Elsevier

Cancer Treatment Reviews

Volume 34, Issue 6, October 2008, Pages 539-557
Cancer Treatment Reviews

ANTI TUMOUR TREATMENT
Adjuvant/neoadjuvant trastuzumab therapy in women with HER-2/neu-overexpressing breast cancer: A systematic review

https://doi.org/10.1016/j.ctrv.2008.03.013Get rights and content

Summary

Background

A systematic review was undertaken to evaluate the evidence for the use of trastuzumab as (neo)adjuvant therapy for women with HER-2/neu-positive breast cancer and to develop and support recommendations pertaining to its use across five domains: as a single-agent therapy, in combination with chemotherapy, methods to identify women who will benefit from it, adverse events associated with it, and optimal dose, schedule, and duration.

Methods

MEDLINE, EMBASE, the American Society of Clinical Oncology, the San Antonio Breast Cancer Symposia proceedings, and the Cochrane Library were searched through May 2007 for reports of randomized controlled trials that met the inclusion criteria.

Results

Eight randomized trials, described across 23 citations, were identified. All six trials of adjuvant trastuzumab reported significantly improved disease-free survival (DFS) while 4 of 6 adjuvant trials showed significant improvement in overall survival (OS) for patients treated with trastuzumab over those that were not. Two trials of trastuzumab in the neoadjuvant setting reported significantly better pathological complete response (pCR) in patients treated with trastuzumab although both studies were limited by small sample size, and longer follow-up is needed.

Conclusion

Although the optimal duration, schedule, and timing of adjuvant trastuzumab remains undefined, the bulk of the available evidence supports that adjuvant trastuzumab be offered for 1 year to all patients with HER-2-positive and node-positive or high-risk node-negative (tumour ⩾1 cm in size) primary breast cancer who are receiving or have received (neo)adjuvant chemotherapy.

Introduction

Since the benefit of adjuvant chemotherapy was first established in the early 1970s, many studies have shown that adjuvant chemotherapy can reduce recurrence and prolong survival in women with breast cancer.1 Although serial generations of clinical trials have lead to incremental improvements in outcomes,1 all of these studies are limited to comparing between single regimens and as a result, the optimal chemotherapeutic regimen for early stage breast cancer remains undefined. Reliable risk assessment for breast cancer relapse remains a challenge, and many patients who receive adjuvant chemotherapy are cured with local therapy alone, thus unnecessarily suffering the toxicity of the ‘shotgun’ approach of cytotoxic chemotherapy. As the identification of prognostic and predictive factors in early breast cancer becomes more refined, and targeted therapies with a more favourable toxicity profile are incorporated into clinical practice, the hope is to build upon past success.

The HER-2/neu gene encodes a 185-kd transmembrane glycoprotein (p185HER–2/neu) that is a member of the family of epidermal growth-factor receptors with intrinsic tyrosine kinase activity. HER-2/neu is overexpressed in 25–30% of human breast cancers.2 Overexpression of p185HER−2/neu in patients with primary breast cancer is associated with a number of adverse prognostic factors, including advanced-stage axillary lymph node involvement, absence of estrogen and progesterone receptors, increased S-phase fraction, and high nuclear grade.3, 4

The murine monoclonal antibody against HER-2/neu, 4D5, has anti-proliferative effects against HER-2/neu-overexpressing breast cancers in vitro and against breast cancer xenografts in vivo.5, 6, 7 However, the immunogenicity of murine antibodies limits their therapeutic use in humans.8 In an effort to overcome this, one of the more effective antibodies, 4D5, has been successfully humanized, retaining murine sequences only in the complementarity-determining regions, thus yielding an agent with significantly lower immunogenicity known as trastuzumab, or commonly known under its trade name Herceptin® (Genentech Inc., San Francisco, CA).

Trastuzumab has been in clinical use for less than a decade, its efficaciousness initially being established as a single agent and, subsequently, in combination with chemotherapy9, 10 for metastatic breast cancer. Because improvement in median survival was rarely seen in the metastatic setting led to the rapid incorporation of trastuzumab in a series of clinical trials of adjuvant chemotherapy for early breast cancer. Therefore, this systematic review was developed to address the following questions with regard to women with HER-2/neu-positive breast cancer:

  • 1.

    Compared with placebo or observation, does single-agent trastuzumab (neo)adjuvant therapy improve clinically meaningful outcomes (overall response rate, disease-free survival, overall survival, toxicity, or quality of life)?

  • 2.

    Compared with (neo)adjuvant chemotherapy alone, does trastuzumab in combination with existing (neo)adjuvant chemotherapy improve clinically meaningful outcomes?

  • 3.

    What is the best way to identify women who will benefit from neo(adjuvant) trastuzumab therapy?

  • 4.

    What are the adverse events associated with neo(adjuvant) trastuzumab therapy?

  • 5.

    What is the optimal dose, schedule, and duration for (neo)adjuvant trastuzumab therapy?

Section snippets

Methods

MEDLINE and EMBASE databases were searched in their entirety, from 1950 and 1980, respectively, up to the last week of May 2007 using the search criteria outlined in Table 1. A complex search strategy that combined disease-specific search terms (e.g., “breast neoplasms”), agent-class terms (e.g., “trastuzumab”) and terms related to publication type (e.g., “randomized controlled trial”) was used. The search strategy employed relevant medical subject headings (MeSH) and Excerpta Medica Tree

Results

Eight randomized trials, described across 23 citations,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 were identified that met the inclusion criteria for this systematic review. Only two trials were identified as randomized phase II, one involving trastuzumab used in the adjuvant setting,28, 29 while the other, neoadjuvant.33 The remainder of trials could be classified as randomized phase III. No trials comparing trastuzumab with observation or

Discussion

Trastuzumab, a novel monoclonal antibody, has rapidly made its way into the arena of adjuvant therapy for early breast cancer. However, despite a substantial body of evidence supporting its use in improving disease-free and overall survival in women with HER-2/neu-overexpressing breast cancer, the optimal dose, schedule, sequencing and duration of trastuzumab therapy remain undefined. Clinicians and patients alike are anxious to apply the benefits of adjuvant trastuzumab in the ‘real world’,

Conclusions

The benefit of adjuvant chemotherapy for breast cancer was established more than 30 years ago, and, since then, subsequent generations of clinical trials have demonstrated incremental benefits resulting from superior chemotherapy regimens and comparable efficacy for chemotherapy given preoperatively or postoperatively.1 The cumulative effects of adjuvant chemotherapy, together with screening mammography, have contributed to a substantial reduction in breast cancer mortality witnessed over the

Conflict of interest statement

Dr. David McCready reports owning stock in excess of CDN$5000 in a company with financial interest in trastuzumab. The additional authors wish to state no conflicts of interest at time of submission.

References (65)

  • P. Carter et al.

    Humanization of an anti-p185HER2 antibody for human cancer therapy

    Proc Natl Acad Sci USA

    (1992)
  • J.M. Extra et al.

    First-line trastuzumab (Herceptin (R)) plus docetaxel versus docetaxel alone in women with HER2-positive metastatic breast cancer (MBC): results from a randomised phase II trial (M77001)

    Breast Cancer Res Treat

    (2003)
  • D.J. Slamon et al.

    Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2

    New Engl J Med

    (2001)
  • Piccart-Gebhart MJ. HERA trial [slides on the Internet]. 2005 American Society of Clinical Oncologists Virtual Meeting:...
  • M.J. Piccart-Gebhart et al.

    Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer

    New Engl J Med

    (2005)
  • D. Slamon et al.

    Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC > T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC > TH) with docetaxel, carboplatin, and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study [abstract]

    Breast Cancer Res Treat

    (2005)
  • Slamon D, Eiermann W, Pienkowski T, Martin M, et al. BCIRG 006: 2nd Interim analysis phase III randomized trial...
  • Slamon D, Eiermann W, Robert N, et al. Phase III trial comparing AC–T with AC-TH and with TCH in the adjuvant treatment...
  • E.A. Perez et al.

    Interim cardiac safety analysis of NCCTG N9831 Intergroup adjuvant trastuzumab trial [abstract]

    J Clin Oncol

    (2005)
  • Perez EA, Suman V, Davidson N, Martino S, Kauffman PA. Further analysis of NCCTG-N9831 [slides on the Internet]. In:...
  • M.Y. Halyard et al.

    Adjuvant radiotherapy (RT) and trastuzumab in stage I-IIA breast cancer: toxicity data from the North Central Cancer Treatment Group phase III trial N9831 [abstract]

    J Clin Oncol

    (2006)
  • Halyard MY, Pisansky TM, Pierce LJ, Solin LJ, Marks LB, Dueck A, et al. Adjuvant radiotherapy and trastuzumab in stage...
  • E. Tan-Chiu et al.

    Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, Human Epidermal Growth Factor Receptor 2-overexpressing breast cancer: NSABP B-31

    J Clin Oncol

    (2005)
  • C.E. Geyer et al.

    Update of cardiac dysfunction on NSABP B-31, a randomized trial of sequential doxorubicin/cyclophosphamide (AC) > paclitaxel (T) vs. AC > T with trastuzumab (H) [abstract]

    J Clin Oncol

    (2006)
  • Geyer CE, Bryant J, Yothers G, Romond E, Ewer M, Keefe D, et al. Four year update of cardiac dysfunction on NSABP B-31:...
  • E.H. Romond et al.

    Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer

    New Engl J Med

    (2005)
  • 25. Romond EH, Perez EA, Bryant J, Suman V, Geyer CE, Davidson N, et al. Joint analysis of NSABP-B-31 and NCCTG-N9831...
  • Joensuu H, Alanko T, Bono P, Jyrkkio S, Kokko R, Korhonen T, et al. Trastuzumab shows no short-term cardiac toxicity...
  • H. Joensuu et al.

    Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer

    New Engl J Med

    (2006)
  • Sledge G, O’Neil A, Thor A, Kahanic SP, Zander PJ, et al. Adjuvant trastuzumab: long-term results of E2198 [slides on...
  • G.W. Sledge et al.

    Adjuvant trastuzumab: long-term results of E2198 [abstract]

    Breast Cancer Res Treat

    (2006)
  • A.U. Buzdar et al.

    Significantly higher pathological complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal group factor receptor 2-positive disease

    J Clin Oncol

    (2005)

    • Cited by (68)

    • PDPN positive CAFs contribute to HER2 positive breast cancer resistance to trastuzumab by inhibiting antibody-dependent NK cell-mediated cytotoxicity

      2023, Drug Resistance Updates

    • Appraising the quality of meta-analysis for breast cancer treatment in the adjuvant setting: A systematic review

      2021, Cancer Treatment and Research Communications

    • Short-duration versus 1-year adjuvant trastuzumab in early HER2 positive breast cancer: A meta-analysis of randomized controlled trials

      2019, Cancer Treatment Reviews

    • LncRNA HOTAIR: A master regulator of chromatin dynamics and cancer

      2015, Biochimica et Biophysica Acta - Reviews on Cancer
      Citation Excerpt :

      A recent study investigated the differences in expression levels of lncRNAs in osteoarthritic cartilages and in normal cartilage using microarray analyses. The analyses identified HOTAIR to be one of the lncRNA to be upregulated in osteoarthritic cartilages [153], suggesting that differential expression of HOTAIR may be associated with the pathogenesis of osteoarthritis [153]. Another study investigated the expression of HOTAIR in pre-eclampsia placentas and its effect on trophoblast cells [154].

    • Can pathologic complete response (pCR) be used as a surrogate marker of survival after neoadjuvant therapy for breast cancer?

      2015, Critical Reviews in Oncology/Hematology
      Citation Excerpt :

      Retrospective studies have been performed evaluating mostly the efficacy of chemotherapy (CT) combined with trastuzumab [33,50–59]. Both pCR rates and patient outcome were significantly improved confirming that the presence of HER2 abnormalities is a major prognostic and predictive factor in breast cancer [48,60,61]. Results have shown that CT combined with trastuzumab could lead to pCR rates ranging from 22% to 48% in luminal-HER2+ and 33% to 70% in HER2-enriched tumors [30,33,51,55].

    • LncRNAs: the good, the bad, and the unknown

      2024, Biochemistry and Cell Biology
    View all citing articles on Scopus
    f

    Tel.: +1 613 544 2631x4502; fax: +1 613 546 8209.

    g

    Tel./fax: +1 416 480 5145.

    h

    Tel.: +1 416 946 6510; fax: +1 416 946 6590.

    i

    Tel.: +1 416 480 4616; fax: +1 416 480 6002.

    j

    Tel.: +1 905 525 9140x22683; fax: +1 905 522 7681.

    View full text
    Copyright © 2008 Elsevier Ltd. All rights reserved.