Research ArticleClinical Studies

Neoadjuvant Chemotherapy With Nab-paclitaxel Plus Trastuzumab Followed by 5-Fluorouracil/Epirubicin/Cyclophosphamide for HER2-positive Operable Breast Cancer: A Multicenter Phase II Trial

SHINYA TOKUNAGA, TSUTOMU TAKASHIMA, SHINICHIRO KASHIWAGI, SATORU NODA, HIDEMI KAWAJIRI, MAO TOKUMOTO, SHIGEHIKO NISHIMURA, TAKEO NISHIMORI, KATSUMI IKEDA, YOSHINARI OGAWA, YOKO MIZUYAMA, TAKESHI SUNAMI, KENJI TEZUKA, SHIGEHITO YAMAGATA, TETSURO ISHIKAWA, SHINZOH KUDOH, MINORU TAKADA, KOSEI HIRAKAWA and MASAICHI OHIRA
Anticancer Research April 2019, 39 (4) 2053-2059; DOI: https://doi.org/10.21873/anticanres.13316

Abstract

Aim: This study was conducted in order to evaluate the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus trastuzumab followed by 5-fluorouracil/ epirubicin/cyclophosphamide (FEC) in a neoadjuvant chemotherapy (NAC) setting for patients with human epidermal growth factor receptor 2 (HER2)-positive operable breast cancer. Patients and Methods: Each patient received four cycles of 260 mg/m2 nab-paclitaxel with 6 mg/kg trastuzumab (8 mg/kg as the loading dose) every 3 weeks (q3w) followed by four cycles of FEC (500/100/500 mg/m2) q3w. The primary endpoint was pathological complete response (pCR) rate. Results: Twenty-nine patients were analyzed for the efficacy and safety of this treatment. All patients completed four cycles of nab-paclitaxel and trastuzumab, and 28 patients completed four cycles of FEC. Twenty-seven patients subsequently underwent surgery. The pCR rate was 74.0%. The most frequent toxicity was sensory neuropathy (96.6%), but grade 3 neuropathy rate was 3.4%. Conclusion: Nab-paclitaxel plus trastuzumab followed by FEC in patients with HER2-positive operable breast cancer is considerably effective and well tolerated.

Neoadjuvant chemotherapy (NAC) is appropriate for many patients with locally advanced breast cancer (BC) and early BC, with the purpose not only of curative resection or breast-conserving surgery (BCS), but also of evaluating the sensitivity of chemotherapy in vivo (1, 2). Long-term prognosis of patients who achieve pathological complete response (pCR) after NAC is favorable (3). Therefore, pCR has been deemed a useful surrogate marker of prognosis.

Persistent activation of signaling pathways as a result of amplification of human epidermal growth factor receptor 2 (HER2) leads to a biologically aggressive malignancy with high sensitivity to cytotoxic chemotherapy. In a meta-analysis of 36 trials enrolling 5,768 patients with HER2-positive breast cancer receiving NAC, those who achieved a pCR had a superior event-free survival (EFS) and overall survival (OS) compared with those who did not (4). Many NAC regimens for HER2-positive breast cancer have been investigated; the principle strategy at present is concurrent use of anthracycline and taxane plus trastuzumab (5).

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a human albumin-bound formulation of paclitaxel nanoparticles of 130 nm in size. It is a novel formulation of taxane developed to avoid adverse effects, such as peripheral neuropathy and allergy caused by cremophor, and the requirement for steroid premedication (6). Nab-paclitaxel is an option for patients who have had a hypersensitivity reaction to paclitaxel or have a contraindication to the steroids, such as poorly controlled diabetes mellitus. The nanoparticle technology of nab-paclitaxel increased the intratumoral concentration of paclitaxel without an associated increase in toxicity compared to cremophor-based paclitaxel (7). In a phase III trial for patients with metastatic BC, 260 mg/m2 nab-paclitaxel every 3 weeks (q3w) significantly improved the overall response rate (ORR) and the time to progression compared with 175 mg/m2 paclitaxel q3w (8). The GBG GeparSepto trial compared 80 mg/m2 paclitaxel weekly with weekly regimen of 150 mg/m2 nab-paclitaxel followed by epirubicin with cyclophosphamide as NAC for patients with locally advanced BC; patients with HER2-positive breast cancer received trastuzmab and pertuzumab (9). Among patients with HER2-positive breast cancer, those treated with nab-paclitaxel tended to achieve a higher pCR rate compared to patients treated with paclitaxel. On the other hand, toxic effects and treatment discontinuations were more frequent with nab-paclitaxel than paclitaxel.

On the basis of these reports, we conducted a multicenter phase II trial evaluating nab-paclitaxel plus trastuzumab q3w for four cycles followed by 5-fluorouracil with epirubicin with cyclophosphamide (FEC) q3w for four cycles in patients with HER2-positive operable breast cancer.

Patients and Methods

Patients. This study was a single-arm, phase II trial. The patients were recruited from eight institutions. We enrolled women aged 20-75 years with histologically confirmed HER2-positive operable BC (T1c-3N0-2M0; stage I-IIIA); Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1; maintained adequate organ functions; white blood cell count of at least 4,000/mm3; neutrophil count of at least 2,000/mm3; platelet count of at least 1×105/mm3; hemoglobin of at least 9 g/dl; aspartate transaminase, alanine transaminase of 2.5 times the upper limit of normal or less; bilirubin of 1.5 mg/dl or less; creatinine of 1.5 mg/dl or less; and normal left ventricular ejection fraction (LVEF) of 55% or more. All tumors were tested for estrogen receptor (ER) and HER2 by immunohistochemistry (IHC) at each institutional laboratory. We considered ER-positive when the labeling index of tumor cells was 1% or more. HER2 positivity was defined as 3+ staining intensity using IHC or HER2 gene amplification by fluorescent in situ hybridization ratio of more than 2.0. Patients who had bilateral BC or active other malignancy; who had a history of any anticancer therapy; with active infection or serious concomitant diseases such as heart failure, diabetes, liver failure, uncontrollable peripheral neuropathy, or severe drug allergy; or who were pregnant or lactating were ineligible.

Treatment. Each patient received four cycles of 260 mg/m2 nab-paclitaxel with 6 mg/kg (8 mg/kg as the initial dose) trastuzumab q3w and then four cycles of 500 mg/m2 5-fluorouracil, 100 mg/m2 epirubicin and 500 mg/m2 cyclophosphamide q3w. Toxicities were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (10). Prophylactic use of granulocyte colony-stimulating factor administration was not allowed. Treatments could not be delayed more than 3 weeks. If adverse events did not improve within this period, the protocol treatment was discontinued. A dose reduction was allowed in the case of febrile neutropenia, grade 3 to 4 thrombocytopenia, or grade 3 to 4 non-hematological toxicities (except for nausea/vomiting and fatigue). The steps of dose reduction were as follows: nab-paclitaxel from 260 to 220 mg/m2 then 180 mg/m2, and epirubicin from 100 mg/m2 to 75 mg/m2 then 60 mg/m2. No dose reduction of trastuzumab, 5-fluorouracil or cyclophosphamide was permitted. Trastuzumab could be continued even if nab-paclitaxel was delayed.

The patients underwent surgery 4 to 9 weeks after NAC completion. Whole breast irradiation was required for BCS, and regional nodal irradiation was recommended for the patients with lymph node metastases. Furthermore, a total of 1 year of trastuzumab was administered after surgery. Five years of adjuvant endocrine therapy was added for all patients with ER-positive disease.

Study end-points. The primary endpoint was the pCR rate. In this study, pCR was defined as no evidence of residual invasive cancer in the breast and axillary lymph nodes (ypT0/Tis and ypN0). All obtained specimens were examined microscopically at each local institution. The secondary endpoints were the objective response rate, rate of BCS, and safety.

Assessment. The clinical tumor responses were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (11) using computed tomography or magnetic resonance imaging. All patients who received at least one cycle of each regimen were evaluated for safety at each visit. Laboratory and non-laboratory toxicities were evaluated based on CTCAE version 4.0.

Statistical analysis. A 45% threshold for pCR was set based on the results of the previous clinical trials of NAC with trastuzumab for HER2-positive disease. On the other hand, phase II National Surgical Adjuvant Breast and Bowel Project (NSABP) FB-AX-003 trial that evaluated weekly nab-paclitaxel plus trastuzumab, followed by FEC plus trastuzumab for locally advanced BC showed a 58% pCR rate (12). In order to detect improvement in the pCR rate, 28 patients were required according to the binominal distribution, with 45% of threshold pCR rate and 65% of expected pCR rate, under an α error of 10% and β error of 20%. Consequently, we aimed to recruit a total of 30 participants.

The protocol was reviewed and approved by each local Institutional Review Board of all participating institutions. This trial was registered on the University Hospital Medical Information Network, Japan (UMIN000008465).

Figure 1.
Figure 1.

CONSORT diagram.

All procedures of this study were conducted in accordance with the Japanese Guideline for Clinical Research of the Ministry of Health, Labor and Welfare, the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All patients provided written informed consent for participation.

Results

Patient population. Between September 2012 and April 2017, 30 eligible patients with operable BC from eight institutions were enrolled in this trial. One patient withdrew from this trial after receiving the first cycle of treatment and was lost to follow-up without evaluation for efficacy. Thus, we analyzed 29 patients for the efficacy and safety of this treatment (Figure 1). The baseline patient characteristics are summarized in Table I. The median age of patients was 52 years (range=33-66 years). All patients were pathologically diagnosed as having invasive ductal carcinoma through core needle biopsy. There were six patients (20.7%) with stage I disease, nine (31.0%) with stage IIA disease, 11 (37.9%) with stage IIB disease, and three (10.3%) with stage IIIA disease. ER positivity was observed in 14 patients (48.3%).

Treatment administration and trial completion. Overall, 28 patients (96.6%) completed eight cycles of protocol treatment. All patients completed four cycles of nab-paclitaxel and trastuzumab (Figure 1). Only one patient (3.4%) needed a schedule delay more than 1 week for nab-paclitaxel due to neutropenia. Twenty-eight patients (96.6%) completed four cycles of FEC. One patient discontinued FEC after the first cycle because of interstitial pneumonitis caused by nab-paclitaxel or trastuzumab. Dose reductions and delays in the schedule of more than 1 week for FEC were required in one (3.4%) and five (17.2%) out of 29 patients, respectively. The mean relative dose intensity was 99.6% for nab-paclitaxel and 96.0% for epirubicin.

Clinical and pathological assessments. Overall, 27 patients (93.1%) underwent definitive curative surgery for primary BC, excluding two patients who refused surgery (Figure 1). BCS was performed for 19 (65.5%) out of 29 patients.

Twenty out of 27 patients [74.0%; 95% confidence intervaI (CI)=57.5-90.6%] achieved pCR (ypT0/is, ypN0). Of these, 11 patients (40.7%) did not have even noninvasive tumor cells in the dissected breasts and lymph nodes (ypT0, ypN0). Eight (57.1%) out of 14 patients with ER-positive disease and 12 (92.3%) out of 13 patients with ER-negative disease achieved pCR (Table II).

The clinical response after nab-paclitaxel plus trastuzumab was observed in 28 (96.5%) out of 29 patients, including clinical CR in seven patients (24.1%) and clinical partial response in 21 patients (72.4%). Clinical response after FEC was observed in 29 (100%) out of 29 patients, including clinical CR in 19 (65.5%) and clinical partial response in 10 (34.5%).

Safety profile. The incidence of treatment-related adverse events (all grade and grade 3/4) are listed in Table III. During therapy with nab-paclitaxel plus trastuzumab, frequent toxicities were peripheral sensory neuropathy (96.6%), myalgia (65.5%), arthralgia (41.4%), alanine aminotransferase increased (55.2%), and aspartate aminotransferase increased (48.3%). Grade 3 or more toxicity included alanine aminotransferase elevation (10.3%). One patient experienced grade 2 interstitial pneumonitis caused by nab-paclitaxel or trastuzumab (3.4%) and discontinued protocol treatment. During FEC, frequent toxicities were nausea (79.3%), leucopenia (72.4%), neutropenia (72.4%), and anemia (62.1%). Grade 3 or more toxicities were neutropenia (48.3%), leucopenia (37.9%), and febrile neutropenia (17.2%). One patient experienced a grade 3 thromboembolic event (3.4%).

Discussion

NAC for BC is provided not only to facilitate curative resection of locally advanced BC and BCS for early BC, but also to evaluate the sensitivity to these drugs (1, 2). In patients with pCR after NAC, long-term prognosis is favorable (3). Therefore, pCR has been established as an excellent surrogate prognostic marker. Because achievement of pCR is associated with great improvement of EFS and OS, new treatment regimens have been evaluated to obtain a higher pCR rate (4).

Paclitaxel and docetaxel are common taxanes used for NAC against BC. However, peripheral neuropathy is frequent in cremophor-based paclitaxel. Nab-paclitaxel is a newly-developed albumin-bound formulation of paclitaxel. This compound is associated with less than 1% incidence of allergies, shorter administration time, and avoidance of steroid premedication (6). In a phase III trial for patients with MBC, tri-weekly nab-paclitaxel at 260 mg/m2 demonstrated significantly higher ORR compared with tri-weekly cremophor-based paclitaxel at 175 mg/m2 (33% vs. 19%, respectively; p=0.01) (8). Grade 3 peripheral neuropathy was more common in the nab-paclitaxel arm than in the cremophor-based paclitaxel (10% vs. 2%, respectively; p<0.01), however, it was manageable and improved rapidly. In a phase II trial for patients with MBC, weekly nab-paclitaxel at 150 vs. 100 mg/m2 demonstrated significantly longer progression-free survival (12.9 vs. 7.5 months, respectively; p=0.0065). It had a tendency for higher ORR compared with tri-weekly docetaxel at 100 mg/m2 without statistical significance (13). Therefore, nab-paclitaxel has not been established as a standard treatment, and it has not clearly been shown which of tri-weekly and weekly regimens of nab-paclitaxel are better (14).

View this table:
Table I.

Patient characteristics.

View this table:
Table II.

Pathological complete response (pCR) by estrogen receptor (ER) status after neoadjuvant chemotherapy (N=29).

This phase II neoadjuvant trial named abraxane plus trastuzumab followed by epirubicin neoadjuvant (ABENO) evaluated the efficacy and safety of tri-weekly nab-paclitaxel at 260 mg/m2 plus trastuzumab followed by FEC for operable BC. The overall pCR (ypT0/Tis ypN0) rate was 74% (95% CI=57.5%-90.6%). This finding is satisfactory in comparison with the previous trials using anthracycline and taxane-containing regimen in patients with HER2-positive BC. In the taxol epirubicin cyclophosphamide herceptin neoadjuvant (TECHNO) phase II trial, the patients, including those with inflammatory BC, received four cycles of EC followed by four cycles of tri-weekly paclitaxel plus trastuzumab, and the pCR rate was 39% (15). In the Z1041 phase III trial, patients were randomly assigned to four cycles of FEC followed by weekly paclitaxel plus trastuzumab or weekly paclitaxel plus trastuzumab followed by four cycles of FEC and weekly trastuzumab, and the pCR rate was 57% and 54%, respectively (16). In the phase II NSABP FB-AX-003 trial, the patients received weekly nab-paclitaxel at 100 mg/m2 plus trastuzumab followed by FEC and trastuzumab, the pCR rate was 58% (17). In the GBG GeparSepto phase III trial, the patients were randomly assigned to weekly paclitaxel at 80 mg/m2 plus trastuzumab and pertuzumab or weekly nab-paclitaxel at 150 mg/m2 plus trastuzumab and pertuzumab, followed by four cycles of epirubicin/cyclophosphamide, and the pCR rates were 63% and 69% (9). In a meta-analysis of patients with HER2-positive BC receiving NAC, those who achieved a pCR had superior EFS and OS compared with those who did not (EFS: HR=0.37, 95% CI=0.32-0.43; OS: HR=0.34, 95% CI=0.26-0.42) (4). The association was even stronger in the hormone receptor-negative subgroup (EFS: HR=0.29, 95%CI=0.24-0.36). In the present trial, the pCR rates were 57% and 92% in those with ER-positive and ER-negative cancer, respectively.

View this table:
Table III.

Adverse events experienced on neoadjuvant chemotherapy.

Achieving dual HER2 receptor blockade by adding lapatinib or pertuzumab to trastuzumab significantly increased the pCR rate from 50% to 60% (17-19). However, these trials have not yet demonstrated whether a higher pCR rate would result in higher EFS and OS (20, 21).

Although 97% of patients experienced peripheral sensory neuropathy during therapy with nab-paclitaxel plus trastuzumab in this study, grade 3 peripheral sensory neuropathy was not observed during the period of nab-paclitaxel administration, however, one patient experienced grade 3 peripheral sensory neuropathy on FEC administration probably caused by nab-paclitaxel. In a previous trial, grade 3 peripheral neuropathy due to nab-paclitaxel was reported to be easily manageable and rapidly improvable (8). During FEC, neutropenia was observed in 72% of patients and grade 3 or more febrile neutropenia was observed in 17% of patients. We were able to continue the treatment in most patients, with one patient requiring a dosage reduction. Symptomatic cardiotoxicity was not observed.

The result of the present trial is limited because it was a single-arm phase II trial with a relatively small sample size, and there was lack of a long-term follow-up. Further randomized controlled trials with a larger sample size are necessary. In addition, pertuzumab should be assessed with regard to the effects on nab-paclitaxel plus trastuzumab for patients with HER2-positive BC.

Conclusion

Nab-paclitaxel plus trastuzumab q3w for four cycles followed by FEC q3w for four cycles in patients with HER2-positive operable BC is considerably effective and well tolerated. We believe that nab-paclitaxel plus trastuzumab show better activity and less toxicity than the other taxane plus trastuzumab.

Acknowledgements

The Authors would like to express their deepest gratitude to the women who participated in this trial and their family members, in addition to the investigators and all staff members at the study sites for their contribution to the study.

Footnotes

  • Authors' Contributions

    ST, TT, SK, SN, HK, SN, TN, KI, YO, YM, TS, KT, SY, TI, KH and MO contributed to conception and design. ST, TT, ST, SN, MT, HK, SK, SY, SN, TN, YM, TS, KT, and TI contributed towards provision of patients. ST, TT, HK, SN, and SK contributed towards collection and assembly of data. ST, TT, ST, SN, TI, SK, MT and MO contributed towards data analysis and interpretation. All Authors contributed to drafting of the manuscript. All Authors read and approved the final manuscript.

  • Conflicts of Interest

    Shinya Tokunaga reports receiving personal fees from Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., and Kyowa Hakko Kirin Co., Ltd.; Tsutomu Takashima reports receiving personal fees from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Eisai Co., Ltd., Pfizer Japan Inc., Novartis Pharma K.K., AstraZeneca K.K., and Takeda Pharmaceutical Co., Ltd.; Shinichiro Kashiwagi reports receiving personal fees from Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Pfizer Japan Inc., Novartis Pharma K.K., Asahi Kasei Pharma Co., Ltd., and Medicon Inc.; Satoru Noda reports receiving personal fees from Chugai Pharmaceutical Co., Ltd., and from Daiichi Sankyo Co., Ltd.; Hidemi Kawajiri reports receiving personal fees from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Pfizer Japan Inc., and Novartis Pharma K.K.; Mao Tokumoto declares no conflict of interest; Shigehiko Nishimura reports receiving personal fees from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., and Canon Medical Systems Co., Ltd.; Takeo Nishimori reports receiving personal fees from Taiho Pharmaceutical Co., Ltd., and Eisai Co., Ltd.; Katsumi Ikeda reports receiving personal fees from Tsumura Co., Ltd.; Shigehito Yamagata reports receiving personal fees from Taiho Pharmaceutical Co., Ltd.; Masaichi Ohira reports receiving personal fees from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. Yoshinari Ogawa, Yoko Mizuyama, Takeshi Sunami, Tetsuro Ishikawa, Kenji Tezuka, Shinzoh Kudoh, Minoru Takada and Kosei Hirakawa declare no conflict of interest in regard to this study.

  • Received January 13, 2019.
  • Revision received February 17, 2019.
  • Accepted February 26, 2019.

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Neoadjuvant Chemotherapy With Nab-paclitaxel Plus Trastuzumab Followed by 5-Fluorouracil/Epirubicin/Cyclophosphamide for HER2-positive Operable Breast Cancer: A Multicenter Phase II Trial
SHINYA TOKUNAGA, TSUTOMU TAKASHIMA, SHINICHIRO KASHIWAGI, SATORU NODA, HIDEMI KAWAJIRI, MAO TOKUMOTO, SHIGEHIKO NISHIMURA, TAKEO NISHIMORI, KATSUMI IKEDA, YOSHINARI OGAWA, YOKO MIZUYAMA, TAKESHI SUNAMI, KENJI TEZUKA, SHIGEHITO YAMAGATA, TETSURO ISHIKAWA, SHINZOH KUDOH, MINORU TAKADA, KOSEI HIRAKAWA, MASAICHI OHIRA
Anticancer Research Apr 2019, 39 (4) 2053-2059; DOI: 10.21873/anticanres.13316
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