ABSTRACT: Trastuzumab(Drug information on trastuzumab) (Herceptin) is a therapeutic monoclonal antibody specific for the human epidermal growth factor receptor type 2 (HER2), a cell-surface tyrosine kinase receptor overexpressed by 25% to 30% of breast cancers. The drug is now regarded as one option for standard therapy in HER2-overexpressing metastatic breast cancers. It is associated with a moderate response rate as a single agent, and in combination with standard chemotherapy, can produce greater response rates and prolong the survival of women with advanced breast cancer. Its activity in metastatic breast cancer has led to active clinical trials examining its potential role in the neoadjuvant and adjuvant settings. The successful clinical development of trastuzumab provides further proof of principle that biologically targeted therapies can have a profound impact on the management of breast cancer. Here we review the clinical development of this novel agent, emphasizing the potential for therapeutic synergy when trastuzumab is combined with both standard chemotherapy and innovative molecularly targeted and biologic agents.
Since the early 1980s, concerted international efforts to optimize the use of traditional cancer treatment modalities have improved the outlook for women with breast cancer. The morbidity associated with surgery, radiation therapy, and chemotherapy has declined, improving quality of life both for women undergoing therapy and for breast cancer survivors. These improvements have also resulted in a decline in breast cancer mortality. Despite this success, 37% of women diagnosed with breast cancer will still relapse and ultimately die of their disease. Therapeutic failure is thought to result from the outgrowth of dormant breast tumor cells that are inherently resistant to standard treatments, leading to an increasing focus on developing novel therapeutics that target specific molecular pathways essential for the initiation and maintenance of the transformed phenotype.
Trastuzumab (Herceptin), a humanized monoclonal antibody specific for the human epidermal growth factor receptor type 2 (HER2), is a novel therapeutic agent that targets signaling pathways essential for transformation in a subset of breast cancers. Its efficacy in the management of HER2-overexpressing breast cancers illustrates the immense potential of targeted therapies for further improving the outcome of breast cancer therapy. Here we review the clinical development of trastuzumab, summarize its role in the management of HER2-overexpressing metastatic breast cancer, and outline ongoing trials evaluating its use in the neoadjuvant and adjuvant settings. Finally, we highlight opportunities for combining trastuzumab with other molecularly targeted biologic agents to achieve a synergistic antitumor effect.
HER2: A Therapeutic Target in Breast Cancer
HER2 is a member of the erbB family of transmembrane tyrosine kinase receptors that also includes the epidermal growth factor receptor (EGFR or HER1), HER3, and HER4. Although HER2 has no ligand of its own (Figure 1), it is preferentially recruited into ligand-activated complexes with other erbB family members, thereby potentiating signaling. At high density in transformed mammary carcinoma cells, HER2 is constitutively activated by phosphorylation, which is thought to promote dimerization and the subsequent promotion of tumor cell growth in a ligand-independent fashion.
HER2 is overexpressed due to gene amplification in 25% to 30% of breast tumors, resulting in more aggressive disease and shorter survival in both node-negative and node-positive patients. Overexpression of HER2 often occurs in the context of other adverse prognostic features, including large tumor size, high histopathologic grade, high S-phase fraction, aneuploidy, and lack of estrogen-receptor and progesterone(Drug information on progesterone)-receptor expression.[ 3] HER2 is thought to be essential for initiating and maintaining tumor growth and progression. HER2 gene amplification occurs early in the development of invasive breast tumors, and is also frequently observed in ductal carcinoma in situ. These features, together with relatively low levels of HER2 expression in normal adult tissues, identify HER2 as an attractive target for breast cancer therapy.
Mechanisms of Action and Preclinical Pharmacology
Trastuzumab is a recombinant, humanized immunoglobulin G (IgG1) monoclonal antibody that is specific for the extracellular domain of HER2. It is thought to inhibit the proliferation of mammary tumor cells by multiple mechanisms. The antibody blocks cell-cycle progression by upregulating p27kip1, an intracellular inhibitor of cyclin-dependent kinase 2 (CDK2), thereby promoting the formation of inactive p27/CDK2 complexes.
Trastuzumab inhibits the recruitment of HER2 into heterodimers with HER1, HER3, and HER4 by accelerating the rate of endocytosis and subsequent degradation, thereby preventing HER2-mediated potentiation of erbB signaling through the ras/Raf/ mitogen-activated protein kinase (MAPK) and phosphoinositide 3- kinase (PI3K)/serine/threonine kinase (Akt) pathways. It has also been shown to inhibit the PI3K/Akt pathway directly. The antibody additionally blocks the metalloproteinase-induced cleavage of HER2, preventing the shedding of the extracellular domain and the concomitant constitutive activation of the membrane-associated cytoplasmic domain.
Trastuzumab also inhibits tumor neovascularization, in part by preventing the induction of proangiogenic factors by HER2 signaling. It further impairs the ability of cells to repair DNA damage by disrupting the activity of the cyclin-dependent kinase inhibitor p21WAF1, and may itself promote the formation of DNA strand breaks.
Finally, trastuzumab has inherent immunomodulatory activity. In a HER2-overexpressing xenograft model, abrogation of the antibody's therapeutic effect in the absence of Fc gamma RIII suggests that much of its therapeutic effect may be due to the recruitment of innate immune effector cells that mediate antibody-dependent cellular cytotoxicity. Trastuzumab may also potentiate the adaptive immune response. It has been shown to augment the activity of HER2-specific CD8+ cytotoxic T lymphocytes in vitro,[ 12] and preclinical data suggest that similar murine antibodies can induce HER2-specific CD8+ cytotoxic T lymphocytes in vivo.
Potential interactions between trastuzumab and radiation or cytotoxic therapy have also been evaluated in HER2-overexpressing xenograft models.[ 14,15] Consistent with its ability to promote the induction and maintenance of DNA strand breaks, the antibody was found to enhance the radiosensitivity of HER2-overexpressing breast tumor cells. In a systematic screen of potential interactions with standard chemotherapeutic agents, trastuzumab synergized with cisplatin(Drug information on cisplatin), docetaxel (Taxotere), thiotepa (Thioplex), cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar), vinorelbine (Navelbine), and etoposide. Additive antitumor activity resulted from the combination of trastuzumab with doxorubicin, paclitaxel(Drug information on paclitaxel), vinblastine(Drug information on vinblastine), or methotrexate(Drug information on methotrexate). Interestingly, the combination of fluorouracil(Drug information on fluorouracil) (5-FU) and trastuzumab was less effective than either drug alone, suggesting therapeutic antagonism. These observations underlie the rationale for testing trastuzumab in combination with chemotherapy in the clinical setting.
Pivotal Trials in Metastatic Breast Cancer
Early Trials—Early phase I and II clinical trials tested trastuzumab as a single agent, or in combination with cisplatin, in heavily pretreated patients with advanced breast cancer. These studies provided preliminary data regarding the safety and clinical activity of trastuzumab in patients with HER2-positive metastastic breast cancer. Based on these studies, three pivotal trials were conducted to further evaluate the safety and efficacy of trastuzumab in women with advanced HER2-overexpressing breast cancer (Table 1).[17-19] All three studies administered trastuzumab at a loading dose of 4 mg/kg intravenously (IV), followed by weekly doses of 2 mg/kg IV until disease progression. This dosing scheme was designed to maintain the serum trough concentrations of 10 to 20 μg/mL shown to be effective in animal models and early clinical trials.
Single-Agent Trastuzumab—Cobleigh and colleagues conducted a large, multinational phase II study of trastuzumab as a single agent in 222 women with HER2-overexpressing (immunohistochemistry [IHC] 2+ or 3+ in a central reference laboratory) stage IV breast cancer that had progressed after one or two chemotherapy regimens for metastatic disease. The primary end point was objective tumor response, and the secondary end points were duration of response, time to disease progression, time to treatment failure, and survival. Pharmacokinetic analysis revealed that about 90% of patients achieved the target trough concentration of 20 μg/mL. When analyzed on an intent- to-treat basis, the overall response rate was 15% (95% confidence interval [CI] = 11%-21%), with 8 complete responses and 26 partial responses. The median response duration was 9.1 months (95% CI = 6.5- 10.5 months), with a median survival of 13 months, a median time to progression of 3.1 months, and a median time to treatment failure of 11 months.
Trastuzumab Plus Chemotherapy—Based on preclinical data demonstrating synergy between trastuzumab and cytotoxic agents, Slamon and colleagues simultaneously conducted a multinational, phase III study that randomized 469 study subjects with HER2-overexpressing (IHC 2+ or 3+ in a central reference laboratory) metastatic stage IV breast cancer to receive chemotherapy alone or chemotherapy plus trastuzumab (at the dosing schedule described above) as first-line therapy. Individuals who received an anthracycline in the adjuvant setting received paclitaxel at 175 mg/m2 every 3 weeks alone or with trastuzumab; the remaining patients received an anthracycline (usu- ally doxorubicin(Drug information on doxorubicin), 60 mg/m2) with cyclophosphamide at 600 mg/m2 every 3 weeks alone or with trastuzumab. Chemotherapy was given for six cycles, and then continued at investigator discretion; weekly trastuzumab at 2 mg/kg was continued until disease progression. The primary end point was time to progression, with secondary end points of overall response rate, duration of response, time to treatment failure, and 1-year survival.
At a median follow-up of 30 months, the addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (7.4 vs 4.6 months, P < .001), a higher overall response rate (50% vs 32%, P < .001), and a longer duration of median response (9.1 vs 6.1 months, P < .001). Combination therapy was associated with a distinct survival advantage, with a longer median survival (25.1 vs 20.3 months, P = .046), a lower rate of death at 1 year (22% vs 33%, P = .008), and a 20% overall reduction in the risk of death. The addition of trastuzumab to paclitaxel increased the overall response rate from 17% to 41% (P < .001), and the median response duration from 4.5 to 10.5 months (P < .01). The addition of trastuzumab to the anthracyclinecontaining regimens increased the overall response rate from 42% to 56% (P = .02), and the median response duration from 6.7 to 9.1 months (P = .005). Importantly, 72% of patients randomized to receive chemotherapy alone subsequently received trastuzumab. This crossover is likely to underestimate the survival benefit associated with the addition of trastuzumab to chemotherapy in this patient population.
Evaluating Dose Levels—Subsequently, Vogel and colleagues reported the results of a randomized, multicenter phase II study that evaluated two dose levels of trastuzumab as first-line therapy for HER2-overexpressing metastatic breast cancer (IHC 2+ or 3+ by a central core laboratory).[ 19] In this trial, 114 women were randomized to receive trastuzumab at either a loading dose of 4 mg/kg followed by 2 mg/kg weekly, or a loading dose of 8 mg/kg followed by 4 mg/kg weekly. The primary end point was overall response rate, and secondary end points were duration of response, time to progression, survival, and quality of life. In an intent-to-treat analysis, the overall response rate was 26% (95% CI = 8.2%-34.4%), and the overall clinical benefit rate (complete response, partial response, minor response, plus stable disease ≥ 6 months) was 38% (95% CI = 28.8%-46.9%). The clinical benefit rate increased to 48% for tumors that scored IHC 3+ for HER2 expression.
Patients with an objective response (57%) or a clinical benefit (51%) had not experienced disease progression at a follow-up of 1 year or more. Importantly, the median survival of 24.4 months observed for trastuzumab monotherapy in this trial compares favorably with the median survival of 25.1 months seen with trastuzumab in combination with chemotherapy, suggesting that patients may not sustain a survival disadvantage if they are managed with trastuzumab alone as firstline therapy for metastatic disease. No relationship between trastuzumab dose and response, survival, or adverse events emerged in this study.
Resulting FDA Approval—Together, these trials established trastuzumab as an effective therapy for HER2-overexpressing metastatic breast cancer. In 1998, the US Food and Drug Administration (FDA) approved trastuzumab for the treatment of HER2-overexpressing metastatic breast cancer in combination with paclitaxel as first-line therapy, and as second- and third-line monotherapy in patients with stage IV disease previously treated with chemotherapy.