MCO Molecular and Clinical Oncology 2049-9450 2049-9469 D.A. Spandidos 10.3892/mco.2015.668 MCO-0-0-668 Articles Examination of the clinical efficacy of eribulin and trastuzumab in HER2-positive recurrent breast cancer KIBATAKAYOSHI 1 MORIINAO 2 3 TAKAHASHIHIROTOSHI 2 OZAKISHINJI 2 ATSUMIMISAO 4 MASUMOTOFUMI 4 SHITAKUBOYOSHIMI 1 YAMASHIROHIROYASU 2 3 Division of Modern Medical Technology, Institute for Clinical Research, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima 737-0023, Japan Department of Breast Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima 737-0023, Japan Department of Breast Surgery, Tenri Hospital, Tenri, Nara 632-8552, Japan Clinical Trial Management Office, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima 737-0023, Japan Correspondence to: Dr Takayoshi Kiba, Division of Modern Medical Technology, Institute for Clinical Research, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, 3-1 Aoyama-cho, Kure, Hiroshima 737-0023, Japan, E-mail: takkiba@hotmail.com 01 2016 05 11 2015 4 1 47 50 05052015 26102015 Copyright © 2015, Spandidos Publications 2015

There are limited studies reported that describe the efficacy of eribulin and trastuzumab in the treatment of recurrent breast cancer. The present study examined the therapeutic efficacy of eribulin and trastuzumab in the treatment of recurrent breast cancer. Between October 2011 and August 2013, 5 recurrent breast cancer patients who were treated with eribulin and trastuzumab were included in the study. The cancer stages in the 5 women who received this regimen were stage IIIB in 1 (20%) and stage IV in 4 (80%). The sites of recurrence were the lung in 3 patients, liver in 2, bone in 1, brain in 1, supraclavicular lymph nodes in 1, infraclavicular lymph nodes in 1 and mediastinal lymph nodes in 1. The median number of prior treatment regimens was 5 (range, 5–11). Complete response was achieved in 0 patients, 1 achieved partial response, 3 had stable disease, and 1 had progressive disease. The overall response rate was 20%, and the clinical benefit rate was 80%. Patients also reported grade 3/4 neutropenia (80.0%). However, hematological toxicity was reversible and manageable. The most common grade 3/4 nonhematological toxicities were fatigue (20.0%), peripheral neuropathy (20.0%) and appetite loss (20.0%). No patients withdrew from treatment, and favorable compliance was achieved in the study. The results indicated that eribulin and trastuzumab have the potential to be one of the drugs for treatment of recurrent breast cancer.

 eribulin trastuzumab breast cancer Introduction

Estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-positive disease with metastatic breast cancer remain incurable (1–3). For metastatic breast cancer, anthracycline- and/or taxane-based chemotherapy is used as standard treatment (4); however, the outcome remains a common issue. Therefore, new treatments are required. The patients with overexpression of HER2 may benefit from trastuzumab, and these may perform more efficiently with chemotherapy regimens that contain anthracycline drugs. HER2 overexpression comprises 15–25% of all breast cancers (5). By contrast, vinca alkaloids, gemcitabine, capecitabine, liposomal anthracyclines and nanoparticle albumin-bound paclitaxel were approved as third-line or later treatment of metastatic breast cancer (6).

Eribulin maculate (E7389) is an analog of the natural marine product, halichondrin B, a nontaxane microtubule dynamics inhibitor extracted from the marine sponge Halichondria okadai, which inhibits microtubule structures via a novel mechanism of action (7). The drug induces an irreversible mitotic block, which leads to cell cycle arrest in the G2/M phase and apoptosis (8). It is distinguished mechanistically from other antimicrotubule agents, such as paclitaxel, ixabepilone and vinblastine (9). Additionally, the drug has potent antiproliferative effects against several different types of human cancer cell lines, including breast, prostate, melanoma and colorectal cancer (10,11), and has evolved activity against paclitaxel-resistant cell lines, including those with mutations in β-tubulin (12). It has also provided a manageable tolerability profile in phase I–II clinical trials and an improvement in overall survival compared with the treatment decided by the physician in a phase III trial (13).

In the present study, eribulin and trastuzumab were administered to 5 patients with recurrent breast cancer between October 2011 and August 2013. The study investigated eribulin and trastuzumab and reports the results obtained.

 Patients and methods <sec> <title>Ethics statement

Only the demographic data of patients were stored in the database in the National Hospital Organization Kure Medical Center and Chugoku Cancer Center (Kure, Japan) to enable the retrieval of files manually based on patient codes. All the data were anonymously analysed without individual patient consent due to the retrospective nature of the study. The Review Board Ethics Committee waived the requirement for individual informed consent and approved the study (Approval Number 26–27, date 8/14/14).

 Patients

Between October 2011 and August 2013, 5 patients with recurrent breast cancer were included in the study. All the patients received neoadjuvant or adjuvant taxane or antracycline chemotherapy following breast surgery. The mean age of the patients at the time of the eribulin and trastuzumab regimen administration was 70 years (range, 53–76 years) (Table I). The interval between tumor resection and local recurrence varied widely from 1.6 to 31.5 months. The histological type of the primary cancer was invasive ductal carcinoma in 5 patients. Pathological lymph node metastases at the time of surgery were classified as n1 in 2 patients, n2 in 1 and n3 in 2. Hormone sensitivity was identified as positive in 2 cases [1 case of ER+/progesterone receptor (PgR)+ and 1 case of ER−/PgR+] and negative in 3. Tamoxifen or aromatase inhibitors were postoperatively administered to all 5 patients.

The status of pre-treatment ER and PgR was assessed by immunohistochemistry (IHC), and HER2 status was assessed by either fluorescent in situ hybridization or a validated IHC method, as previously described (14–16). Patients with HER2-receptor overexpression at the 3+ level (PATHWAY® HER2, clone 4B5; Ventana Medical Systems Inc., Tucson, AZ, USA) were immediately eligible for inclusion. When immunostaining was observed in >1% of tumor nuclei, the tumor was considered positive for the ER or PgR (16). Breast cancers were classified into five subtypes, as previously described (16).

The cancer stages in the 5 women who received this regimen were stage IIIB in 1 (20%) and stage IV in 4 (80%). The sites of recurrence were the lung in 3 patients, liver in 2, bone in 1, brain in 1, supraclavicular lymph nodes in 1, infraclavicular lymph nodes in 1 and mediastinal lymph nodes in 1. The median number of prior treatment regimens was 5 (range, 5–11).

Eribulin mesylate and trastuzumab were administered as previously described (15,17). Concomitant medication that did not interfere with the evaluation of eribulin could be administered, including antiemetics, antidiarrheal therapy, corticosteroids and antihistamines. Granulocyte colony-stimulating factor was allowed according to the American Society of Clinical Oncology guidelines and standard practice, including prophylactic use of growth factors (18).

Patients treated with bisphosphonates or denosumab at study entry could continue treatment. Other antitumor therapies were not allowed. This treatment cycle was repeated as long as the therapeutic effects were observed. The efficacy of eribulin and trastuzumab was assessed from the 2nd or 3rd cycle following administration according to the Response Evaluation Criteria in Solid Tumors guidelines (19).

 Statistical analysis

Pearson χ2 tests were used to assess differences in overall response rates by group. All statistical analyses were performed using SPSS software, version 19.0 (IBM Corp., Tokyo, Japan). P=0.05 was considered to indicate a statistically significant difference.

 Results <sec> <title>Patient variables

Among the 5 patients, 0 achieved complete response, 1 achieved partial response, 3 had stable disease, and 1 had progressive disease. The overall response rate was 20%, and the clinical benefit rate was 80%. The mean duration of eribulin and trastuzumab administration was 9 cycles (4–11). The status of hormone sensitivity did not affect the overall response rate (P=0.33, χ2).

 Toxicities

All 5 patients were evaluated for toxicity using the Common Terminology Criteria for Adverse Events version 4.0 (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). Hematological toxicity was reversible and manageable. Patients reported grade 3/4 neutropenia (80.0%) (Table II). Although grade 4 neutropenia occurred, the patients were treated with granulocyte colony-stimulating factors. The most common grade 3/4 nonhematological toxicities were fatigue (20.0%), peripheral neuropathy (20.0%) and appetite loss (20.0%). There were no treatment-related fatalities. As these toxicities were mild, eribulin and trastuzumab dose omission was rare, and the study achieved favorable compliance.

 Discussion

The present study examined the efficacy of eribulin and trastuzumab in recurrent breast cancer. In a multicenter, phase II, single-arm study, 52 patients with recurrent or metastatic HER2-positive breast cancer received first-line eribulin with trastuzumab. The overall response rate was 71.2% with a median time to first response of 1.3 months; duration of response and progression free survival was 11.1 and 11.6 months, respectively (20). In the present study, the overall response rate was 20%, and the clinical benefit rate was 80%.

The toxicity profile was generally acceptable (Table II). The major toxicity was myelosuppression (the incidence of grade 3/4 toxicity was 80% for neutropenia), fatigue (the incidence of grade 3 was 20%), peripheral neuropathy (the incidence of grade 3 was 20%), and appetite loss (the incidence of grade 3 was 20%). Although grade 4 neutropenia occurred, the patients were treated with granulocyte colony-stimulating factors. Treatment-related fatalities were not observed. Consistent with this, the trial was reported by Wilks et al (20), who treated 52 patients with locally recurrent or metastatic HER2-positive breast cancer with eribulin and trastuzumab. The most common grade 3/4 treatment-emergent adverse events were neutropenia in 20 (38.5%) patients, peripheral neuropathy in 14 (26.9%; all grade 3), fatigue in 4 (7.7%) and febrile neutropenia in 4 (7.7%). Grade 3 adverse events included thrombocytopenia (in 28% of patients), fatigue (in 12%), peripheral neuropathy (in 12%) and neutropenia (in 11%), whereas grade 4 events (thrombocytopenia, neutropenia, vomiting, diarrhea and weakness) occurred in 14% of patients; otherwise, no severe adverse events occurred. The activity of eribulin with trastuzumab appears comparable with that of other combinations currently recommended for metastatic HER2-positive breast cancer (13). Although incidence rates vary, peripheral neuropathy is a common adverse event in patients treated with microtubule-targeted agents occurring in <30% of patients (21). Peripheral neuropathy grade 3/4 also occurs frequently in patients treated with eribulin. In the phase 3 EMBRACE trial, 35% of eribulin-treated patients had neuropathy, however, <9% had grade 3/4 neuropathy (13). Wilks et al (20) recently reported that 36 (69.2%) patients experienced neuropathy, and 14 (26.9%) experienced grade 3 neuropathy; no grade 4 neuropathy was observed. This higher rate of grade 3 neuropathy was likely due to the prolonged duration of eribulin treatment in this first-line setting.

In conclusion, recent clinical studies and the present study demonstrate that due to the high clinical benefit rate and acceptable safety profile, a combination of eribulin/trastuzumab is an acceptable treatment option for metastatic HER2-positive breast cancer. This may be a reflection of inadequate sample size. The present study is a retrospective study, and therefore, these results should be confirmed in further prospective studies.

 Acknowledgements

The authors would like to thank Mrs. Kanako Tanaka for her excellent research assistance.

 Abbreviations ER

estrogen receptor

 HER2

human epidermal growth factor receptor 2

 References UenoMKibaTNishimuraTKitanoTYanagiharaKYoshikawaKIshiguroHTeramukaiSFukushimaMKatoHInamotoTChanges in survival during the past two decades for breast cancer at the Kyoto university hospitalEur J Surg Oncol33696699200710.1016/j.ejso.2007.01.02917376645 PetrelliFCabidduMCazzanigaMECremonesiMBarniSTargeted therapies for the treatment of breast cancer in the posttrastuzumab eraOncologist13373381200810.1634/theoncologist.2007-017318448551 BeslijaSBonneterreJBursteinHCocquytVGnantMGoodwinPHeinemannVJassemJKöstlerWJKrainerMSecond consensus on medical treatment of metastatic breast cancerAnn Oncol18215225200710.1093/annonc/mdl15516831851 UenoNTBuzdarAUSingletarySEAmesFCMcNeeseMDHolmesFATheriaultRLStromEAWasaffBJAsmarLCombined-modality treatment of inflammatory breast carcinoma: Twenty years of experience at M. D. Anderson cancer centerCancer Chemother Pharmacol40321329199710.1007/s0028000506649225950 RévillionFBonneterreJPeyratJPERBB2 oncogene in human breast cancer and its clinical significanceEur J Cancer34791808199810.1016/S0959-8049(97)10157-59797688 Muñoz-CouseloEPérez-GarcíaJCortésJEribulin mesylate as a microtubule inhibitor for treatment of patients with metastatic breast cancerOnco Targets Ther4185192201122162924 JimenoAEribulin: Rediscovering tubulin as an anticancer targetClin Cancer Res1539033905200910.1158/1078-0432.CCR-09-102319509144 SmithJAWilsonLAzarenkoOZhuXLewisBMLittlefieldBAJordanMAEribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instabilityBiochemistry4913311337201010.1021/bi901810u20030375 HuyckTKGradisharWManuguidFKirkpatrickPEribulin mesylateNat Rev Drug Discov10173174201110.1038/nrd338921358731 HamelENatural products which interact with tubulin in the vinca domain: Maytansine, rhizoxin, phomopsin A, dolastatins 10 and 15 and halichondrin BPharmacol Ther553151199210.1016/0163-7258(92)90028-X1287674 TowleMJSalvatoKABudrowJWelsBFKuznetsovGAalfsKKWelshSZhengWSeletskyBMPalmeMHIn vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin BCancer Res6110131021200111221827 NewmanSEribulin, a simplified ketone analog of the tubulin inhibitor halichondrin B, for the potential treatment of cancerCurr Opin Investig Drugs810571066200718058576 CortesJO'ShaughnessyJLoeschDBlumJLVahdatLTPetrakovaKCholletPManikasADiérasVDelozierTEribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): A phase 3 open-label randomized studyLancet377914923201110.1016/S0140-6736(11)60070-621376385 García-MartínezEGilGLBenitoACGonzález-BillalabeitiaEConesaMAGarcíaGarcía TGarcía-GarreEVicenteVde la PeñaAyala FTumor-infiltrating immune cell profiles and their change after neoadjuvant chemotherapy predict response and prognosis of breast cancerBreast Cancer Res16488201410.1186/s13058-014-0488-525432519 IshidaTKibaTTakedaMMatsuyamaKTeramukaiSIshiwataRMasudaNTakatsukaYNoguchiSIshiokaCPhase II study of capecitabine and trastuzumab combination chemotherapy in patients with HER2 overexpressing metastatic breast cancers resistant to both anthracyclines and taxanesCancer Chemother Pharmacol64361369200910.1007/s00280-008-0882-819082596 KibaTMoriiNTakahashiHOzakiSAtsumiMMasumotoFYamashiroHPathological response rate in hormone-positive breast cancer patients treated with neoadjuvant FEC and triweekly docetaxel: A case seriesBreast Cancer (Dove Med Press)7245250201526357489 McIntyreKO'ShaughnessyJSchwartzbergLGlückSBerrakESongJXCoxDVahdatLTPhase 2 study of eribulin mesylate as first-line therapy for locally recurrent or metastatic human epidermal growth factor receptor 2-negative breast cancerBreast Cancer Res Treat146321328201410.1007/s10549-014-2923-924699910 SmithTJKhatcheressianJLymanGHOzerHArmitageJOBalducciLBennettCLCantorSBCrawfordJCrossSJ2006 update of recommendations for the use of white blood cell growth factors: An evidence-based clinical practice guidelineJ Clin Oncol2431873205200610.1200/JCO.2006.06.445116682719 TherassePArbuckSGEisenhauerEAWandersJKaplanRSRubinsteinLVerweijJVan GlabbekeMvan OosteromATChristianMCGwytherSGNew guidelines to evaluate the response to treatment in solid tumors. European organization for research and treatment of cancer, national cancer institute of the united states, national cancer institute of CanadaJ Natl Cancer Inst92205216200010.1093/jnci/92.3.20510655437 WilksSPuhallaSO'ShaughnessyJSchwartzbergLBerrakESongJCoxDVahdatLPhase 2, multicenter, single-arm study of eribulin mesylate with trastuzumab as first-Line therapy for locally recurrent or metastatic HER2-positive breast cancerClin Breast Cancer14405412201410.1016/j.clbc.2014.04.00425024001 LeeJJSwainSMPeripheral neuropathy induced by microtubule-stabilizing agentsJ Clin Oncol2416331642200610.1200/JCO.2005.04.054316575015

Patient characteristics (n=5).

Characteristics Patients
Age, median years (range) 70 (53–76)
Gender, n
  Male 0
  Female 5
Eastern Cooperative Oncology Group performance status, n (%)
  0     5 (100)
  ≥1 0 (0)
Pathological lymph node metastases at the time of surgery, n (%)
  n1   2 (40)
  n2   1 (20)
  n3   2 (40)
Hormone sensitivity, n (%)
  ER+/PgR+   1 (20)
  ER+/PgR− 0 (0)
  ER−/PgR+   1 (20)
  ER−/PgR−   3 (60)
American Joint Committee on Cancer stage, n (%)
  IIIA 0 (0)
  IIIB   1 (20)
  IV   4 (80)
Metastases, n (%)
  Lung   3 (60)
  Liver   2 (40)
  Bone   1 (20)
  Brain   1 (20)
  Supraclavicular lymph nodes   1 (20)
  Infraclavicular lymph nodes   1 (20)
  Mediastinal lymph nodes   1 (20)
Organs receiving treatment, n (%)
  1   3 (60)
  2 0 (0)
  3   1 (20)
  4   1 (20)
Treatment regimens prior to progression, median (range) 5 (5–11)
Type of prior treatment regimen, n (%)
  Docetaxel/trastuzumab   4 (80)
  Navelbine/trastuzumab   4 (80)
  Capecitabine/trastuzumab   4 (80)
  Trastuzumab alone   3 (60)
  Paclitaxel/trastuzumab   2 (40)
  Lapatinib/capecitabine   2 (40)
  S1/trastuzumab   2 (40)
  S1/lapatinib/capecitabine   2 (40)
  Cyclophosphamide/lapatinib/capecitabine   2 (40)
  Cyclophosphamide/capecitabine/trastuzumab   2 (40)
  Toremifene/trastuzumab   2 (40)
  S1/cyclophosphamide/trastuzumab   1 (20)
  Gemcitabine/trastuzumab   1 (20)
  Navelbine/gemcitabine/trastuzumab   1 (20)
  Cyclophosphamide/trastuzumab   1 (20)
  Anastrozole/trastuzumab   1 (20)

All adverse events (n=5).

Grades, n (%)
Adverse event 1 2 3 4
Anemia   1 (20)   2 (40) 0 (0) 0 (0)
Neutropenia 0 (0) 0 (0)   2 (40)   2 (40)
Nausea   3 (60) 0 (0) 0 (0) 0 (0)
Fatigue   2 (40)   1 (20)   1 (20) 0 (0)
Peripheral neuropathy   1 (20)   1 (20)   1 (20) 0 (0)
Gait disturbance 0 (0)   1 (20) 0 (0) 0 (0)
Appetite loss   2 (40) 0 (0)   1 (20) 0 (0)
Stomatitis   1 (20)   1 (20) 0 (0) 0 (0)
Diarrhea   2 (40) 0 (0) 0 (0) 0 (0)
Constipation   2 (40) 0 (0) 0 (0) 0 (0)