI, 0.79 to 1.13; P .522; Fig 4A). The overall CBR was similar between the letrozole-lapatinib and letrozole-placebo arms (62% v 64%, respectively) within the 6 months since discontinuation/none group, regardless of PgR status (Fig 4B). In the less than 6 months since discontinuation group (n 200), the median duration of prior adjuvant tamoxifen was 2.8 years; median time since discontinuation was only 1 month. By contrast, the HR in this group was 0.78 (95% CI, 0.57 to 1.07; P .117; Fig 5A), with an increase in median PFS from 3.1 to 8.3 months favoring the combination. A numerically higher CBR was found in the letrozole-lapatinib arm versus letrozole-placebo arm (44% v 32%, respectively; OR 0.6; 95% CI, 0.3 to 1.1; P .112; Fig 5B), and analysis based on PgR (positive or negative) status showed a
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consistent numerical difference in favor of the combination arm, especially for those with PgR-negative tumors, with ve (36%) of 14 patients having clinical benet in the letrozole-lapatinib arm versus two (15%) of 13 patients treated with letrozole alone (Fig 5B). However, by logistic regression analysis, no interaction between treatment group and PgR status was seen. Safety Patients received treatment for a median of 40 weeks in the letrozole-lapatinib arm and 38 weeks in the letrozole-placebo arm, with compliance (pill count agreement of 80%) of more than 95% in both arms. The most common adverse events were diarrhea, rash, nausea, arthralgia, and fatigue (majority were grade 1 or 2), with a higher incidence in the combination arm for diarrhea and rash (Table 2). Of the 60 patients (10%) who had grade 3 or 4 diarrhea in the
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First-Line Lapatinib Letrozole in Hormone ReceptorPositive MBC

A
Alive Without Progression (%)

100 80 60 40 20

A
Alive Without Progression (%)
Letrozole 2.5 mg + lapatinib 1,500 mg (88 events; median PFS, 8.2 mo) Letrozole 2.5 mg + placebo (89 events; median PFS, 3.0 mo) P = .019

100 80 60 40 20

Letrozole 2.5 mg + lapatinib 1,500 mg (413 events; median PFS, 11.9 mo) Letrozole 2.5 mg + placebo (476 events; median PFS, 10.8 mo) P = .026

10

15

20

25

30

35

40

45

50

10

15

20

25

30

35

40

45

50

Time Since Random Assignment (months)

Patients at risk Letrozole + 111 lapatinib Letrozole 108
69 43 33 26 20 18 12 12 8 7 4 5 1 2 1 2

Time Since Random Assignment (months)

Patients at risk Letrozole + 642 lapatinib Letrozole 644
438 403 294 291 208 212 120 140 78 80 51 53 26 23 11 13 2 7

B
Patients (%)

70 60 50 40 30 20

Letrozole 2.5 mg + placebo Letrozole 2.5 mg + lapatinib 1,500 mg P = .003 48% P = .021 28% 23% 11% 14% 20% 15% 29%

B
Patients (%)

70 60 50 40 30 20 10

Letrozole 2.5 mg + placebo Letrozole 2.5 mg + lapatinib 1,500 mg

P = .761 58% 56%

P = .726 27% 28% 32% 33% 25% 26%

10

4% 5%

4% 5%

CR

PR

SD 6 mo

ORR

CBR

CR

PR

SD 6 mo

ORR

CBR

C
Surviving (%)

100 80 60 40 20

Letrozole 2.5 mg + lapatinib 1,500 mg Letrozole 2.5 mg + placebo

Fig 3. Clinical efcacy in intent-to-treat population. Kaplan-Meier estimates of (A) progression-free survival (PFS) and (B) response rates and clinical benet rates (CBR). CR, complete response; PR, partial response; SD, stable disease; ORR, overall response rate.

10

15

20

25

30

35

40

45

50

Time Since Random Assignment (months)

Patients at risk Letrozole + 111 lapatinib 108 Letrozole
104 93 89 76 80 69 64 59 48 38 32 31 19 15 9 8 4 2

Fig 2. Clinical efcacy in human epidermal growth factor receptor 2positive population. (A) Kaplan-Meier estimates of progression-free survival (PFS), (B) response rates and clinical benet rates (CBR), and (C) Kaplan-Meier estimates of overall survival. CR, complete response; PR, partial response; SD, stable disease; ORR, overall response rate.

normal) compared with eight patients on the combination arm. Two of the eight women on the combination arm and the patient in the letrozole-placebo arm required drug discontinuation, with resolution of liver function tests thereafter; the other six patients resolved laboratory abnormalities without drug discontinuation. Any serious adverse event related to study drug occurred in 8% of patients receiving the combination compared with 4% of patients receiving letrozoleplacebo. There were a total of 16 fatalities related to serious adverse events (eight deaths in each arm), of which only three were deemed related to study drug (one in letrozole-lapatinib arm [hepatobiliary] and two in letrozole-placebo arm [one cardiac, one dyspnea]). No new or unexpected safety signals for either drug were identied.

DISCUSSION

combination arm, 15% required discontinuation. For the remainder, diarrhea was managed by dose reduction (19%), dose interruption (36%), or supportive intervention without treatment dose adjustments (31%). Treatment-related LVEF decline and elevation of liver function transaminases were infrequent. Seven patients had a symptomatic LVEF declinetwo patients (0.3%) on letrozole-placebo and ve patients (0.8%) on lapatinib-letrozole). One patient on the letrozole-placebo arm was thought to have had drug-induced liver injury (ALT/AST 3 upper limit of normal, total bilirubin 1.5 upper limit of normal, and alkaline phosphatase 2 upper limit of
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Coexpression of HER2 in HR-positive breast cancer confers relative endocrine resistance, and preclinical models have used targeted strategies to enhance efcacy of either tamoxifen or estrogen deprivation.13,14,32-34 The Trastuzumab in Dual HER2 ER-Positive Metastatic Breast Cancer (TAnDEM) trial evaluated anastrozole with or without the addition of trastuzumab in HR-positive, HER2positive MBC (n 208)9 and showed that the combined approach had a signicant benet for PFS. Our study demonstrated that in a similar HR-positive, HER2-positive population (n 219), the combination of letrozole and lapatinib signicantly prolonged PFS
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Johnston et al

A
Alive Without Progression (%)

100 80 60 40 20

Alive Without Progression (%)

Letrozole 2.5 mg + lapatinib 1,500 mg (median PFS, 14.7 mo) Letrozole 2.5 mg + placebo (median PFS, 15.0 mo) P = .522

100 80 60 40 20

Letrozole 2.5 mg + lapatinib 1,500 mg (median PFS, 8.3 mo) Letrozole 2.5 mg + placebo (median PFS, 3.1 mo) P = .117

10

15

20

25

30

35

40

45

50

10

15

20

25

30

35

40

45

50

Time Since Random Assignment (months)

Patients at risk 382 Letrozole + lapatinib Letrozole 370
282 283 202 214 147 158 87 106 55 62 37 41 20 16 7 9 1 6

Time Since Random Assignment (months)

Patients at risk Letrozole + 96 lapatinib Letrozole 104
53 43 36 31 25 21 15 14 10 9 8 5 3 4 1

B
80 70

Letrozole 2.5 mg + placebo Letrozole 2.5 mg + lapatinib 1,500 mg 235 370 64% 62% 178 263 68%

B
80
Letrozole 2.5 mg + placebo Letrozole 2.5 mg + lapatinib 1,500 mg 31 53 58% 34 58 59%

Patients (%)

63%

Patients (%)

60 50 40 30 20 10

236 382

169 269

70 60 50 40 30 20 10
33 104 32% 2 13 15% 42 96 44% 34 72 47% 5 14 36%

29 78 37%

Overall CBR

PgR+

PgR-

Overall CBR

PgR+

PgR-

Fig 4. Clinical efcacy in the human epidermal growth factor receptor 2negative population predened subgroup with an interval of 6 months since discontinuation of prior adjuvant tamoxifen or no prior adjuvant tamoxifen. (A) Kaplan-Meier estimates of progression-free survival (PFS) and (B) response and clinical benet rates (CBR). Progesterone receptor (PgR) status was measured only in known estrogen receptorpositive patients.

Fig 5. Clinical efcacy in the human epidermal growth factor receptor 2negative population predened subgroup with an interval of less than 6 months since discontinuation of prior adjuvant tamoxifen. (A) Kaplan-Meier estimates of progression-free survival (PFS) and (B) response and clinical benet rates (CBR). Progesterone receptor (PgR) status was measured only in known estrogen receptorpositive patients.

compared with letrozole alone (median PFS, 8.2 v 3.0 months respectively), representing a statistically signicant 29% reduction in the risk of disease progression. Consistent with these ndings, a superior CBR (48% with letrozole-lapatinib v 29% with letrozole alone) and trend toward improvement in OS were also seen. This trial demonstrated that for HR-positive, HER2-positive patients with MBC, the combination of letrozole and lapatinib is superior to an AI plus placebo. Importantly, the population of women with HER2-positive MBC treated in the studies discussed earlier differ signicantly from patients enrolled onto two randomized trials of rst-line taxane-based chemotherapy with or without trastuzumab that showed a survival advantage with the addition of targeted therapy.35,36 In the endocrine studies, all patients with HER2-positive MBC had HR-positive disease compared with only 40% to 60% of patients in the chemotherapy studies; also, patients in the endocrine studies were older (median age, 60 v 53 to 55 years, respectively) and had a lower incidence of visceral metastases. Although each of the four trials conrmed a benet with the addition of a targeted therapy over endocrine or chemotherapy alone, these differences in populations preclude direct comparisons. Our study supports letrozole-lapatinib as a possible therapeutic approach to control HR-positive, HER2-positive MBC in appropriate
6
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patients for a signicant period of time before chemotherapy and trastuzumab are required. In HR-positive breast carcinomas that are initially HER2 negative, EGFR and HER2 pathways may become upregulated on development of endocrine resistance, and a combined growth factor receptor and endocrine-targeted approach could delay acquired resistance.37,38 Clinically, for patients who relapse during adjuvant therapy with tamoxifen-resistant MBC where growth factor receptors may have become upregulated, dual targeted therapy could enhance the objective response rate compared with AIs alone. Alternatively, in hormone-sensitive MBC without prior tamoxifen exposure, combined therapy could delay the emergence of acquired resistance over time by preventing upregulation of growth factor receptors. Osborne et al15 demonstrated a trend toward improved PFS for the addition of the EGFR TKI getinib to tamoxifen versus tamoxifen alone in patients who were either endocrine nave or more than 12 months since completion of prior adjuvant endocrine therapy (median PFS, 10.9 v 8.8 months, respectively; HR 0.84; 95% CI, 0.59 to 1.18; P .31); in a small subset of patients with known HER2-positive tumors (n 37), an improvement in PFS was also seen (median PFS, 6.7 v 5.8 months, respectively; HR 0.54; 95% CI, 0.25 to 1.15; P .11). In 93 HRpositive MBC patients, Cristofanilli et al16 reported prolongation of
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First-Line Lapatinib Letrozole in Hormone ReceptorPositive MBC

Table 2. Adverse Events Letrozole Placebo (n 624) Grade 1 Adverse Event Diarrhea Rash Nausea Arthralgia Fatigue Back pain Vomiting Headache Cough Hot ush Asthenia Pain in extremity Dyspnea Pruritus Alopecia Constipation Anorexia Dry skin Epistaxis Nail disorder

Letrozole Lapatinib (n 654) Grade 4 No. 0 0 0 0 0 1 1 0 0 0 0 0 2 0 0 0 0 0 0 0 % 0 0 0 0 0 1 1 0 0 0 0 0 1 0 0 0 0 0 0 0 Grade 1 No. 210 186 141 81 77 50 63 63 59 54 55 39 31 54 82 54 51 71 63 60 % 32 28 22 12 12 8 10 10 9 8 8 6 5 8 13 8 8 11 10 9 Grade 2 No. 147 100 53 39 47 42 38 26 19 12 20 25 27 23 2 6 16 15 6 11 % 22 15 8 6 7 6 6 4 3 2 3 4 4 4 1 1 2 2 1 2 Grade 3 No. 58 7 6 7 10 12 7 2 2 3 5 2 5 2 1 0 5 1 1 1 % 9 1 1 1 2 2 1 1 1 1 1 1 1 1 1 0 1 1 1 1 Grade 4 No. 2 0 0 0 0 0 1 0 0 0 0 0 1 0 0 0 0 0 0 0 % 1 0 0 0 0 0 1 0 0 0 0 0 1 0 0 0 0 0 0 0

Grade 2 No. 27 15 40 37 42 42 21 28 15 27 19 24 27 11 1 17 18 2 3 1 % 4 2 6 6 7 7 3 4 2 4 3 4 4 2 1 3 3 1 1 1

Grade 3 No. 6 0 4 8 3 13 4 3 2 0 5 5 7 1 0 2 2 0 1 0 % 1 0 1 1 1 2 1 1 1 0 1 1 1 1 0 1 1 0 1 0

No. 91 68 85 100 63 41 42 52 73 65 45 42 36 43 44 48 34 25 7 5

% 15 11 14 16 10 7 7 8 12 10 7 7 6 7 7 8 5 4 1 1

A statistically signicant (P .05) effect was observed between treatment groups for the total incidence of these adverse events.

PFS with the addition of getinib to anastrozole compared with anastrozole alone (median PFS, 14.6 v 8.2 months, respectively; HR 0.55; 95% CI, 0.32 to 0.94). In both trials, no information was provided on the number of patients who were totally endocrine nave or had received prior tamoxifen, which could be an important predictor for benet from combined therapy in delaying time to progression of disease. In this study, 952 patients with HR-positive MBC were conrmed centrally as having original HER2-negative primary breast cancer. In addition, the protocol predened a stratication based on prior adjuvant antiestrogen exposure. In the 752 patients with 6 months since discontinuation of antiestrogen therapy or no prior antiestrogen therapy, two thirds had no prior endocrine therapy, and one third had taken tamoxifen for a median of 5 years, with at least 3 years since discontinuation. Essentially, this represents a hormonesensitive population. The efcacy data show that in the endocrinesensitive population, there was no signicant improvement in PFS or CBR for the combination (Fig 4). In contrast, the 200 patients who experienced relapse less than 6 months since discontinuation had all received tamoxifen for a median of 2.9 years and entered the study with a median of less than 1 month since discontinuation. These patients would be considered clinically relatively tamoxifen resistant, and in this group, a statistically nonsignicant trend toward improvement in both PFS and CBR was seen (Fig 5). These data in the HER2-negative population suggest that there is no benet for the addition of an EGFR/HER2-targeted therapy to an AI in an HRpositive, HER2-negative, endocrine-sensitive or -nave MBC population but suggest there could be possible benet for patients who experience relapse early during adjuvant tamoxifen therapy (consistent with preclinical models where growth factor activity is enhanced in association with endocrine resistance).10,34,37,38 Lack of PgR expreswww.jco.org

sion has been suggested as a surrogate for enhanced growth factor receptor activity in ER-positive breast cancer,39,40 and although a trend in favor of clinical benet from the combination was observed in tamoxifen-resistant patients with PgR-negative tumors, the numbers in this subset are too small to draw denitive conclusions, and overall, no substantial benet in favor of PgR-negative tumors was seen in this trial. Primary tumors have been collected from more than 80% of patients enrolled onto the trial; further biomarker studies in tamoxifen-treated patients are clearly warranted to identify a tumor phenotype that may predict relapse and subsequent benet from combined letrozole and lapatinib. The inability of lapatinib to delay progression with letrozole in the endocrine-sensitive, HR-positive, HER2-negative population is in contrast to the preclinical37,38 and clinical15,16 data reported with the EGFR TKI getinib. One potential explanation is that tamoxifen may induce different endocrine resistance pathways to aromatase inhibition. Specically, tamoxifen has been demonstrated in preclinical models to enhance upregulation of EGFR and HER2.11,38 Consequently, getinib may synergize well with tamoxifen in endocrine-sensitive disease to delay EGFR/HER2 activation. In contrast, aromatase inhibition may induce different resistance pathways to tamoxifen and, when combined with an EGFR/HER2 inhibitor in endocrine-sensitive disease, may fail to provide added benet. The initial benet seen with getinib plus anastrozole in a small phase II study16 was not observed in a second randomized phase II trial with the combination.41 Our study showed that lapatinib plus letrozole failed to delay endocrine resistance in more than 750 patients with endocrine-sensitive, EGFR/HER2-negative disease. Indeed, this lack of benet in hormone-sensitive breast cancer was demonstrated preclinically by the failure of trastuzumab and letrozole when combined
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Johnston et al

from the outset to delay endocrine resistance in HR-positive xenografts, albeit that combined therapy was effective at the time resistance to letrozole had developed.42 In summary, this trial conrmed that for patients with known HR-positive, HER2-positive MBC, a combined targeted therapy approach is superior to endocrine therapy alone. The letrozole-lapatinib combination was well tolerated and produced a clinically meaningful improvement in several efcacy end points. As such, combination therapy with lapatinib and letrozole could be considered an effective treatment option for patients with known HR-positive, HER2positive MBC.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a nancial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a U are those for which no compensation was received; those relationships marked with a C were compensated. For a detailed description of the disclosure categories, or for more information about ASCOs conict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conicts of Interest section in Information for Contributors. Employment or Leadership Position: Julie Maltzman, GlaxoSmithKline (C); Allison Florance, GlaxoSmithKline (C); Lisa ORourke, GlaxoSmithKline (C); Cristina Oliva, GlaxoSmithKline (C); Steven Stein, GlaxoSmithKline (C) Consultant or Advisory Role: Xavier Pivot, Roche (C), GlaxoSmithKline (C), Novartis (C); Veronique Dieras, GlaxoSmithKline Breast Advisory Board (C), Novartis Advisory Board (C); Alexey Manikhas, GlaxoSmithKline (C); M. John Kennedy, GlaxoSmithKline (C); Michael F. Press, GlaxoSmithKline (C), Genentech (C); Mark Pegram, GlaxoSmithKline (C) Stock Ownership:

Julie Maltzman, GlaxoSmithKline; Allison Florance, GlaxoSmithKline; Lisa ORourke, GlaxoSmithKline; Steven Stein, GlaxoSmithKline Honoraria: Stephen Johnston, GlaxoSmithKline; John Pippen Jr, AstraZeneca, Genentech, GlaxoSmithKline; Xavier Pivot, Roche, Cephalon; Saeed Sadeghi, GlaxoSmithKline; Veronique Dieras, Lecture Symposium; Henry Leonidas Gomez, GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca; Michael F. Press, GlaxoSmithKline, Genentech; Mark Pegram, GlaxoSmithKline Research Funding: Stephen Johnston, GlaxoSmithKline; Xavier Pivot, Roche, Amgen; Alexey Manikhas, GlaxoSmithKline; M. John Kennedy, GlaxoSmithKline; Michael F. Press, GlaxoSmithKline, Genentech Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS
Conception and design: Stephen Johnston, Julie Maltzman, Lisa ORourke, Cristina Oliva, Steven Stein, Mark Pegram Administrative support: Julie Maltzman, Lisa ORourke Provision of study materials or patients: Stephen Johnston, John Pippen Jr, Xavier Pivot, Mikhail Lichinitser, Saeed Sadeghi, Veronique Dieras, Henry Leonidas Gomez, Gilles Romieu, Alexey Manikhas, M. John Kennedy, Julie Maltzman, Lisa ORourke, Mark Pegram Collection and assembly of data: Saeed Sadeghi, Michael F. Press, Julie Maltzman, Allison Florance, Lisa ORourke, Steven Stein Data analysis and interpretation: Stephen Johnston, Xavier Pivot, Veronique Dieras, Michael F. Press, Julie Maltzman, Allison Florance, Lisa ORourke, Cristina Oliva, Steven Stein, Mark Pegram Manuscript writing: Stephen Johnston, Xavier Pivot, Michael F. Press, Julie Maltzman, Allison Florance, Lisa ORourke, Cristina Oliva, Steven Stein, Mark Pegram Final approval of manuscript: Stephen Johnston, John Pippen Jr, Xavier Pivot, Saeed Sadeghi, Veronique Dieras, Gilles Romieu, M. John Kennedy, Michael F. Press, Julie Maltzman, Lisa ORourke, Cristina Oliva, Steven Stein, Mark Pegram
of estrogen receptor-positive, HER-2/neu-positive breast cancer. Cancer Res 66:8266-8273, 2006 15. Osborne K, Neven P, Dirix L, et al: Randomized phase II study of getinib (IRESSA) or placebo in combination with tamoxifen in patients with hormone receptor positive metastatic breast cancer. Breast Cancer Res Treat 106:S107, 2007 (suppl 1) 16. Cristofanilli M, Valero V, Mangalik A, et al: A phase II multicenter, double-blind, randomized trial to compare anastrozole plus getinib with anastrozole plus placebo in postmenopausal women with hormone receptor-positive (HR) metastatic breast cancer (MBC). J Clin Oncol 26:44s, 2008 (suppl; abstr 1012) 17. Blackwell KL, Kaplan EH, Franco SX, et al: A phase II, open-label, multicenter study of GW572016 in patients with trastuzumab-refractory metastatic breast cancer. Ann Oncol 20:1026-1031, 2009 18. Burstein HJ, Storniolo AM, Franco S, et al: A phase II study of lapatinib monotherapy in chemotherapy refractory HER2-positive and HER2negative advanced or metastatic breast cancer. Ann Oncol 19:1068-1074, 2008 19. Gomez HL, Doval DC, Chavez MA, et al: Efcacy and safety of lapatinib as rst-line therapy for ErbB2-amplied locally advanced or metastatic breast cancer. J Clin Oncol 26:2999-3005, 2008 20. Iwata H, Toi M, Fujiwara Y, et al: Phase II clinical study of lapatinib (GW572016) in patients with advanced or metastatic breast cancer. Breast Cancer Res Treat 100:S68, 2006 (suppl; abstr 1091)
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Acknowledgment We would like to acknowledge the women who participated in this study as well as the investigators and their staff; the members of the Independent Data Monitoring Committee; Tim Kelly from GlaxoSmithKline; Novartis Oncology; and The Phillips Group for technical assistance in preparation of the article. Appendix

The following investigators and institutions also participated in the study: S. Abadie-Lacourtoisie, Center Paul Papin, Angers, France; W. Abenhardt, Gemeinschaftspraxis Hematologie and Internistische Onkologie, Munchen, Germany; E. Alba, Hospital C.U. Virgen de la Victoria, Malaga, Spain; J. Ales, Hospital Ruber Internacional Medical Oncology Department C/La Maso , Madrid, Spain; H.J. Allen, Comprehensive Cancer Centers of Nevada, Las Vegas, NV; I. Alvarez Lopez, Hospital de Donostia, San Sebastia n, Spain; D.M. Anderson, St. Francis Regional Medical Center, Shakopee, MN; M. Andersson, Rigshospitalet Onkologisk, Koebenhavn Oe, Copenhagen, Denmark; A. Anton, Hospital Miguel Servet Paseo Isabel La Catolica, Zaragoza, Spain; A. Ardizzoni, Unita Operativa di Oncologia Medica, Parma, Italy; R. Asbury, Interlakes Oncology & Hematology, Rochester, NY; L. Assersohn, St Georges Hospital, London, United Kingdom; Z. Aziz, Jinnah Hospital, Faisal Town, Lahore, Pakistan; G. Baake, Fahltakamp, Pinneberg, Germany; M. Baki, Fovarosi Onkormanyzat Szent Margit Korhaz, Budapest, Hungary; G. Beadle, Royal Brisbane & Womens Hospital, Brisbane, Australia; J.V. Beattie, Missouri Cancer Care, St. Charles, MO; S. Ben Ahmed, Hopital Ferhat Hached, Taouk, Tunisia; J. Bines, Instituto Nacional do Cancer, Rio de Janciro, Brazil; R. Blachly, Northeast Arkansas Clinic, Jonesboro, AR; M. Blees, Leuzenbacher, Altenkirchen, Germany; J. Blondal, St. Josephs Health Centre, Ontario, Canada; E. Bobbio Pallavicini, Ospedale Maggiore Di Crema, Crema, Italy; V. Borisov, City Oncology Clinical Center, Moscow, Russia; L.D. Bosserman, The Robert & Beverly Lewis Family Cancer Care Center, Pomona, CA; H. Boussen, Institute Saleh Azaiez, Tunis, Tunisia; H. Boussen, Polyclinique Taouk, Tunis, Tunisia; M. Bozac, Djelatnost za Interne Bolesti, Opca Bolnica Pula, Croatia; T.W. Brotherton, Danville Hematology & Oncology, Inc, J, Danville, VA; O. Brudler, HamatologischOnkologische Praxis Augsburg, Augsburg, Germany; G. Calderillo-Ruiz, Hospital Medica Sur, Mexico; O. Camara, Universitaetsklinikum Jena Klinik fur Fraueheikunde and Geburtshilfe, Jena, Germany; B. Cantos, Clinica Puerta de Hierro, C/San Martin de Porres 4 Farmacologia Clinica, Madrid, Spain; J. Ca rdenas-Sa nchez, Centro Estatal de Cancerologia de Colima, Colima, Mexico; C. Carmen, Hospital Ramon y Cajal, Madrid, Spain; R.R. Carroll, Robert R. Carroll MD PA, Gainesville, FL; J. Castellanos, Hospital General IsIas Cics, Vigo, Spain; D. Chan, Cancer Care Associate Medical Group, Inc, Redondo Beach, CA; J. Chang, DRCC Lakeridge Health, Oshawa Canada; H.C. Chung, Yonsei University College of Medicine, Seoul, Korea; E. Ciruelos, Hospital Doce de Octubre, Madrid, Spain; V.
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Johnston et al

Cohen, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Canada; S. Cold, Odense University Hospital, Odense, Denmark; R.E. Coleman, Shefeld Teaching Hospital National Health Service (NHS) Trust, Shefeld, United Kingdom; F.A. Collichio, University of North Carolina Hospital, Chapel Hill, NC; H.J. Cordes, Stresemannallee 3, Frankfurt, Germany; G.J. Creemers, Catharina Ziekenhuis, the Netherlands; J. Crown, St. Vincents Hospital, Dublin, Ireland; N. Davidson, Broomeld Hospital, Chelmsford, Essex, United Kingdom; S.J. Davidson, The Thomas and Dorothy Leavey Cancer Center, Northridge, CA; A. Davis, The Canberra Hospital, Garran-Australian Capital Territory, Canberra, Australia; P.C. De Jong, St. Antonius Ziekenhuis, Nieuwegein, the Netherlands; J. De La Cruz-Vargas, Torre Medica Cristobal Colon Segunda, Guerrero, Mexico; A. Decensi, S.C. Oncologia Medica e Preventiva, Genova, Italy; S. Delaloge, Institut Gustave Roussy, Villejuif, France; S. Diab, Rocky Mountain Cancer Center, Denver, CO; R.A. Dichmann, Central Coast Medical Oncology Corporation, Santa Maria, CA; V. Die ras, Institut Curie, Paris, France; L. Dreosti, Pretoria Academic Hospital, Pretoria, South Africa; J. Dufresne, Centre Hospitalier Universitaire de Sherbrooke Hopital, Fleurimont, Canada; W. Eiermann, Fraunklinik vom Roten Kreuz, Munchen, Germany; A. Elias, University of Colorado Health Science Center, Aurora, CO; F.L.G. Erdkamp, Maasland Ziekenhuis Sittard, Sittard, the Netherlands; L. Fehrenbacher, Kaiser Permanente Medical Center, Vallejo, CA; E. Filipczyk-Cisarz, Dolnoslakie Centrum Onkologii, Wroclow, Poland; R.E. Fisher, Longmont Clinic, Longmont, CO; P. Flynn, Metro-Minnesota Community Clinical Oncology Program (CCOP), St Louis Park, MN; A. Former Pi-Majlis, Providencia, Santiago, Chile; H. Forstbauer, Schlossstr. 18, Troisdorf, Germany; S.X. Francko, Memorial Cancer Institute/Breast Cancer Center, Hollywood, FL; M. Frikha, Ho pital Habib Bourguiba, Sfax, Tunisia; S. Fuxius, Kurfuerstenanlage 34, Heidelberg, Germany; J. Gapski, Trillium Health Centre, Ontario, Canada; C.E. Geyer, Allegheny General Hospital, Pittsburgh, PA; D.D. Gibbs, Christchurch Hospital, Christchurch, New Zealand; G. Gill, Royal Adelaide Hospital, Adelaide, Australia; M. Glados, Suedring 15, Coesfeld, Germany; S. Gluck, University of Miami Hospital and Clinics, Miami, FL; L. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; H.M. Gomez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; V. Gorbunova, Russian Oncological Research Center after N.N. Biokhin RAMS, Russia, Moscow; G. Grana, The Cancer Institute of New Jersey at Cooper, Voorhees, NJ; D. Grenier, Cancer Care Manitoba, Manitoba, Canada; L. Grogan, Beaumont Hospital, Dublin, Ireland; R. Gupta, Mid West Regional Hospital, Limerick, Ireland; M. Gupta, Dokota Clinic LTD, Fargo, ND; J. Gurtler, Metairie, LA; M.K. Hagan, Virginia Cancer Institute, Richmond, VA; H.A. Hahm, Northwest Georgia Oncology Centers, P.C., Marietta, GA; B. Haley, University of Texas Southwestern Medical Center, Dallas, TX; M. Hansen, Hilleroed Sygehus Medicinsk Dagafsnit, Denmark; W.G. Harker, Utah Cancer Specialists, Salt Lake City, UT; E. Hoering, Gemeinschaftspraxis Gastroenterologie/Hematology, Stuttgart, Germany; G. Hu, KelseySeyboid Clinic, Houston, TX; E.H. Hu, Central Hematology Oncology Medical Group, Inc, Alhambra, CA; P.S.G.J. Hupperets, AZM, Maastricht, the Netherlands; S. Hurvitz, University of California, Los Angeles, Los Angeles, CA; N. Iannotti, Hematology/Oncology Associates of the Treasure Coast, Port St Lucie, FL; Y.H. Im, Samsung Medical Centre, Seoul, Korea; F.J.F. Jeurissen, MC Haaglanden, Den Haag, the Netherlands; J.K. Joffe, Calderdale and Hudderseld NHS Trust, Hudderseld, United Kingdom; S.RD. Johnston, Royal Marsden Hospital, London, United Kingdom; A Jones, Royal Free Hospital, London, United Kingdom; K.M. Josten, Aukammallee 33, Wiesbaden, Germany; K. Kammerer, Pest Megyei Flor Ferenc Korhaz Onkologia Osztaly, Semmelweis, Hungary; F.C. Kass, Santa Barbara Hematology Oncology Medical Group, Inc, Santa Barbara, CA; M. Keane, University College Hospital, Galway, Ireland; J. Kennedy, St. James Hospital, Dublin, Ireland; P. Kennedy, Metropolitan Hematology/Oncology Medical Group, Los Angeles, CA; A. Kleine-Tebbe, Charite-Campus Virchow Klinikum-Gynaekologie, Berlin, Germany; H. Kluger, Yale University School of Medicine, New Haven, CT; A. Korfel, Medizinische Klinik III, Berlin, Germany; R. Kreienberg, Universitatesklinikum Ulm, Ulm, Germany; E.D. Kreuser, Krankenhaus der Barmherzige Brueder, Ragensburg, Germany; S. Kurbel, Klinika za Onkologiju, KB Osijek, Croatia; R.M. Langdon, Nebraska Methodist Hospital, Omaha, NE; G.L. Lerzo, Hospital de Oncologia Maria Cure, Buenos Aires, Argentina; M. Lichinitser, Russian Oncological Research Center after N.N. Biokhin RAMS, Moscow, Russia; A.K.D. Liem, Pacic Shores Medical Group, Long Beach, CA; C. Lindner, Frauenklinik Elim, Hamburg, Germany; R. Lipp, Innovation Onkologie Research, Hamburg, Germany; A. Lluch Herna ndez, Hospital Clinico de Valencia Avda. Blasco Iban ez, Valencia, Spain; T. Lopez, New Mexico Cancer Care Associates Cancer Institute of New Mexico, Santa Fe, NM; J. Lo pez-Herna ndez, Centro Estatal de Cancerologia, Durango, Mexico; K. Maart, Sr Georges Hospital, Eastern Cape Oncology Centre, Elizabeth, South Africa; D. Mackova, Masaarykuv Onkologicky Ustav, Bruo, Czech Republic; A. Mahmood, Department of Oncology and Radiotherapy, Combined Military Hospital, Rawalpindi, Pakistan; A. Makris, Mount Vernon Hospital, Northwood Middlesex, United Kingdom; A.B. Marantz, Hospital Fernandez, Buenos Aires, Argentina; M. Margeli, Hospital Germans Trias i Pujol Ctra Canyet S/N, Badalona, Spain; M. Martn Jime nez, Hospital Clinico San Carlos, Madrid, Spain; A. Mayadagli, Dr Lut Kirdar Kartal Egitim ve Arastirma Hospital, Istanbul, Turkey; S.S. Mccachren, Thompson Cancer Survival Center, Knoxville, TN; R. Mcdermott, Adelaide and Meath Hospital (AMNCH), Dublin, Ireland; R.E. Mcintyre, Ventura County Hematology-Oncology Specialists, Oxnard, CA; O.G. Melnyk, Bay Area Cancer Research Group, Concord, CA; M. Mendez Uren a, H. de Mostoles C, Madrid, Spain; M.R. Modiano, Arizona Clinical Research Center, Inc, Tucson, AZ; M. Mousseau, Hopital Albert Michalon, Grenoble, France; L. Mueller, E.W. Muller, Slingeland Ziekenhuis, Doetinchem, the Netherlands; S. Muller-Hagen, Hamtologisch-Onkologischer Schwerpunkt, Hamburg, Germany; G. Mullins, Bon Secours Hospital, Cork, Ireland; M. Munoz Mateu, Hospital Clinic i Provincial cC/Villaroel, Barcelona, Spain; J.C. Nadal, Instituto Alexander Flemin, Buenos Aires, Argentina; G.G. Nagargoje, Hubert H. Humphery Cancer Center North Memorial Health Care, Robbinsdale, MN; A. Nusch, Gem. Praxis Drs. Nusch und Kalhori, Friedrichstr. Velbert Germany and Ratingen, Germany; S. OReilly, South Inrmary Victoria University Hospital, Cork, Ireland; M. Osvath, Komarom-Esztergom Megyei Onkormanyzat Szent Borbala Megyei Korhaz, Dozsa Gyorgy, Hungary; B. Parker, University of
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First-Line Lapatinib Letrozole in Hormone ReceptorPositive MBC

California, San Diego Medical Center, San Diego, CA; R. Patel, Comprehensive Blood and Cancer Center, Bakerseld, CA; M.D. Pegram, Sylvester Comprehensive Cancer Center, Miami, FL; C.A.S. Pereira Filho, Clnica de Assiste ncia Multidisciplinar em Oncologia, Baha, Brazil; G. Perez-Manga, Hospital Gregorio Maranon, Madrid, Spain; T. Pienkowski, Maria Sklodowska-Curie Memorial Cancer Centre, Warsaw, Poland; P. Pimentel, Hospital Alberto Sabogal Jiron Colina, Lima, Peru; J.E. Pippen, P.A. Sammons Cancer Center, Dallas, TX; X. Pivot, Hopital Jean Minjur, Besancon, France; J. Polikoff, Southern California Permanente Medical Group, San Diego, CA; L. Provencher, Centre Hospitalier Aflie Universitaire de Quebec, Quebec, Canada; B.T. Pruitt, Don & Sybil Harrington Cancer Center, Amarillo, TX; J. Raats, Panorama Medi-clinic, Panorama Cape Town, South Africa; S.M. Raza, Shaukat Khanum Memorial Cancer Hospital & Research Centre, Mohammad Ali Johar Town, Lahore, Pakistan; D.W. Rea, Sandwell and West Birmingham Hospitals NHS Trust, W. Midland, United Kingdom; J. Reyes-Vidal, Clinica Las Condes, Santiago, Chile; J. Rifa , Hospital Son Dureta, Mallorca, Spain; J. Rimailho, Centre Hospitalier Universitaire (CHU) Paul de Viguier, Toulouse, France; K. Rinn, Swedish Cancer Institute, Seattle, WA; J.S. Ro, National Cancer Center, Gyeonggi-do, Korea; C.J. Rodenburg, Meander MC, loc. St Elisabeth, Amersfoort, the Netherlands; J. Rolski, Chemotherapy Department Oncology Centre, Krakow, Poland; G. Romieu, Centre Val dAurelle-Paul Lamarque, Montpellier, France; M. Roselli, Oncologia Medica, Dipartimento di Medicina Interna, Rome, Italy; J.-A. Roy, Hospital du Sacre Coeur de Montreal, Montreal, Quebec, Canada; J. Rubins, Interlakes Oncology & Hematology, Rochester, NY; S. Sabesan, The Townsville Hospital, Queensland, Australia; R.A. Saez, Watson Clinic LLP, Lakeland, FL; M.N. Saleh, Georgia Cancer Specialists, Tucker, GA; P. Salman, Fundacion Arturo Lopez Perez, Santiago, Chile; J. Sa nchez, Hospital Universitario San Ignacio, Bogota , Colombia; V. Schulz, Systemedic GmbH, Kiel, Germany; L.S. Schwartzberg, The West Clinic, Memphis, TN; C.W. Seidler, Fallon Clinic, Inc at Worcester Medical Center, Worcester, MA; V. Semiglazov, Petrov Research Institute of Oncology, St. Petersburg, Russia; F. Senecal, Northwest Medical Specialties, Tacoma, WA; T. Siddiqui, Shands Teaching Hospital, Gainesville, FL; S. Siena, Ospedale Niguarda CAGranda, Milan, Italy; J.D. Skelton, Boca Raton Community Hospital Inc, Boca Raton, FL; B.G. Sleckman, St Johns Mercy Medical Center, St Louis, MO; H.P. Sleeboom, Ziekenhuis Leyenburg, Den Haag, the Netherlands; P.G. Soerensen, Amtssygehuset I Roskilde, Roskilde, Denmark; L. Sre ter, Semmelweis Egyetem, Altalanos Orvostudomanyi Kar, Budapest, Hungary; V. Stahalova, FNB Ustav Radiacni Onkologie, Praha, Czech Republic; A.M. Storniolo, Indiana University Hospital, Indianapolis, IN; I. Sza nto , Fovarosi Onkormanyzat Szent Istvan Korhaz, Budapest, Hungary; M. Szucs, Bacs-Kiskun Megye Onkormanyzati Korhaza, Nyiriu, Hungary; J.A. Taguchi, Sansum Santa Barbara Medical Foundation Clinic, Santa Barbara, CA; H.W. Tessen, Koesler Str. 10b, Goslar, Germany; A. Thomas, Universitaetsklinikum Charite Klinik fur Frauenheilkunde und Geburtehilfe, Berlin, Germany; S.P. Thomas, Oncology Hematology Associates of Central Illinois, Peoria, IL; L. Thurzo , Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Orvoses, Koranyi Fasor, Hungary; C. Timcheva, National Center of Oncology, Soa, Bulgaria; A. Tomova, Department of Chemotherapy, Oncological Dispensary, Plovdiv, Bulgaria; V. Trillet-Lenoir, CH Lyon Sud Service Oncologie Me dicale, Pierre Benite, France; J. Tujakowski, Regional Oncology Centre, Bydgoszcz, Poland; V. Tzekova, Medical University, Soa Bulgaria; M. Unsal, SSK Okmeydam Hospital, Istanbul, Turkey; L. Vanlemmens, Centre Oscar Lambret, Lille, France; C.A. Vargas, Fundacion Santa Fe De Bogota, Bogota, Colombia; J. Vidal, Hospital Josep Trueta Servicio de Oncologie Avda de Franca, Girona, Spain; E.E. Voest, University Medical Center Utrecht, Utrecht, the Netherlands; C.L. Vogel, Comprehensive Cancer Care Specialists at Boca Raton Lynn Regional Cancer Center-West, Boca Raton, FL; F. Von Koch, Klinikum der Universitat Munchen, Munchen, Germany; K. Von Maillot, Frauenklinik des Ostalbklinikums Aalen Brust Centrum, Germany; G. Von Minckwitz, Klinikum der Johann Wolfgand, Goethe-Universist Geburtshilfe, Frankfurt, Germany; E. Vrdoljak, Klinika za Onkologiju, Split, Croatia; A.M. Wardley, Christie Hospital NHS Trust, Manchester, United Kingdom; M. Wood, Fletcher Allen Health Care, Burlington, VT; P. Wuelng, Universitatsklinikum Munster Klinik und Poliklinik fur Frauenheilkunde und Geburtshilfe, Munster, Germany; L. Yelle, Hopital Notre-Dame, Universite de Montreal, Montreal, Quebec, Canada; J. Younus, London Health Sciences Centre, London, United Kingdom; J. Zaluski, Wielkopolskie Centrum Onkologii, Poznan, Poland.

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