Primary systemic chemotherapy for inflammatory breast cancer

Primary Systemic Chemotherapy forInflammatory Breast Cancer*Sarah Sinclair, DO1 and Sandra M. Swain, MD2

The advent of multimodality therapy for patients with inflammatory breast cancer (IBC), consisting of neoadjuvant

chemotherapy, particularly taxanes, surgery, radiotherapy, and hormonal therapy, has improved survival. A pathologic

complete response to neoadjuvant chemotherapy in locally advanced breast cancer and IBC improves outcomes,

which suggests that obtaining a pathologic complete response to neoadjuvant chemotherapy has prognostic signifi-

cance. The benefit of high-dose chemotherapy has shown encouraging results; however, this approach needs to be

prospectively evaluated and to date remains experimental. Vascular endothelial growth factor, a promoter of angio-

genesis, is highly expressed in IBC, making the angiogenesis pathway an attractive therapeutic target. A better

understanding of the complex biology of IBC is needed for the development of additional targeted agents to further

improve outcomes for patients with this aggressive form of breast cancer. Cancer 2010;116(11 suppl):2821–8. VC 2010

American Cancer Society.

KEYWORDS: inflammatory breast cancer, neoadjuvant chemotherapy, multimodality therapy, bevacizumab.

Inflammatory breast cancer (IBC) accounts for approximately 1% to 6% of all breast cancer cases in the UnitedStates.1 This rare and aggressive form of breast cancer is defined clinically by the rapid development of erythema andedema (peau d’orange) of at least 1=3 of the skin overlying the breast, often without a palpable mass.2 Lee and Tannenbaumwere the first to describe IBC in 1924 from a small series of patients at Memorial Hospital in New York.3 Plugging of thedermal lymphatics of the breast with tumor emboli is responsible for the clinical appearance of IBC; however, this is notmandatory for diagnosis.4 IBC is a clinical diagnosis associated with a poor prognosis. Many women present withadvanced disease at diagnosis. Certain biologic characteristics of IBC, as well as different genes, are associated with itsaggressiveness and poor outcome. In addition, IBC highly expresses vascular endothelial growth factor (VEGF) and basicfibroblast growth factor, both promoters of angiogenesis.5 This review will focus on systemic chemotherapy in the treat-ment of IBC.

Multimodality Therapy

The treatment of IBC has greatly improved with the development of multimodality therapy. Historically, surgery was thefirst treatment modality for IBC; when used alone, it was not successful in achieving local control or improving survival.Similarly, Kell and Morrow reported an average 5-year overall survival (OS) rate of 4% in 293 patients with IBC treatedwith mastectomy with or without radiation.6 The addition of chemotherapy followed sequentially by surgery and radia-tion resulted in an improvement in disease-free survival (DFS) and OS for patients with this aggressive form of breastcancer.

Currently, the standard approach to treatment of IBC per the National Comprehensive Cancer Network (NCCN)guidelines is neoadjuvant chemotherapy with an anthracycline-based regimen with or without a taxane.7 If human epider-mal growth receptor 2 (HER-2)/neu is overexpressed, trastuzumab as part of systemic chemotherapy is indicated, but notconcomitantly with anthracyclines because of increased cardiac toxicity. The nonanthracycline regimen docetaxel,

*Proceedings of the First International Inflammatory Breast Cancer Conference, Supplement to Cancer.

DOI: 10.1002/cncr.25166, Received: December 1, 2009; Accepted: January 14, 2010, Published online May 19, 2010 in Wiley InterScience (www.interscience.wiley.

com)

Corresponding author: Sandra M. Swain, MD, Medical Director, Washington Cancer Institute, Washington Hospital Center 110 Irving Street NW Washington, DC

20010; Fax: (202) 877-8113; [email protected]

1Department of Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; 2Washington Cancer Institute, Washington Hospital Center,

Washington, District of Columbia

The articles in this supplement were presented at the First International Inflammatory Breast Cancer Conference, Houston, Texas, December 5-7, 2008.

Cancer June 1, 2010 2821

Original Article

carboplatin, trastuzumab significantly improved DFS andOS compared with doxorubicin and cyclophosphamidefollowed by paclitaxel in early breast cancer. Less cardiactoxicity was also reported in the nonanthracycline arm(docetaxel, carboplatin, trastuzumab), compared with thedoxorubicin and cyclophosphamide followed by pacli-taxel and trastuzumab. Trastuzumab for a total of 1 year isrecommended. Also per NCCN guidelines, mastectomywith axillary lymph node dissection is recommended inIBC patients who respond to preoperative chemotherapy.After surgery, patients should have radiation therapy, andhormonal therapy if indicated.7

A retrospective analysis of 179 patients with nonme-tastatic IBC by Perez et al showed an improvement inboth 5- and 10-year DFS in patients treated with multi-modality therapy that included chemotherapy, surgery,and radiation compared with those treated without thisapproach.8 The combined modality approach yielded a 5-year DFS rate of 40%, as compared with 24% for thosetreated with radiation and surgery, and 6% for thosetreated with radiation alone or in combination withchemotherapy without surgery. The 10-year DFS rateswere 35%, 24%, and 0%, respectively.8

Neoadjuvant Chemotherapy: A Component ofMultimodality Treatment

Neoadjuvant chemotherapy, also referred to as primarychemotherapy or preoperative chemotherapy, has severalpotential benefits in the treatment of IBC. These benefitsinclude down-staging of the primary tumor, which couldincrease operability in some cases, and provide earliertreatment of systemic micrometastases. The University ofTexas M. D. Anderson Cancer Center has treated a largeseries of IBC patients with multimodality therapy. In1997, Ueno et al reported an update on the 20-year expe-rience of 178 patients with IBC treated on 4 different pro-

spective trials at The University of Texas M. D. AndersonCancer Center.9 Doxorubicin-based preoperative chemo-therapy, radiotherapy, or mastectomy followed by adju-vant chemotherapy was administered to all patients. Theoverall response rate was 71%. The 5-year and 10-year OSrates were 40% and 33%, respectively. An estimated 28%of patients were reported to be alive and free of disease at15 years. The response to preoperative chemotherapy wasthe most important prognostic marker, with the highestrates of DFS reported in those who achieved a completeresponse to preoperative chemotherapy (Table 1).9

A retrospective study by Harris et al evaluated thelong-term outcome of combined modality therapy in 54IBC patients. A clinical complete response after preopera-tive chemotherapy with cyclophosphamide, methotrexate,and 5-fluorouracil (CMF) or cyclophosphamide, doxoru-bicin, and 5-fluorouracil with or without preoperativeradiation was seen in 52% of patients. Mastectomy wasperformed in 50 patients after preoperative therapy(chemotherapy only, n ¼ 15; chemotherapy and radia-tion, n¼ 35). Pathologic complete response to combinedchemotherapy and radiation was seen in 13 (37%)patients. Two (12%) patients had a pathologic completeresponse to preoperative chemotherapy alone. Patientswho achieved a pathologic complete response had supe-rior 10-year survival rates compared with those in whomresidual disease was present in the breast or lymph nodes(46% vs 31%, respectively; P ¼ .09).10 A retrospectivestudy in 38 women with IBC treated with CMF � vin-cristine, prednisone (VP) or 5-flurouracil, doxorubicin,cyclophosphamide (FAC) compared response and sur-vival of these 2 regimens. The overall response rate to pre-operative CMF � VP and FAC was 57% and 100%,respectively. The median OS for those who receivedCMF � VP was 18 months, compared with 30 monthsfor FAC.11

Table 1. Primary Systemic Chemotherapy: Multimodality Therapy

Study No. of Patients Neoadjuvant Regimen ORR, % OS, %

Ueno 19979 178 FAC�VP 71 5-year: 40; 10-year: 35

Bauer 199511 38 CMF�VP 57

FAC 100

Harris 200310 54 CMF or CAF 52 5-year: 56

Low 200412 46 CAFM 57 10-year: 26.7; 15-year: 20

Veyret 200642 102 FEC-HD 91 10-year: 41.2

ORR indicates overall response rate; OS, overall survival; FAC, 5-fluorouracil, doxorubicin, and cyclophosphamide; VP,

vincristine and prednisone; CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; CAF, cyclophosphamide, doxorubi-

cin, and 5-fluorouracil; CAFM, cyclophosphamide, doxorubicin, 5-fluorouracil, and methotrexate; FEC-HD, high-dose 5-

fluorouracil, epirubicin, and cyclophosphamide.

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2822 Cancer June 1, 2010

A prospective study at the National Cancer Instituteenrolled 107 patients with stage III breast cancer, ofwhom 46 had IBC. Patients were treated to best responsewith cyclophosphamide, doxorubicin, 5-fluorouracil, andmethotrexate followed by hormonal therapy, as indicated.Median follow-up time was 16.8 years, and the overallresponse rate for the 46 IBC patients was 57%. Ten- and15-year OS rates of 26.7% and 20% were reported,respectively. Pathologic complete response was reportedin 31 (29%) of the 107 patients.12

Anthracyclines

Primary systemic chemotherapy is an essential com-ponent of the combined-modality treatment of IBC result-ing in improved survival outcomes. Anthracyclines havebeen widely used for the treatment of both inflammatoryand noninflammatory breast cancer. The Early BreastCancer Trialists’ collaborative group reported in a 15-yearupdate that 6 months of adjuvant anthracycline-basedchemotherapy regimen with either FAC or FEC (FAC orfluorouracil, doxorubicin, cyclophosphamide; FEC or flu-orouracil, epirubicin, cyclophosphamide) reduced the an-nual breast cancer death rate by 38% in women diagnosedat age <50 years and 20% in women who were diagnosedbetween the ages of 50 and 69 years.13

The University of Texas M. D. Anderson CancerCenter series enrolled 178 IBC patients prospectively on4 different trials. This series compared 4 anthracycline-containing regimens combined with locoregional therapythat included mastectomy and/or radiation.9,14-16 Therewere no significant differences in DFS or OS ratesbetween the 4 protocols. Median DFS for the entire groupwas 21 months, and the median OS was 40 months.Overall local control rate was 82%. Within this series, theoverall response rate, defined as complete response (CR)þ partial response (PR), was 72%, and the CR was12%.9,14-16 Addition of anthracyclines to primary sys-temic chemotherapy improved outcomes compared withnonanthracycline-containing regimens (Table 2).

Taxanes

The addition of taxanes to systemic chemotherapyhas also been investigated in IBC patients. A retrospectiveanalysis of 240 patients with IBC, treated on 6 consecu-tive trials from 1973 to 2000, was performed to determinethe significance of adding paclitaxel to an anthracycline-based regimen.17 One hundred seventy-eight patientswere treated with FAC alone, and 62 patients were treatedsequentially with FAC followed by paclitaxel. The objec-

tive response rates were similar in both groups: FAC(74%) and FAC þ paclitaxel (82%). The pathologic CRrate in the breast and axillary lymph nodes was signifi-cantly higher in those treated with paclitaxel comparedwith FAC alone: 25% versus 10%, respectively. The addi-tion of paclitaxel resulted in an improvement in medianOS and progression-free survival (PFS) as compared withFAC alone. This was statistically significant in thosepatients who had estrogen receptor-negative IBC. MedianOS was 54 months versus 32 months (P ¼ .03), respec-tively, and median PFS was 27 months versus 18 months(P ¼ .04), respectively.17 The superior outcomes com-pared with historical controls of IBC patients treated withanthracycline- and taxane-containing regimens haveestablished their use in the treatment of IBC.

Multimodality treatment of IBC is crucial to achieveimproved outcomes in this aggressive disease. A retrospec-tive analysis was performed on 485 patients with IBCdiagnosed in British Columbia between 1980 and 2000.The focus was to determine whether changes in chemo-therapy, radiation therapy, and mastectomy improvedlocoregional control or survival in women with IBC.18 Byusing 5 different chemotherapy regimens, 308 patientswere treated curatively and were the study participants.Two-hundred fifty-two patients were treated with eitherFAC, doxorubicin and cyclophosphamide (AC)/mitoxan-trone and fluorouracil, or AC. Fifty-six patients receivedeither cyclophosphamide, epirubicin, fluorouracil (CEF),doxorubicin and paclitaxel/cisplatin and paclitaxel, ordoxorubicin, cyclophosphamide, methotrexate, etopo-side, fluorouracil, and cisplatin (Quartet). A pathologic

Table 2. Anthracycline-Containing Regimens: The Universityof Texas M. D. Anderson Cancer Center Experience

MDACCSeries

No. ofPatients(N5178)

InductionRegimen

ORR, %

Koh 199014 40þ23 FAC 71

39 FACVP 72

Singletary 199415 63 FAC 70

43 FACVP 65

70 FACVP�MV 70

Buzdar 199516 63 FAC 71

43 FACVP 65

72 FACVP�MV 75

Ueno 19979 178 FAC 71

FACVP

FACVP�MV

MDACC indicates The University of Texas M. D. Anderson Cancer Center;

ORR, overall response rate; FAC, 5-fluorouracil, doxorubicin, and cyclo-

phosphamide; FACVP, FAC plus vincristine and prednisone; FACVP � MV,

FACVP � methotrexate and vinblastine.

Inflammatory Breast Cancer/Sinclair and Swain


CR was seen in 35% of patients treated with CEF, doxor-ubicin and paclitaxel/cisplatin and paclitaxel, Quartet-doxorubicin, cyclophosphamide, methotrexate, etopo-side, fluorouracil, and cisplatin. There was a significantlyimproved 10-year breast cancer-specific survival (BCSS)in patients treated with CEF, doxorubicin and paclitaxel/cisplatin and paclitaxel, and Quartet regimens comparedwith patients treated with AC/mitoxantrone and fluo-rouracil or FAC. Ten-year BCSS and local recurrence-freesurvival (LRFS) for CEF, doxorubicin and paclitaxel/cis-platin and paclitaxel, Quartet versus AC/mitoxantroneand fluorouracil or FAC chemotherapy was 43.7% versus23.6%, respectively (P ¼ .04) and 66.8% versus 48%,respectively (P ¼ .03). Local control was improved withmastectomy. The LRFS rate was 59% to 63% with mas-tectomy and 34%without mastectomy (P¼ .0001).18

Pathologic complete response

An improvement in 5-year OS and DFS was reportedby Kuerer et al in patients with locally advanced breast can-cer who achieved a pathologic complete response to neoad-juvant chemotherapy.19 Hennessy et al reported that of 61patients with IBC who had cytologically confirmed axillarylymph node (ALN) metastases and were treated withanthracycline- and taxane-based neoadjuvant chemotherapy,14 patients (23%) achieved an axillary lymph node patho-logic CR. Patients who had a pathologic CR in the axillarylymph nodes had superior OS and DFS rates of 82.5% and78.6%, compared with 37.1% and 25.4%, respectively, inthose with residual axillary disease.20 In addition, FAC þpaclitaxel resulted in significantly more patients achievingan ALN pathologic CR compared with those who receivedFAC alone (45% vs 16%, respectively P¼ .01).

A 2-arm randomized neoadjuvant phase 3 trial com-pared (arm 1) standard AC given every 3 weeks for 5cycles followed by weekly paclitaxel to (arm 2) metro-nomic therapy consisting of weekly doxorubicin and dailyoral cyclophosphamide followed by weekly paclitaxel ininflammatory and locally advanced breast cancer. A totalof 372 patients were randomized, of whom only 265 wereevaluable for outcome. The preliminary results showedthat the pathologic CR rate for IBC patients was 33% inarm 2 compared with 12% in arm 1 (P ¼ .033). Theauthors suggest that metronomic therapy was more effec-tive. However, conclusions cannot be drawn at this time,because of the preliminary nature of the results, whichexcluded 100 patients.21

In addition to the observation by Kuerer et al thatpathologic CR improved survival in locally advanced

breast cancer (LABC) patients who were treated with neo-adjuvant chemotherapy, several clinical trials thatexcluded IBC patients have also reported an improvedsurvival in patients who achieve a pathologic CR afterneoadjuvant chemotherapy. Pathologic complete responseis, therefore, often considered to be a surrogate markerfor improved long-term prognosis. Trials that haveincorporated small numbers of IBC patients havereported a similar survival advantage for patients whoachieved a pathologic CR; however, most of these studiesare retrospective. It is also important to mention that themethods for assessment of a pathologic CR have notbeen standardized throughout most trials. The impactthat neoadjuvant chemotherapy and pathologic CR inIBC have on survival is unclear at this time (Table 3).

High-dose chemotherapy

Dose-intense neoadjuvant chemotherapy was eval-uated by Somlo et al in a retrospective analysis of 120patients with IBC in an attempt to improve treatmentoutcome.22 Patients were treated with conventional-dosechemotherapy and surgery followed by single or tandemcycle dose-intense chemotherapy. At a median follow-upof 61 months, the 5-year relapse-free survival and OSwere 44% and 64%, respectively. Multivariate analysisshowed that ER/PR estrogen receptor/progesterone recep-tor positivity and <4 positive axillary lymph nodes werethe best predictors of which patients would benefit fromtandem dose-intense chemotherapy.

The PEGASE 02 trial was designed to evaluate theresponse and toxicity of high-dose sequential chemother-apy and peripheral blood stem cell support as primarychemotherapy in patients with nonmetastatic IBC.23

Ninety-five patients with nonmetastatic IBC were treatedwith high dose chemotherapy (FAC) followed by bloodstem cell transplant. Mastectomy and radiotherapy wereperformed after completion of primary chemotherapy.The estimated 3-year survival was 70% (95% confidenceinterval [CI], 60%-79%). The 3-year recurrence-free sur-vival was 44% (95%CI, 33%-54%).23

A prospective study of 177 women with high-riskprimary breast cancer, which included 18 women withIBC who were treated with high-dose primary chemother-apy, resulted in a 5-year OS rate of 36% and a 5-year DFSrate of 28%. The benefits were seen in women who wereyounger and had fewer lymph nodes involved.24 The ben-efit of high-dose chemotherapy in the treatment of IBChas shown encouraging survival outcomes. This approach,

Original Article


however, needs to be prospectively evaluated and remainsexperimental.

HER-2 targeted agents

Overexpression of HER-2 in invasive breast canceris associated with a high recurrence rate and reduced sur-vival.25 An increased incidence of HER-2 overexpressionhas been reported in IBC patients.26 NOAH, a phase 3neoadjuvant trial, was designed to compare the additionof trastuzumab with an anthracycline- and taxane-basedchemotherapy regimen to chemotherapy alone in patientswith HER-2–positive locally advanced breast cancer.Event-free survival at 3 years was significantly improvedin the trastuzumab plus chemotherapy arm comparedwith chemotherapy alone (70.1% vs 53.3%; hazard ratio,0.56; P¼ .007).27 Recently, preliminary results of a phase2 trial that evaluated the combination of lapatinib andpaclitaxel as neoadjuvant systemic chemotherapy in IBCpatients with HER-2 overexpression showed a 77%clinical response rate and a 17% pathologic CR rate.28

These results are consistent with those seen in non-IBC.HER-2–targeting agents will be discussed in detail in asubsequent review in this journal.

Biological Therapies and Angiogenesis

Angiogenesis is a multistep process necessary for tumorcell growth and metastasis. IBC highly expresses VEGFand basic fibroblast growth factor, both of which areangiogenic factors.5 The degree of intratumoral microves-sel density (MVD) is also believed to reflect the angio-

genic activity generated by the tumor cells and theirsupportive stroma. TumorMVD has been associated withincreased aggressiveness of breast cancer.29,30 IBC is ahighly vascular disease. Therefore, the relationshipbetween tumor MVD and IBC was investigated byMcCarthy et al.29 Microvessel density from 67 Tunisianbreast tumors with or without an inflammatory pheno-type were determined by immunostaining intratumoralmicrovessels. The median intratumoral microvessel countwas 25.5 in IBC and 6.5 in non-IBC tumors (P ¼ .009),which suggests that IBC tumors have a significantlyincreasedMVDwithin the tumor mass.29

VEGF, a potent promoter of angiogenesis, is re-sponsible for stimulation of endothelial cell migration,proliferation, and survival.31 Potential mechanisms ofanti-VEGF therapies include reduction of the number oftumor vessels and reduction of the number of circulatingendothelial and progenitor cells in the tumor, which mayreduce metastatic seeding.31-33 Bevacizumab is a recombi-nant humanized antibody that binds to VEGF. The East-ern Cooperative Oncology Group E2100 evaluated theuse of bevacizumab and paclitaxel as first-line therapy inpatients with metastatic breast cancer. The combinationshowed a significant improvement in PFS and overallresponse rate when compared with paclitaxel alone (11 vs6 months, respectively, P<.001; and 28% vs 14%,respectively).34

NCI-0173, a pilot study in 21 patients with previ-ously untreated IBC or locally advanced breast cancer,was conducted at the National Cancer Institute.35 One

Table 3. Nontrastuzumab Neoadjuvant Chemotherapy and Pathologic Complete Response Rates for Inflammatory Breast Cancer

Study No. of Patients Regimen pCR, % Criteria for pCR

Viens 199923 86 FAC-HD!G-CSFþSCT 32 No invasive tumor in breast

26 No invasive tumor in ALN

Vandebroek 200343 19 ED 21 No invasive tumor in breast and ALN

Ditsch 200644 42 E!T 21 Not specified

51 ET 12

Gonzalez-Angulo 200445 48 FAC or FAC!T 19 No invasive tumor in breast and ALN

Cristofanilli 200417 178 FAC 10 No invasive tumor in breast and ALN

62 FAC!T 25

Veyret 200642 102 FEC-HD 14.7 No invasive tumor in breast and ALN

Baldini 200446 68 CAF or CEF 3 No invasive tumor in breast and ALN

Hennessy 200620 50 FAC 16 No invasive tumor in ALN

11 FAC!T 45

Ellis 200621 132 AC!T(conventional) 12 No invasive tumor in breast

133 AC!T (metronomic) 32

pCR indicates pathologic complete response; FAC-HD, high-dose 5-fluorouracil, doxorubicin, and cyclophosphamide; G-CSF, granulocyte colony-stimulating

factor; SCT, stem cell transplantation; ALN, axillary lymph nodes; ED, epirubicin and docetaxel; E, epirubicin; T, paclitaxel; ET, epirubicinþpaclitaxel; FAC!T,

FAC plus paclitaxel; FEC-HD, high-dose fluorouracil, epirubicin, and cyclophosphamide; CAF, cyclophosphamide, doxorubicin, and 5-fluorouracil; CEF, cyclo-

phosphamide, epirubicin, and 5-fluorouracil; AC!T (conventional), doxorubicin at a dose of 60 mg/m2 and cyclophosphamide at a dose of 600 mg/m2 every 3

weeks for 5 cycles followed by weekly paclitaxel for 12 weeks; AC!T (metronomic), doxorubicin at a dose of 24 mg/m2 weekly � 15 and cyclophosphamide

at a dose of 60 mg/m2 /d orally � 15.



cycle of bevacizumab was administered followed by 6cycles of bevacizumab with doxorubicin and docetaxelgiven every 21 days. Eight additional cycles of bevacizu-mab were given after locoregional therapy with or withouthormonal therapy, as indicated. The objectives of thisstudy were to evaluate molecular changes in tumor ofVEGF, activated phosphorylated-VEGF receptor 2(VEGFR2), total VEGFR2, tumor MVD, tumor cell ap-optosis, and proliferation. Dynamic contrast-enhancedmagnetic resonance imaging was also used to assess vascu-lar permeability. Clinical PR (CPR) of in 67% (14patients), stable disease in 24% (5 patients), and progres-sive disease in 9% (2 patients) were seen based on imag-ing. One patient with a CPR had a complete pathologicresponse. The overall response rate was 67% (95% CI,43%-85.4%).35

The 67% overall response rate reported in the NCI-0173 trial with IBC and LABC patients treated with neo-adjuvant bevacizumab alone or with chemotherapy wasencouraging. There was a median decrease of 66.7% inphosphorylated VEGFR2 in tumor cells (P¼ .004) and amedian increase of 128.8% in tumor apoptosis (P ¼.0008) after 1 cycle of bevacizumab alone, which persistedwith chemotherapy.35 This suggests that blockade ofVEGF inhibits the activation of VEGFR2 and induces thetumor apoptosis. However, the molecular markers thatmay predict response to treatment were not well under-stood, and therefore were investigated further in thiscohort of patients.36 The purpose of this study was toidentify biomarkers and gene expression profile signaturesto distinguish patients who respond to treatment fromthose who do not. CD31, an endothelial cell adhesionmolecule, and PDGFR-b, a receptor of VEGF-A, both ofwhich are tumor angiogenic markers, were measured atbaseline before bevacizumab, after bevacizumab alone,and then followed by bevacizumab plus chemotherapy.CD31 and platelet-derived growth factor receptor(PDGFR)-b were shown to be significantly expressed inpatients who responded to treatment compared withthose who did not (median 33.5 vs 0.25, P ¼ .0004) and(median 5.9 vs 0.6, P¼ .01), respectively. Tumor VEGF-A, a known target of bevacizumab, was higher at baselineand showed a trend toward association with response toall treatment. Other biomarkers such as MVD, ki67, p53status, and apoptosis were not associated with response.Of the 1339 gene ontology classes, 26 were differentiallyexpressed between responders and nonresponders(P<.005). The gene ontology classes for VEGFR activityand mitosis were significantly associated with response to

bevacizumab followed by bevacizumab plus chemother-apy. Those with higher tumor gene expression of VEGF-A, CD31, and PDGFR-b were more likely to benefitfrom treatment with bevacizumab plus chemotherapy,which suggests that bevacizumab may be given as a tar-geted agent, although this will need to be confirmed in alarger cohort of patients.36

SU5416 (semaxanib), a small organic molecule thatinhibits VEGF-mediated signaling through the Flk-1/KDR (VEGFR2) tyrosine kinase receptor, was combinedwith doxorubicin in a phase 1B study in patients withstage IIIB or IV IBC.37 Eighteen patients were enrolled inthis study. Neutropenia was the dose-limiting toxicity,and overall median survival was not reached. Congestiveheart failure occurred in 4 (22%) patients, which prohib-its further investigation of SU5416 with doxorubicin.There was a significant decline in tumor blood flow and atrend toward a decline in tumor microvessel density aftertreatment. Multitargeted tyrosine kinase inhibitors andfarnesyl transferase inhibitors in combination with chem-otherapy are additional targeted agents currently beingtested in IBC.38,39

A randomized, multicenter, phase 3 study compar-ing the combination of pazopanib and lapatinib versuslapatinib monotherapy in patients with IBC who overex-press HER-2 is currently ongoing. There is also an open-label pazopanib arm designed to evaluate whether pazopa-nib given alone and lapatinib given alone would be safeand effective to treat patients with IBC. Pazopanib is anoral investigational angiogenesis inhibitor that selectivelyinhibits VEGFR, PDGFR, and c-kit, which are importantproteins involved in angiogenesis. Progression after priorchemotherapy and trastuzumab is an eligibility require-ment. The primary endpoint is PFS. Secondary endpointsinclude OS, overall response rate, safety, and tolerabil-ity.40 In addition, there are multiple clinical trials withcombination chemotherapy regimens for IBC that arecurrently ongoing (Table 4).41

Conclusions

The application of multimodality treatment has improvedsurvival for patients with IBC. It is clear that the additionof anthracyclines and taxanes to neoadjuvant chemother-apy regimens has improved both DFS and OS comparedwith historical controls. Cristofanilli et al showed in a ret-rospective analysis of IBC patients that the addition ofpaclitaxel to FAC improved median OS and PFS com-pared with FAC alone.17 Thus, the addition of taxanes toprimary systemic chemotherapy improves survival

Original Article


outcomes in IBC, and should be incorporated into thetreatment regimen. If HER-2/neu is over expressed, as perthe NCCN guidelines, the nonanthracycline regimendocetaxel, carboplatin, trastuzumab is indicated. Trastu-zumab for a total of 1 year is recommended. HER-2–tar-geting agents will be discussed in detail in a subsequentreview in this journal. The NCI-0173 trial has shown thatneoadjuvant bevacizumab in combination with an anthra-cycline/taxane chemotherapy regimen inhibited the acti-vation of VEGFR2 and induced tumor apoptosis. Theoptimal chemotherapeutic regimen, however, remains tobe defined, and further studies are needed to delineate theparticular molecular markers and genes associated withthis rare and aggressive form of breast cancer. Future trialsto evaluate targeted agents in combination with standardtherapies are necessary to further improve survival for IBCpatients.

CONFLICT OF INTEREST DISCLOSURESThis supplement was sponsored by the Houston affiliate ofSusan G. Komen for the Cure, the National Cancer Institute,and the State of Texas Rare and Aggressive Breast CancerResearch Program. The First International Inflammatory BreastCancer Conference was supported in part by GlaxoSmithKline,Pfizer, Eli Lilly and Company, and Cardinal Health. SanofiAventis has provided funds for travel. Research support was pro-vided by Bristol-Myers Squibb and Genentech.

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Table 4. Chemotherapy Agents in Clinical Evaluation for IBC and LABC

Agent NCTIdentification No.

Phase

Docetaxel, epirubicin, and pegfilgrastim 00066443 1/2

Doxorubicin, cyclophosphamide, paclitaxel, and filgrastim 00016406 3

Paclitaxel, cyclophosphamide, melphan, etoposideþPBSCT 00019162 1/2

High-dose busulfan, melphalan, thiotepaþPBSCTþIL-2 and GM-CSF 00003199 2

Gemcitabine, epirubicin, and paclitaxel 00193050 2

Cyclophosphamide, epirubicin, and capecitabine 00008034 1

Bevacizumab, docetaxel, and capecitabine 00576901 2

CMF vs HDCTþPBSCT 00003680 3

Gemcitabine, epirubicin, and ABI-007(neoadjuvant) 00193206 2

Sunitinibþpaclitaxel!doxorubicin þoral cyclophosphamide (neoadjuvant) 00513695 2

FEC!paclitaxelþbevacizumab (neoadjuvant) 00559845 2

IBC indicates inflammatory breast cancer; LABC, locally advanced breast cancer; NCT, National Clinical Trial; PBSCT, pe-

ripheral blood stem cell transplantation; IL-2, interleukin-2; GM-CSF, granulocyte-macrophage colony-stimulating factor;

CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; HDCT, high-dose chemotherapy; ABI-007, albumin-bound

paclitaxel; FEC, 5-fluorouracil, epirubicin, and cyclophosphamide.



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Primary systemic chemotherapy for inflammatory breast cancer

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