Skip to main content

Advertisement

SpringerLink
Log in

Single-arm, neoadjuvant, phase II trial of pertuzumab and trastuzumab administered concomitantly with weekly paclitaxel followed by 5-fluoruracil, epirubicin, and cyclophosphamide (FEC) for stage I–III HER2-positive breast cancer

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

The purpose of this two-cohort Phase II trial was to estimate the pathologic complete response (pCR: ypT0/is ypN0) rate when trastuzumab plus pertuzumab are administered concurrently during both the taxane and anthracycline phases of paclitaxel and 5-fluorouracil/epirubicin/cyclophosphamide (FEC) neoadjuvant chemotherapy.

Methods

The pCR rates were assessed separately in hormone receptor (HR) positive and negative cases following Simon’s two-stage design, aiming to detect a 20% absolute improvement in pCR rates from 50 to 70 and 70 to 90% in the HR-positive and HR-`negative cohorts, respectively.

Results

The HR-negative cohort completed full accrual of 26 patients; pCR rate was 80% (95% CI 60–91%). The HR+ cohort was closed early after 24 patients due to lower than expected pCR rate of 26% (95% CI 13–46%) at interim analysis. Overall, 44% of patients (n = 22/50) experienced grade 3/4 adverse events. The most common were neutropenia (n = 10) and diarrhea (n = 7). There was no symptomatic heart failure, but 28% (n = 14) had ≥ 10% asymptomatic decrease in LVEF; in one patient, LVEF decreased to < 50%. Cardiac functions returned to baseline by the next assessment in 57% (8/14) of cases.

Conclusions

Eighty percent of HR-negative, HER2-positive breast cancers achieve pCR with paclitaxel/FEC neoadjuvant chemotherapy administered concomitantly with pertuzumab and trastuzumab. These results are similar to pCR rates seen in trials using HER2-targeted therapy during the taxane phase only of sequential taxane–anthracycline regimens and suggest that we have reached a therapeutic plateau with HER2-targeted therapies combined with chemotherapy in the neoadjuvant setting.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Mougalian SS, Soulos PR, Killelea BK et al (2015) Use of neoadjuvant chemotherapy for patients with stage I to III breast cancer in the United States. Cancer 121(15):2544–2552

    Article  PubMed  Google Scholar 

  2. Boughey JC, Peintinger F, Meric-Bernstam F et al (2006) Impact of preoperative versus postoperative chemotherapy on the extent and number of surgical procedures in patients treated in randomized clinical trials for breast cancer. Ann Surg 244(3):464

    PubMed  PubMed Central  Google Scholar 

  3. Symmans WF, Wei C, Gould R et al (2017) Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol 35(10):1049–1060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Buzdar AU, Valero V, Ibrahim NK et al (2007) Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2–positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res 13(1):228–233

    Article  CAS  PubMed  Google Scholar 

  5. Slamon D, Eiermann W, Robert N et al (2011) Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365(14):1273–1283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Viani GA, Afonso SL, Stefano EJ, De Fendi LI, Soares FV (2007) Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer 7(1):153

    Article  PubMed  PubMed Central  Google Scholar 

  7. Gianni L, Eiermann W, Semiglazov V et al (2010) Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 375(9712):377–384

    Article  CAS  PubMed  Google Scholar 

  8. Buzdar AU, Ibrahim NK, Francis D et al (2005) Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23(16):3676–3685

    Article  CAS  PubMed  Google Scholar 

  9. Buzdar AU, Suman VJ, Meric-Bernstam F et al (2013) Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol 14(13):1317–1325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gianni L, Pienkowski T, Im Y-H et al (2012) Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13(1):25–32

    Article  CAS  PubMed  Google Scholar 

  11. Schneeweiss A, Chia S, Hickish T et al (2013) Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24(9):2278–2284

    Article  CAS  PubMed  Google Scholar 

  12. Baselga J, Bradbury I, Eidtmann H et al (2012) Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379(9816):633–640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Guarneri V, Frassoldati A, Bottini A et al (2012) Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2–positive operable breast cancer: results of the randomized phase II CHER-LOB study. J Clin Oncol 30(16):1989–1995

    Article  CAS  PubMed  Google Scholar 

  14. Robidoux A, Tang G, Rastogi P et al (2013) Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol 14(12):1183–1192

    Article  CAS  PubMed  Google Scholar 

  15. Guarneri V, Lenihan DJ, Valero V et al (2006) Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the MD Anderson Cancer Center experience. J Clin Oncol 24(25):4107–4115

    Article  CAS  PubMed  Google Scholar 

  16. Seidman A, Hudis C, Pierri MK et al (2002) Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20(5):1215–1221

    Article  CAS  PubMed  Google Scholar 

  17. Bayraktar S, Gonzalez-Angulo AM, Lei X et al (2012) Efficacy of neoadjuvant therapy with trastuzumab concurrent with anthracycline-and nonanthracycline-based regimens for HER2-positive breast cancer. Cancer 118(9):2385–2393

    Article  CAS  PubMed  Google Scholar 

  18. Rimawi M, Cecchini R, Rastogi P et al (2017) Abstract S3-06: A phase III trial evaluating pCR in patients with HR+, HER2-positive breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) ± estrogen deprivation: NRG oncology/NSABP B-52. Cancer Res. 77(4 Supplement):S3-06–S03-06

    Article  Google Scholar 

  19. Untch M, Loibl S, Bischoff J et al (2012) Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol 13(2):135–144

    Article  CAS  PubMed  Google Scholar 

  20. Hurvitz S, Miller J, Dichmann R et al (2013) Abstract S1-02: Final analysis of a phase II 3-arm randomized trial of neoadjuvant trastuzumab or lapatinib or the combination of trastuzumab and lapatinib, followed by six cycles of docetaxel and carboplatin with trastuzumab and/or lapatinib in patients with HER2+ breast cancer (TRIO-US B07). Cancer Res 73(24 Supplement):S1-02–S01-02

    Article  Google Scholar 

  21. Carey LA, Berry DA, Cirrincione CT et al (2015) Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol 34(6):542–549

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hurvitz SA, Martin M, Symmans WF et al (2016) Pathologic complete response (pCR) rates after neoadjuvant trastuzumab emtansine (T-DM1 [K]) + pertuzumab (P) vs docetaxel + carboplatin + trastuzumab + P (TCHP) treatment in patients with HER2-positive (HER2+) early breast cancer (EBC) (KRISTINE). J Clin Oncol 34(suppl):500

    Google Scholar 

  23. Kummerow KL, Du L, Penson DF, Shyr Y, Hooks MA (2015) Nationwide trends in mastectomy for early-stage breast cancer. JAMA Surg 150:9–16

    Article  PubMed  Google Scholar 

Download references

Funding

Genentech.

Author information

Authors and Affiliations

  1. Yale Cancer Center, Yale School of Medicine, 333 Cedar St., PO Box 208032, New Haven, CT, 05620, USA

    Julia Foldi, Sarah Mougalian, Andrea Silber, Donald Lannin, Brigid Killelea, Anees Chagpar, Nina Horowitz, Courtney Frederick, Lawrence Rispoli, Trisha Burrello, Maysa Abu-Khalaf, Kert Sabbath, Tara Sanft, Debra S. Brandt, Erin W. Hofstatter, Christos Hatzis, Michael P. DiGiovanna & Lajos Pusztai

Authors
  1. Julia Foldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarah Mougalian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrea Silber
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Donald Lannin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Brigid Killelea
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anees Chagpar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nina Horowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Courtney Frederick
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lawrence Rispoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Trisha Burrello
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Maysa Abu-Khalaf
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kert Sabbath
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Tara Sanft
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Debra S. Brandt
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Erin W. Hofstatter
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Christos Hatzis
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Michael P. DiGiovanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Lajos Pusztai
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Study design: LP, MD, and CH. Patient accrual: SM, AS, DL, BK, AC, NH, MA-K, KS, TS, DSB, EWH, MD, and LP. Data analysis: CF, TB, JF, LR, LP, and CH. Manuscript writing: JF and LP. Final review of manuscript: all authors.

Corresponding author

Correspondence to Lajos Pusztai.

Ethics declarations

Conflict of interest

Sarah Mougalian: Consultant/Adviser-Eisai Pharmaceuticals, Hylapharm LLC; Funding-NCCN/Pfizer, Michael DiGiovanna: Renumeration-Dako, Noemarkers (Royalties).

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 65 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Foldi, J., Mougalian, S., Silber, A. et al. Single-arm, neoadjuvant, phase II trial of pertuzumab and trastuzumab administered concomitantly with weekly paclitaxel followed by 5-fluoruracil, epirubicin, and cyclophosphamide (FEC) for stage I–III HER2-positive breast cancer. Breast Cancer Res Treat 169, 333–340 (2018). https://doi.org/10.1007/s10549-017-4653-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-017-4653-2

Keywords

Search

Navigation