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