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Doi:10.1016/s1470-2045(12)70049-9

Articles
Neoadjuvant bevacizumab, trastuzumab, and chemotherapy
for primary infl ammatory HER2-positive breast cancer
(BEVERLY-2): an open-label, single-arm phase 2 study

Jean-Yves Pierga, Thierry Petit, Thierry Delozier, Jean-Marc Ferrero, Mario Campone, Joseph Gligorov, Florence Lerebours, Henri Roché, Thomas Bachelot, Emmanuelle Charafe-Jauff ret, Maria Pavlyuk, Sandrine Kraemer, François-Clément Bidard, Patrice Viens Summary
Background Bevacizumab and trastuzumab are effi

cacious for treatment of advanced or HER2-positive metastatic Published Online
breast cancer; however, few data exist for this regimen in infl ammatory breast cancer. In our phase 2 trial, we aimed February 28, 2012
to assess effi
cacy and safety of neoadjuvant bevacizumab combined with trastuzumab and chemotherapy in patients DOI:10.1016/S1470-
with primary HER2-positive infl ammatory breast cancer.
See Online/Comment
DOI:10.1016/S1470-
Methods In our phase 2, multicentre, open-label, single-arm, non-comparative trial, we enrolled women (aged 2045(12)70081-5
≥18 years) with histologically confi rmed HER2-positive non-metastatic infl ammatory breast cancer at private or public Institut Curie, Paris, France
oncology centres in France. Before surgery, patients were treated with fl uorouracil, epirubicin, cyclophosphamide,
(Prof J-Y Pierga MD,
and bevacizumab (cycles 1–4) and docetaxel, bevacizumab, and trastuzumab (cycles 5–8) in 3-week cycles. After F-C Bidard MD); Université Paris
Descartes, Paris, France
surgery, patients received adjuvant radiotherapy, trastuzumab, and bevacizumab. For the primary endpoint, we (J-Y Pierga, F-C Bidard); Centre
assessed the proportion of patients who achieved a pathological complete response (defi ned by central review of Paul Strauss, Strasbourg,
surgical specimens according to Sataloff classifi cation, counting missing data as failure) and adverse events in all France
(Prof T Petit MD); Centre
enrolled patients. This study is registered with ClinicalTrials.gov, number NCT00717405.

François Baclesse, Caen, France
(T Delozier MD); Centre Antoine
Lacassagne, Nice, France

Findings Between Oct 23, 2008, and Oct 28, 2009, we enrolled 52 patients at 21 centres. 42 (81%) of 52 patients received (Prof J-M Ferrero MD); Institut
all eight cycles of neoadjuvant therapy and 49 (94%) underwent surgery. After neoadjuvant therapy, 33 of 52 patients had de Cancérologie de
a pathological complete response according to central review (63·5%, 95% CI 49·4–77·5). The most common adverse l’Ouest–René Gauducheau,

Saint Herblain, France
events were asthenia and nausea (both occurred in 36 [69%] of 52 patients). 25 (48%) patients had grade 3–4 neutropenia, (M Campone MD); Hôpitaux
which was the most common grade 3–4 adverse event. Only one grade 3 or worse adverse event regarded as related to Universitaires Paris Est–Tenon,
bevacizumab was reported (hypertension, one patient). Four patients (8%) had cardiac failure.

Alliance pour la Recherche en
Cancerologie, Paris, France
(J Gligorov MD); Institut Curie
Interpretation Neoadjuvant treatment with bevacizumab, trastuzumab, and chemotherapy was effi
cacious and well Hôpital René Huguenin,
tolerated in patients with previously untreated primary infl ammatory breast cancer. Further confi rmation of use of Saint-Cloud, France
bevacizumab in infl ammatory breast cancer is needed.

(F Lerebours MD); Institut
Claudius Regaud, Toulouse,
France
(Prof H Roché MD);
Funding Roche (France).
Centre Léon-Bérard, Lyon,
France
(T Bachelot MD);
Introduction
targets HER2, has improved outcomes in metastatic breast Institut Paoli-Calmettes,
Infl ammatory breast cancer is a very aggressive form of cancer and early disease.
Marseille, France
7,8 Combination of trastuzumab (Prof E Charafe-Jauff ret MD, locally advanced breast cancer, and accounts for up to with various chemotherapy regimens for the neoadjuvant Prof P Viens MD); Roche,
5% of all cases.1 Such cancer is characterised by the treatment of locally advanced breast cancer, including Neuilly-sur-Seine, France
clinical appearance of infl
ammation with oedema infl ammatory breast cancer, has also been assessed in (M Pavlyuk MD, S Kraemer MSc);
and Aix-Marseilles Université,
(termed peau d’orange) and redness of the skin.2 Typically, several clinical studies.9–13 A substudy of the NOAH trial9 Marseille, France
infl ammatory breast cancer is diagnosed in young assessed response to standard chemotherapy in 76 women (P Viens, E Charafe-Jauff ret)women, who are more likely to have metastasis than are with infl ammatory breast cancer, 62 of whom had HER2- Correspondence to:those with other types of breast cancer.3 Multimodal positive disease. Trastuzumab was coadministered with Prof Patrice Viens, Institut Paoli treatment regimens—including endocrine treatment, chemotherapy in 31 patients with HER2-positive disease, Calmettes and Aix-Marseilles chemotherapy, surgery, and radio 54·8% of whom achieved a pathological complete response Université, 232 Boulevard Sainte adjuvant approaches have greatly improved the prognosis (pCR), compared with 19·3% of those with HER2-positive Marseille, France for infl ammatory breast cancer,4 resulting in a 5-year disease who received chemotherapy alone.10 viensp@marseille.fnclcc.fr
survival of about 40%.5 However, women with this cancer Infl ammatory breast cancer is characterised patho- have worse prognosis than do those with non- logically by high vascularity and increased micro vessel infl ammatory locally advanced breast cancer.1 density because of high expression of angiogenic factors Overexpression of HER2 occurs in 15–25% of patients (eg, VEGF).3 VEGF is a key mediator of angiogenesis and with breast cancer.6 HER2 positivity is generally associated is involved in endothelial and tumour cell growth and with aggressive disease; however, introduction of the motility and blood vessel permeability.14 Infl ammatory humanised monoclonal antibody trastuzumab, which breast cancer’s vascular nature probably makes it www.thelancet.com/oncology Published online February 28, 2012 DOI:10.1016/S1470-2045(12)70049-9
Articles
especially amenable to anti-angiogenic treatment. Use of infl ammation and oedema on >50% of the breast bevacizumab, a VEGF-targeting monoclonal antibody, surface) by Institut Gustave-Roussy classifi cation26 or as resulted in substantially improved progression-free presence of tumour emboli in the lymph vessels of the survival and response in patients with advanced breast superfi cial derma on skin biopsy sampling. Eligible cancer in four randomised phase 3 trials15–18 and showed patients had to have Eastern Cooperative Oncology neoadjuvant activity in a pilot study in patients with Group (ECOG) performance status of 0–2, life previously untreated locally advanced breast cancer or expectancy of 3 months or more, HER2-positive infl ammatory breast cancer.19 tumours (assessed locally but reviewed centrally after Combination of bevacizumab and trastuzumab for the last inclusion), known hormone receptor status, treatment of advanced or HER2-positive metastatic breast and no metastases. Hormone-receptor positivity was cancer has been assessed in two trials.20,21 First, an open- defi ned as overexpression of 10% or more. label, phase 1 dose-escalation trial20 of three doses of Patients with non-infl ammatory breast cancer with bevacizumab in combination with trastuzumab noted tumoral skin permeation, bilateral breast cancer, preliminary clinical responses in fi ve (56%) of nine previous cancer history relapsing 5 years or more before patients and two other patients developed stable disease. study entry, and in-situ contralateral breast carcinoma The combination of bevacizumab and trastuzumab was were ineligible, as were those who had previously been well tolerated with no reported grade 3–4 adverse events. treated with chemotherapy, radiotherapy, or endocrine After this encouraging outcome, a phase-2 study21 was therapy for breast cancer. Other exclusion criteria were done in 37 women with advanced HER2-positive breast major surgery or substantial traumatic injury 28 days or cancer. Patients received trastuzumab (4 mg/kg loading less before start of study treatment or anticipation of the dose followed by 2 mg/kg weekly) and bevacizumab at need for major surgery during study treatment; minor the recommended phase 2 dose (10 mg/kg every 2 weeks). surgery 24 h or less before fi rst bevacizumab infusion; The overall response rate was 54·1% (20 of 37 patients), non-healing wound, active peptic ulcer or bone fracture; with one patient achieving a complete response and or history of abdominal fi stula, gastrointestinal 19 achieving partial responses; 11 patients (29·7%) had a perforation, or intra-abdominal abscess within 6 months best response of stable disease. Grade 3–4 drug-related of enrolment; uncontrolled hypertension; or pregnancy. adverse events included dyspnoea, left ventricular dys- Patients were not allowed to have received hormonal function, hyper tension, and proteinuria.
therapy in the 3 weeks before enrolment in this study.
We undertook this phase 2 study on the basis of All patients provided signed written informed consent previous results with trastuzumab plus chemotherapy, before study-specifi the reported activity of bevacizumab in infl ammatory separately for the translational research studies. breast cancer, and the effi cacy of bevacizumab plus Approval for study design, conduct, and the informed trastuzumab in advanced and metastatic disease. We consent documentation was received on March 29, 2009, aimed to assess the effi cacy and safety of preoperative from the independent ethics committee (Comité de treatment with bevacizumab, trastuzumab, and chemo- Protection des Personnes Sud Méditerranée I, Institut therapy in patients with primary infl ammatory HER2- Paoli Calmettes, Marseille, France).
positive breast cancer. We also assessed the potential of
circulating tumour cells and circulating endothelial cells Procedures
as effi
cacy biomarkers, since circulating tumour cell HER2 status was assessed by investigators by immuno- positivity has been shown to be an independent histochemistry (IHC), fl uorescence in-situ hybridisation prognostic factor in patients with non-metastatic breast (FISH), or chromogenic in-situ hybrid cancer receiving either adjuvant22 or neoadjuvant and reanalysed centrally with IHC and silver in-situ chemotherapy,23 and both circulating tumour and hybridisation (SISH) assays by an experienced pathologist circulating endothelial cells have been reported as effi cacy (EC-J) who was masked to patient’s data, including the biomarkers in patients with metastatic breast cancer original IHC test results. HER2 status in IHC was receiving antiangiogenic therapy plus chemotherapy.24,25 assessed with the A485 polyclonal antibody (Dako, Glostrup, Denmark) on the BenchMark XT system (Ventana Medical Systems, Tucson, AZ, USA). Biopsy Study design and patients
samples were graded according to the HercepTest (Dako) In our phase 2, multicentre, open-label, non- randomised, Simon (two-stage), single-arm, non- We did the SISH analyses with the INFORM HER2 comparative trial, we enrolled women (aged ≥18 years) technology (Ventana Medical Systems) and BenchMark who had histologically confi rmed breast cancer and XT system according to standard procedures. For all confi rmed infl ammatory breast cancer. Infl ammatory biopsy samples, HER2 signals and chromosome 17 were breast cancer was defi ned as T4d (any N), stage II counted in X60 tumour cell nuclei. We quantifi ed HER2 (infl ammation, erythema, and/or oedema localised to as the ratio of HER2 to chromosome 17 signals with the <50% of the breast surface), or stage III (generalised conventional historical interpretation scale and also by the www.thelancet.com/oncology Published online February 28, 2012 DOI:10.1016/S1470-2045(12)70049-9
Articles
Neoadjuvant trastuzumab 8 mg/kg loading dose Neoadjuvant bevacizumab 15 mg/kg every 3 weeks for 24 weeks Figure 1: Study design and treatment schedule
American Society of Clinical Oncology and College of healed properly, and was given for 4–6 weeks according American Pathologists reporting scheme. HER2 amplifi - cation was defi ned as the ratio of HER2 to chromosome 17 No bevacizumab treatment interruption or dose centromeric signals of X2·2.27 All tumours with six or changes were planned, unless the patient’s weight varied more HER2 signals per nuclei had a ratio of X2·2 and by more than 10%, in which case the dose was therefore were classifi ed as amplifi ed tumours. All recalculated. Trastuzumab and bevacizumab were tumours with fewer than six HER2 signals per nuclei had discontinued defi nitively in patients with a symptomatic an HER2 to chromosome 17 ratio of less than 1·8 and decrease (or temporarily in patients with an asymptomatic were deemed to be non-amplifi ed. decrease to <50%) in left ventricular ejection fraction, Our trial had four planned stages (fi gure 1). In stage 1, and B-type natriuretic peptide assessment was requested. patients received neoadjuvant treatment with fl uor o-uracil, epirubicin, cyclophosphamide, and bevacizumab Patients (N=52)
(cycles 1–4) followed by docetaxel, bevacizumab, and trastuzumab (cycles 5–8). In stage 2, patients underwent surgery (mastectomy and axillary node dissection) with trastuzumab maintenance during the perioperative period. In stage 3, patients received adjuvant treatment with radiotherapy, trastuzumab, and bevacizumab. Lymph node involvement based on clinical staging Endocrine therapy was introduced at the investigator’s discretion in patients with hormone receptor-positive disease. In stage 4, patients were followed up for 5 years after inclusion of the last patient. The study is in progress, and we report data from stages 1 and 2 here.
Neoadjuvant chemotherapy was intravenous fl uor o- uracil (500 mg/m²), epirubicin (100 mg/m²), and cyclophosphamide (500 mg/m²) on day 1 of a 3-week cycle for four cycles followed by intravenous docetaxel (100 mg/m²) on day 1 for a further four cycles. Premedication was given according to local practice.
Infl ammatory breast cancer classifi cation In the neoadjuvant phase, patients received intravenous bevacizumab (15 mg/kg) once every 3 weeks for eight injections. Bevacizumab was stopped at least 4 weeks before surgery and restarted during or after radiotherapy once the wound was healed entirely. Adjuvant bevacizumab (15 mg/kg) was given every 3 weeks for up to 30 weeks. Trastuzumab was given at an initial intra- venous loading dose of 8 mg/kg and then at a dose of Data are median (IQR, range) or n (%). ECOG=Eastern Cooperative Oncology Group. 6 mg/kg once every 3 weeks from cycle 5 of neoadjuvant IGR=Institut Gustave-Roussy. PEV=poussée évolutive (acute exacerbation). treatment, and was continued in the perioperative period cient biopsy material was available to allow grading in four patients.
for about 30 weeks after surgery. Mandatory radiotherapy Table 1: Baseline characteristics of patients
was started 2–4 weeks after surgery, if the wound had www.thelancet.com/oncology Published online February 28, 2012 DOI:10.1016/S1470-2045(12)70049-9
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After asymptomatic decreases in left ventricular ejection involvement (ie, Sataloff classifi cation TA and NA or NB fraction, trastuzumab and bevacizumab were reinitiated or Chevalier classifi cation Ch1 and Ch2).
at the standard dose (no dose reduction). Patients were Additional secondary endpoints were disease-free subsequently monitored until the end of the study. survival, recurrence-free interval, overall survival, safety Bevacizumab was permanently discontinued if held for (adverse events coded according to the MedDRA two consecutive or two intermittent cycles. Trastuzumab guidelines and their intensity graded by the National was discontinued if held for three intermittent or two Cancer Institute Common Terminology Criteria for consecutive cycles.
Adverse Events version 3.0), cardiac safety according to The primary endpoint was the proportion of patients New York Heart Association classifi cation (for patients with a pCR assessed by central review of surgical with cardiac failure), and translational research. specimens according to Sataloff classifi cation.28 Translational research studied factors that were predictive Secondary endpoints were the proportion of patients of effi cacy and included biology, pharmacokinetics, with a pCR assessed by central review according to pharma co genetics, pharmacogenomics, proteomics, and Chevallier classifi cation29 and also as assessed by the imaging studies. Clinical tumour response was assessed investigators according to Sataloff classifi cation. For by the investigators. We defi ned clinical response as assessment of response, at least 20 tissue blocks were absence of infl ammatory signs, fi xed lymph nodes, or prepared for every patient, according to a standardised visceral dissemination of the disease.
methodological approach.30 Haematoxylin and eosin- For translational research studies, we obtained fi ve stained slides of surgical resection specimens after supplementary blood samples (2×10 mL) from every chemotherapy were reviewed centrally (EC-J) by patient: one before the fi rst bevacizumab administration microscope. On the basis of patients’ pathological (neoadjuvant period), one before the fi rst trastuzumab response in the primary breast site and/or in the lymph administration (neoadjuvant period), one before surgery, nodes, and in line with published data,31 we designated one before bevacizumab reintroduction (adjuvant period), patients as having a pCR when surgical samples showed and one at the end of adjuvant treatment (fi nal visit). All total or near-total treatment eff ect and absence of nodal samples were analysed within 3 days at the Institut Curie (Paris, France) by Claire Mathiot. Circulating tumour cell Axillary lymph node response28
and circulating endothelial cell counts were measured in 7·5 mL and 4 mL samples, respectively, with CellSearch (Veridex LLC, Raritan, NJ, USA). HER2 immuno cyto-fl uorescence staining (FITC-conjugated antibody HER81, Sataloff classifi cation (central review)
Veridex LLC) was assessed on detected circulating tumour cells and categorised as class 0–3; as per Riethdorf and colleagues,32 we only regarded classes 2 and 3 as Statistical analysis
We calculated the sample size on the basis of a Simon two-stage design for phase 2 study. From the proportion Sataloff classifi cation (investigator review)
of patients with a pCR reported in the PEGASE 02 study,33 we regarded a proportion of patients with a pCR assessment. Assuming a risk of α=0·05 (type I error) and β=0·10 (type II error), we needed to include 45 patients (maximum) in two stages. To allow for non- assessable data for up to 10% of patients for the primary Chevalier classifi cation (central review)*
endpoint, we enrolled 52 patients. The fi rst stage included 24 patients who were followed up until assessment of pathological response. If six or more pathological complete responses were noted, recruitment NA=evidence of treatment eff ect, no metastatic disease. NB=no nodal metastasis or treatment eff ect. NC=evidence of For the primary outcome, we show the proportion of treatment eff ect but nodal metastasis still present. ND=viable metastasis disease, no treatment eff ect. TA=total or near patients with a pCR on central review according to total therapeutic primary site response. TB=>50% (but not total or near total) primary site response. TC=<50% primary Sataloff classifi cation with 95% CI (missing data for site response, but eff ect evident. TD=no primary site response.
Table 2: Pathological clinical response rate according to Sataloff classifi cation (assessed by central review
did not undergo surgery were regarded as failure). Only or investigators) and Chevalier classifi cation (assessed by central review) in 52 enrolled participants
patients with centrally confi rmed HER2 amplifi cation www.thelancet.com/oncology Published online February 28, 2012 DOI:10.1016/S1470-2045(12)70049-9
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were included in the assessment of pathological response ventricular ejection fraction of 55% or more at inclusion. rate. Missing data were regarded as failures. The patient 42 (81%) of 52 patients received all eight cycles of with a polyploidy IHC2+/SISH-negative did not reach neoadjuvant therapy. 45 (87%) patients received eight complete response and was also regarded as a failure. If cycles of bevacizumab and 50 (96%) patients received at 14 or more patients had a pCR by the end of the inclusion least four preoperative cycles of trastuzumab; 49 (94%) period (ie, after the second phase), the strategy was patients underwent mastectomy and three patients (6%) regarded as eff ective. We also did sensitivity analyses did not undergo surgery in the study.
excluding patients with missing data. 17 (71%) of 24 patients had a pCR in the fi rst stage of We analysed cell count data with descriptive analyses, the study, and thus recruitment into the second stage was in terms of the variation between timepoints and continued. 33 of 52 patients had a pCR (63·5%, 95% CI correlation with pCR. We assessed signifi cance between 49·4–77·5; table 2). In the investigator-based assessment, values with the Wilcoxon signed-rank test for circulating endothelial cell counts and a McNemar’s non-parametric test for circulating tumour cell counts.
Grade 1–2
Grade 3–4
All grades*
Analyses were done with SAS version 9.1. This study is (patients)
(patients)
registered with ClinicalTrials.gov, number NCT00717405, Role of the funding source
The sponsor was involved in protocol development and data analysis, and had a role in writing the report. The sponsor was not involved in the interpretation of the data; data for interpretation were provided as raw data tables to PV, TB, TD, MC, EC-J, J-MF, JG, and J-YP. All authors were given the opportunity to comment on the draft report and saw and approved the fi nal version. PV had fi nal responsibility for the decision to submit for Between Oct 23, 2008, and Oct 28, 2009, we enrolled 52 patients with HER2-positive infl ammatory breast cancer at 21 private or public oncology centres in France. Table 1 summarises baseline characteristics. 11 (21%) of 52 patients had a cutaneous biopsy, four of whom had lymphatic emboli in the superfi cial derma. Although the eligibility criteria for this trial allowed for the inclusion of patients solely on the basis of presence of tumour emboli within the vasculature of the superfi cial derma, all enrolled patients also had clinical symptoms of infl ammatory breast cancer as agreed in the international consensus report of the infl ammatory breast cancer consortium.34 Investigator-assessed HER2 overexpression was IHC3+ in 46 patients (88%), IHC3+/FISH-positive in one patient (2%), IHC3+/CISH-positive in one patient (2%), FISH-positive in two patients (4%), and IHC2+/FISH-positive in two patients (4%). Central HER2 review was undertaken in 46 patients and was IHC3+ in fi ve patients (11%), IHC3+/CISH-positive in one patient (2%), IHC3+/SISH-positive in 34 patients (74%), IHC2+/ SISH-positive in two patients (4%), IHC3+/SISH-negative in three patients (7%; two patients had polyploid tumours), and IHC2+/SISH-negative in one patient (2%; patient had a polyploid tumour). We did not centrally review Data are n (%) or n. *Grade missing for some events; patients could have more HER2 expression in six patients because of insuffi than one event of diff erent grades. †Reported at any time.
material. All patients had adequate haematological, liver, Table 3: Adverse events occurring in more than 10% of patients by grade
renal, coagulation, and cardiac function and a left www.thelancet.com/oncology Published online February 28, 2012 DOI:10.1016/S1470-2045(12)70049-9
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Log circulating endothelial cells per 4 mL Figure 2: Circulating tumour cell (A) and circulating endothelial cell (B) counts in individual patients during treatment
We calculated p values with McNemar’s test (A) or the Wilcoxon signed-rank test (B). *Cycle 5 versus baseline (data for 45 patients). †End of treatment versus cycle 5
(data for 39 patients). ‡Before adjuvant treatment versus end of treatment (data for 35 patients).
During the neoadjuvant phase, all patients had at least Baseline
Before cycle 5
4 weeks before 4 weeks after
one adverse event; 38 patients (73%) had at least one grade 3 or worse adverse event, of whom ten (26%) had Circulating tumour cells
an adverse event deemed related to bevacizumab. Table 3 shows adverse events occurring in more than 10% of patients. The only grade 3 or worse adverse event deemed related to bevacizumab was hypertension (in Circulating endothelial cells
one patient). 25 serious adverse events were reported in 16 (31%) of 52 patients, including febrile neutropenia or febrile bone marrow aplasia (in ten patients [19%]), anal abscess (in two patients [4%]), and ejection fraction decrease, pyrexia, appendicitis, septic shock, back pain, Data are n, n (%), or median (IQR, range). hyperthermia, malaise, metrorrhagia, jugular vein thrombosis, hand-foot syndrome, and vomiting (one Table 4: Circulating tumour cell and circulating endothelial cell counts
patient each [2%]). Four patients (8%) had cardiac failure. In one patient, ejection fraction decreased from 35 of 52 patients had a pCR (67·3%, 53·6–81·0). Thus, 70% to 45% after four cycles of fl uorouracil, epirubicin, because the proportion of patients with a pCR was higher and cyclophosphamide; the latest documented ejection than the 40% cutoff used in the statistical assumption, fraction showed recovery to 60%. One patient had an we regarded the combination as eff ective. The sensitivity ejection fraction of 44% decreasing to 38% in conjunction analysis under taken after central review also showed a with a tachyarrhythmia (atrial fi brillation) and another pCR in 33 of 47 patients with available data (70·2%, patient had an ejection fraction that decreased from 56·1–84·4); the remaining two patients from the 49 who 70% to 49% on study, followed by recovery. One other underwent mastectomy were regarded as having patient had an ejection fraction of 50% during the study treatment failure in the analysis because of an absence of that recovered to 65%; this patient had an associated assessable tissue. Much the same results were noted in underlying pericardial eff usion. Of the four cardiac the hormone receptor-positive subgroup (11 of 18 patients failures, two were New York Heart Association grade 2 [61·1%, 95% CI 35·8–86·4] had a pCR).
(two symptomatic cardiac failures) and two were New At the end of neoadjuvant therapy, 44 (98%) of York Heart Association grade 1 (two left ventricular 45 assessable patients had a clinical response (ie, an dysfunction without clinical symptoms). One patient absence of infl ammatory signs, fi xed lymph nodes, or received granulocyte colony-stimulating factor after visceral dissemination of the disease). One patient had onset of neutropenia and the patient fully recovered.
stable disease. Data for disease-free survival, recurrence- Three (6%) of 52 patients prematurely discontinued free interval, and overall survival are immature at present.
bevacizumab because of adverse events (one each of skin www.thelancet.com/oncology Published online February 28, 2012 DOI:10.1016/S1470-2045(12)70049-9
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toxicity, bone marrow failure, and colitis). Two patients treatment regimen in HER2-positive infl ammatory (4%) discontinued all treatment prematurely because of breast cancer (panel). Conventionally, patients with toxicity (one because of persistent thrombocytopenia and infl ammatory breast cancer are less likely to respond to one because of grade 4 febrile neutropenia). No deaths treatment and have a poorer prognosis than are those related to treatment occurred. Reported postoperative with other breast cancers. However, advances have been event rates were much the same as those reported with made in the treatment of patients with infl ammatory neoadjuvant chemotherapy without bevacizumab. The cancer in the past 15 years. In the phase 2 PEGASE 02 most common postoperative complications were seroma study,33 patients received neoadjuvant chemotherapy (in 14 [29%] of 49 patients) and wound-healing with cyclo phosphamide, doxorubicin, and fl uorouracil. complications (in fi ve [10%] of 49 patients). No bleeds Although the clinical response rate was high (90%), occurred that required surgery.
pCR was achieved in only 32% of patients, which In the translational research study, we assessed nevertheless compared favourably with traditional potential relations between circulating tumour cell chemo therapy regimens (pCR 0–25%).33 This outcome counts, circulating endothelial cell counts, and pCR showed the chemosensitivity of infl ammatory breast according to investigator review of pCR. At baseline, cancer. However, much the same proportion of patients 18 (35%) of 52 patients had one or more circulating achieved a pCR in PEGASE 07 (33 [38%] of 87 patients) tumour cell per 7·5 mL (range 1–92 cells). Circulating in patients receiving primary high-dose chemo therapy tumour cells positivity and circulating endothelial cell (epirubicin and cyclophosphamide with autologous counts did not correlate with clinical–pathological charac- peripheral blood stem-cell transplantation) followed by teristics at baseline. The circulating tumour cell detection surgery, radiotherapy, and observation.35 In a randomised rate decreased signifi cantly during the fi rst cycles of study13 of patients with infl ammatory breast cancer chemotherapy plus bevacizumab (p=0·03), and remained assigned to receive chemotherapy alone or chemotherapy low and stable throughout the following cycles (fi gure 2, plus trastuzumab, fi ve of 19 (26%) patients who received table 4). We noted a progressive and signifi cant increase chemotherapy alone achieved a pCR compared with in the circulating endothelial cell count until presurgery 15 of 23 (65%) who received chemotherapy and bevacizumab discontinuation (fi gure 2).
trastuzumab (p=0·02). After treatment of a second There was no correlation between circulating tumour cohort with chemotherapy and trastuzumab, 27 of cell detection and pCR at any timepoint. A circulating 45 (60%) patients had achieved a pCR.13 Much the same endothelial cell count of fewer than 20 cells per 4 mL (as result was reported in a cohort of patients with in the criteria suggested by ATHENA24) after the fi rst infl ammatory breast cancer who were treated with four cycles of therapy was positively associated with pCR chemotherapy plus trastuzumab (10 [63%] of 16 patients (23 [48%] of 48 patients assessed; p=0·01). The clinical achieved a pCR).36 The proportion of patients with a pCR response rate was 98%, meaning that correlation testing that we noted in our study—63·5%—was high and was could not be done for this endpoint. In terms of much the same as previous studies of trastuzumab lymphatic dissemination of cancer cells, we noted no combination therapy in locally advanced breast cancer signifi cant correlation between circulating tumour cell (including infl ammatory breast cancer).13,36 positivity and axillary lymph node status either at Analysis of these data suggests that bevacizumab and baseline (clinical nodal status, p=0·33) or after treatment trastuzumab plus chemotherapy is a positive step in terms (pathological nodal status, p=0·18). Of 48 patients with of achievement of pCR. Although survival data are not circulating endothelial cell values at baseline and cycle 5, available for our study so far, previous studies have linked eight presented with hypertension. A non-parametric pCR with signifi cant improvements in long-term out-Wilcoxon test showed no signifi cant correlation between comes in the setting of HER2-positive primary breast the variation in circulating endothelial cell counts cancer, including disease-free survival and overall (cycle 5–baseline) and hypertension (p=0·91).
survival.37 In the TECHNO trial,37 patients achieving a pCR In 18 patients with circulating tumour cells, HER2 had signifi cantly improved 3-year disease-free survival immuno cytofl uorescence status was regarded as strong and overall survival compared with those who did not (either class 2 or 3 staining) in 15 patients (and negative achieve a pCR. Addition of trastuzumab to neoadjuvant in two and non-assessable in one) and was globally chemotherapy in NOAH9 further improved 3-year event-homogeneous on visual examination. During treatment, free survival in patients with HER2 positive infl ammatory HER2 immuno fl uorescence was stable over time; we breast cancer (hazard ratio 0·27, 95% CI 0·11–0·65).
noted a change in only two patients (one became HER2 Although toxicity was generally consistent with reports from previous studies, cardiac toxicity in our study was higher than has been reported in phase 3 trials of Discussion
bevacizumab plus chemotherapy in patients with In the BEVERLY-2 study, we showed that bevacizumab metastatic breast cancer.38,39 However, toxicity in our plus fl uorouracil, epirubicin, and cyclophosphamide, study was lower than that reported in the TORI-B03 study40 followed by docetaxel and trastuzumab, is an active of fi rst-line bevacizumab plus trastuzumab in www.thelancet.com/oncology Published online February 28, 2012 DOI:10.1016/S1470-2045(12)70049-9
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disease. Circulating tumour cell detection rates (one or Panel: Research in context
more cells per 7·5 mL) in the neoadjuvant setting were 23% in REMAGUS0223 and 22% in GeparQuattro,32 with Systematic review
4% crossing the threshold (≥5 cells per 7·5 mL) for We systematically reviewed PubMed, Web of Knowledge, and ClinicalTrials.gov with the positivity in REMAGUS02 and 3% in GeparQuattro. In keywords “infl ammatory breast cancer” between Jan 1, 2002, and Jan 1, 2007, for articles our study, the detection rate at baseline of 35% was published in English. Our search identifi ed no publications or planned/ongoing clinical trials higher than either of these non-infl ammatory breast of trastuzumab and bevacizumab in non-metastatic HER2-positive infl ammatory breast cancer studies; seven (13%) of 52 patients in BEVERLY-2 cancer. For non-metastatic infl ammatory breast cancer, the present standard of care is a had a baseline circulating tumour cell count of fi ve or neoadjuvant combination of anthracyclines and a taxane, with additional trastuzumab in more cells per 7·5 mL, although they had no distant HER2-positive patients. These fi ndings, together with the potentially important role of metastases. This diff erence may be a result of the high neoangiogenesis in infl ammatory breast cancer, led us to initiate the BEVERLY-2 study.
vascularisation and metastatic potential of infl ammatory Interpretation
breast cancer. Concentrations of circulating tumour cells In our phase 2 study, we showed a high rate of pathological complete response and provide dropped between baseline and cycle 5 (p=0·03). This cacy of the combination of a taxane-anthracycline chemotherapy large and early decrease diff ers from reports in two backbone with trastuzumab and bevacizumab in this rare disease. When combined with the previous neoadjuvant studies without bevacizumab, in results of the infl ammatory breast cancer subgroup analysis within the NOAH study,10 our which positivity for circulating tumour cells was stable or data suggest that the combination of a taxane-anthracycline chemotherapy backbone with slightly decreased during treatment.23,32 This decrease trastuzumab should be a standard treatment for non-metastatic infl ammatory breast cancer was consistent with reports from ATHENA24 and for patients with HER2-positive disease. The importance of bevacizumab within this IC 2006-0425 in metastatic breast cancer, suggesting it is combination needs further confi rmation.
related to bevacizumab use. In agreement with previous reports from the REMAGUS02,23 and GeparQuattro,32 HER2-expressing unresectable locally advanced breast detection of circulating tumour cells was not correlated cancer or metastatic breast cancer. As in TORI-B03,40 most cases were mild-to-moderate and were resolved. Cardiac Baseline circulating endothelial cell counts and their toxicity was not reported in the GeparQuinto41 study and increase before the introduction of trastuzumab at cycle 5 no factors have yet been identifi ed that are predictive for were much the same as those reported in patients with cardiac toxicity with this regimen. Further study is needed metastatic breast cancer who were treated with an to assess the combination’s safety. The ongoing equivalent regimen (chemotherapy and bevacizumab) in phase 3 studies BETH (NCT00625898) and AVEREL ATHENA.24 This increase and the reported kinetics of (NCT00391092) are presently assessing bevacizumab and circulating endothelial cells overall might be attributable trastuzumab in HER2-positive breast cancer. The phase 3 to the eff ect of bevacizumab, the chemotherapy, or their NeoALLTO study42 excluded patients with infl ammatory combination. In our study, a circulating endothelial cell breast cancer and although about 40% of patients in count of fewer than 20 cells per 4 mL before cycle 5 was NeoSphere43 had locally advanced breast cancer (32%) or signifi cantly associated with attainment of pCR. This infl ammatory breast cancer (6%), no response analysis has correlation suggests circulating endothelial cells are a been undertaken in this subpopulation.
We are unable to compare studies in infl ammatory bevacizumab, and trastuzumab neoadjuvant regimen in breast cancer with those in non-infl ammatory breast patients with infl ammatory breast cancer; this fi nding cancer. In non-infl ammatory breast cancer studies, few should be confi rmed in independent trials. Follow-up is patients undergo complete mastectomy and identifi cation required to allow investigation of the correlation between of complete responses is often more straightforward in circulating tumour cell counts, circulating endothelial patients with a partial mastectomy. Treatment of HER2- cell counts, and survival endpoints in this study.
positive breast cancer is evolving, with randomised Costa and colleagues48 suggested that neoadjuvant studies suggesting a trend towards increased rates of chemotherapy achieves equivalent responses in patients pCR with trastuzumab in combination with lapatinib with infl ammatory breast cancer or locally advanced and other tyrosine-kinase inhibitors.42,44–47 However, breast cancer when compared with operable breast because these studies were done in metastatic breast cancer. However, no recent randomised phase 3 trials cancer and advanced breast cancer, whether this devoted to infl combination is a valid treatment strategy for infl ammatory published to support this suggestion. Several diff erent breast cancer remains to be seen.
options could be proposed to confi rm our results Our study is the fi rst to report circulating tumour cell including a randomised phase 2 trial, a comparison with detection specifi cally in patients with non-metastatic a theoretical pCR rate expected in our study with validated infl ammatory breast cancer. Circulating tumour cell nomograms, or a proof-of-concept study in which count, via CellSearch, is approved by the US Food and bevacizumab is introduced if initial response is absent Drug Administration for management of metastatic by clinicoradiological, circulating tumour-circulating breast cancer, but is investigational in non-metastatic endothelial cell counts, and/or FDG-PET assessment.
www.thelancet.com/oncology Published online February 28, 2012 DOI:10.1016/S1470-2045(12)70049-9
Articles
Our study has limitations. Because this trial was non- 10 Baselga J, Semiglazov V, Manikhas GM, et al. Effi randomised and non-comparative, assessment of the neoadjuvant trastuzumab in patients with infl ammatory breast cancer: data from the NOAH (NeOAdjuvant Herceptin) phase III contribution of bevacizumab in this setting was diffi trial. Eur J Cancer Suppl 2007; 5: 193 (abstr 2030).
In the absence of a standardised pCR defi nition, the 11 Petrelli F, Borgonovo K, Cabiddu M, Ghilardi M, Barni S. standards systems used in France (Sataloff and Chevalier Neoadjuvant chemotherapy and concomitant trastuzumab in breast cancer: a pooled analysis of two randomized trials. Anticancer Drugs cations) were used, although they are not 2011; 22: 128–35.
commonly used in some other countries. Survival data 12 Wildiers H, Neven P, Christiaens MR, et al. Neoadjuvant are not available and longer follow-up is needed to fully capecitabine and docetaxel (plus trastuzumab): an eff ective non-anthracycline-based chemotherapy regimen for patients with assess the benefi t of this treatment regimen in the long locally advanced breast cancer. Ann Oncol 2011; 22: 588–94.
term. Nevertheless, our study showed that the combination 13 Buzdar AU, Valero V, Ibrahim NK, et al. Neoadjuvant therapy with paclitaxel followed by 5-fl uorouracil, epirubicin, and cacious and well tolerated in patients with previously cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast untreated primary infl ammatory breast cancer; follow-up cancer: an update of the initial randomized study population and is needed to assess long-term toxicity and eff ects on data of additional patients treated with the same regimen.
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survival. Phase 3 data are also needed to confi rm the long- 14 Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004; 25: 581–611.
Contributors
15 Gray R, Bhattacharya S, Bowden C, Miller K, Comis RL. Independent review of E2100: a phase III trial of bevacizumab plus J-YP, TD, MC, JG, HR, and PV recruited and managed patients in the paclitaxel versus paclitaxel in women with metastatic breast cancer. study and J-YP, MC, JG, FL, HR, and TB were involved in data collection. J Clin Oncol 2009; 27: 4966–72.
J-YP, TD, MP, SK, and PV participated in protocol development. J-YP, 16 Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab TD, J-MF, HR, EC-J, MP, SK, F-CB, and PV analysed and interpreted the plus docetaxel compared with placebo plus docetaxel for the data. J-YP, MP, SK, and PV prepared the fi rst draft of the manuscript. All fi rst-line treatment of human epidermal growth factor receptor authors were given the opportunity to comment on the draft manuscript 2-negative metastatic breast cancer. J Clin Oncol 2010; 28: 3239–47.
and saw and approved the fi nal version of the report. 17 Robert NJ, Diéras V, Glaspy J, et al. RIBBON-1: randomized, Confl icts of interest
double-blind, placebo-controlled, phase III trial of chemotherapy J-YP and JG have had consultant or advisory roles for and have received with or without bevacizumab for fi rst-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or honoraria and research funding from Roche. TP has had consultant or metastatic breast cancer. J Clin Oncol 2011; 29: 1252–60.
advisory roles for Roche and Novartis and has received honoraria from 18 Brufsky A, Bondarenko I, Smirnov V, et al. RIBBON-2: Roche. TB and PV have had consultant or advisory roles for and have a randomized, double-blind, placebo-controlled, phase III trial received research funding from Roche. MP and SK are employees of cacy and safety of bevacizumab in combination Roche. All other authors declared that they have no confl icts of interest.
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