Herceptin: the future in adjuvant breast cancer therapy

New drugs for the treatment of breast cancer are generally introduced into clinical practice in the metastatic setting. However, it is well known that therapeutic response improves when drugs are used earlier in the disease. Therefore, once drugs have shown a major therapeutic impact in the metastatic setting, investigation in the adjuvant setting should be prioritized. Herceptin has shown significant efficacy and an ability to extend survival in human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer patients and is well tolerated. Four major randomized, multicenter adjuvant clinical trials of Herceptin in patients with HER2-positive primary breast cancer have been started or are planned. The designs of these trials are described. With a total of over 12 000 patients, these studies should provide the information necessary to confirm the clinical potential of Herceptin as adjuvant therapy. The inclusion of a variety of regimens, including different durations of Herceptin therapy in the Herceptin Adjuvant (HERA) Trial, will allow the optimal therapeutic approach to be identified, and the size and generally pragmatic designs should encourage clinicians to enroll patients. The establishment of the role of Herceptin in the adjuvant setting will offer women with HER2-positive primary breast cancer the chance for improved survival. This is particularly important given that HER2-positive breast cancer patients form a high-risk group with a poor overall prognosis.     

Drugs targeted against protein kinases

Current treatments for cancer (surgery, radiation and chemotherapy) are successful for early stage localised disease but have severe side effects. New treatments are needed to increase the cure rate and life expectancy of patients. With the discovery of oncogenes, tumour suppressor genes and an understanding of their role in the development of the malignant disease, a new era of therapy has begun. Cancer is a manifestation of deregulated signalling pathways that mediate cell growth and programmed cell death. Protein kinases are essential elements in these signalling pathways. In the US, Novartis launched Gleevec (imantinib, STI-571) in May 2001 as the first anticancer drug whose mechanism of action is kinase inhibition. In Phase I trials, 23/24 patients with chronic myelogenous leukaemia (CML) had complete remissions and the drug is relatively non-toxic. Herceptin (trastuzumab) is a monoclonal antibody (mAb) against a member of the growth factor receptor family (HER-2/neu) that was launched in 1998 by Genentech for the treatment of breast cancer. Trastuzumab has an excellent antitumour profile, particularly when used in combination with doxorubicin and paclitaxol. These drugs are pioneering the treatment of cancer based on the molecular understanding of the disease. Numerous drugs that target growth factor receptors and their signalling pathways are in advanced clinical trials. Herein, antibodies against receptors and small molecule inhibitors of kinases in signalling pathways will be summarised. Inter-disciplinary preclinical studies have identified chemicals that target specific kinases. We believe that clinical studies of these agents will yield new anticancer agents that target specific diseases and that are less toxic than current agents.     

Trials of new combinations of Herceptin in metastatic breast cancer

Herceptin extends survival in human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer patients when administered with paclitaxel or anthracycline/cyclophosphamide (AC), and the combination with 3-weekly paclitaxel is the current standard first-line therapy. However, other combinations may be equally effective. This review provides information on recent and ongoing trials of new Herceptin combinations. Preliminary results indicate that Herceptin plus epirubicin/cyclophosphamide may be effective without the cardiotoxicity of the AC combination. Weekly paclitaxel plus Herceptin has produced responses in 83% of HER2-positive patients treated. Co-administering Herceptin with other cytotoxic agents has also been investigated, with combination partners being chosen based on in vitro synergy with Herceptin, known efficacy as monotherapy and convenience of weekly administration (e.g. docetaxel, vinorelbine). High response rates have been observed in these clinical trials, e.g. up to 80% in combination with vinorelbine. Furthermore, Herceptin in combination with weekly paclitaxel, docetaxel or vinorelbine was well tolerated: there was no significant cardiotoxicity or unexpected toxicity and the combination showed an adverse event profile similar to that seen with monotherapy with the cytotoxic agent. Thus, Herceptin produces additional clinical benefit when added to all the cytotoxic agents with which it has been examined, further demonstrating its potential for use in HER2-positive breast cancer patients.     

From HER2 to herceptin

HER2 overexpression occurs in 25% of breast cancers and seems to correlate with poor prognosis. HER2 overexpression may predict tamoxifen failure and different response rates to chemotherapeutic agents such as the taxanes and anthracyclines. The detection of HER2 and its overexpression is performed using fluorescent in situ hybridisation (FISH) and/or immunohistochemistry (IHC). Trastuzumab [Herceptin (H)] is a humanised IgG monoclonal antibody specific for the growth factor receptor HER2. Pre-clinical trials using monoclonal antibodies have shown inhibition of breast tumour growth in athymic nude mice. Phase II and III clinical trials have evaluated the efficacy and safety of Herceptin in women with metastatic breast cancer in combination with other agents and as a single agent. Currently, Trastuzumab and paclitaxel is the only combination indicated for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2. It is also indicated as a single agent in women with HER2-overexpressing metastatic breast cancer that has progressed after previous chemotherapy. Herceptin is a well-tolerated drug and the side-effects that are commonly seen with chemotherapy, such as neutropenia, alopecia and mucositis, are rarely observed. The main risk factors for cardiotoxicity are concurrent or previous anthracycline exposure. The potential role of Herceptin in the adjuvant setting is currently being evaluated.     

Targeted therapies in breast cancer: established drugs and recent developments

In the past few years many encouraging advancements have been made in understanding the molecular mechanisms underlying carcinogenesis and tumor progression. These improvements have led to the identification of promising new targets for cancer therapy. There has been much success with the HER2 targeting antibody trastuzumab (Herceptin) in the treatment of early stage and metastatic breast cancer. Consequently, several antibodies inhibiting cellular signaling of VEGF and EGFR were tested with respect to their efficacy in breast cancer. In phase II and III clinical trials the humanized anti-VEGF antibody bevacizumab (Avastin) alone or in combination with capecitabine exhibited responses in patients with metastatic breast cancer. Recent developments focus on small molecules interfering with different signal transduction pathways in tumor cells. Numerous inhibitors of EGF and VEGF receptor tyrosine kinases and farnesyl transferases are in early stages of clinical development for breast cancer. Another promising approach is the targeting of endothelins and their two G-protein coupled receptors (ET(A)R und ET(B)R). In this article, we will shortly outline well established targeted treatments and discuss the current development of novel agents to be utilized for molecular targeted breast cancer therapy. Due to the heterogeneity of disease and varying response to conventional systemic therapies, these new perceptions may lead to substantial patient benefit and provide a promising basis for future clinical application.     

人类表皮生长因子受体-2在乳腺癌研究中进展

人类表皮生长因子受体-2（ human epidermal growth factor receptor-2, HER-2）是乳腺癌诊治过程中重要的预后指标和HER-2靶向药物的治疗指标。乳腺癌患者中约30％会出现HER-2的过表达,HER-2检测的目的就是鉴别出那些可以从HER-2靶向治疗中获益的人群。目前靶向治疗药物包括赫赛、拉帕替尼和T-DM1等。这些治疗可以大大提高HER-2阳性浸润性乳腺癌患者的生存期。所以选择适当的检测标准准确判读HER-2状态是乳腺癌患者预后判断以及制定有效治疗方案的先决条件,对乳腺癌的诊疗具有积极的指导作用。     

Biosimilars lining up to compete with Herceptin – opportunity knocks

Trastuzumab is a monoclonal antibody developed by Genentech as a treatment for breast cancer and gastric cancer when the cancer cells overexpress HER2, a membrane-bound receptor activated by epidermal growth factor. Now marketed by Roche under the trade name Herceptin, trastuzumab has been readily adopted as treatment for some of the most invasive types of breast cancer. The cost for Herceptin is over $50,000 for a full course of treatment. With the development of regulatory pathways for biosimilar products, and the imminent expiry of patents covering Herceptin, several companies have developed biosimilar trastuzumab products. As biosimilar manufacturers look for opportunities to market biosimilar trastuzumab products, Roche has positioned itself to protect its market by developing additional anti-HER2 products complementary to Herceptin. The advent of competition from biosimilars should bring some opportunity for cost savings for patients, as well as incentive for continued advancement in development of better treatments to fight breast cancer.     

Novel pharmacological approaches in the treatment of breast cancer

Breast cancer is the most common malignancy among women. Novel pharmacological agents, including hormonal, cytotoxic and biological therapies, are currently being developed and tested in clinical trials and may offer patients more treatment options and an improved chance of long-term survival. Signal transduction inhibitors that block endocrine or growth factor pathways have demonstrated exciting antitumour effects in clinical trials. In addition to new chemotherapeutic drugs, numerous biological agents including growth factor receptor-directed monoclonal antibodies and tyrosine kinase inhibitors that target specific molecular lesions are being examined as potential breast cancer treatments.     

Novel pharmacological approaches in the treatment of breast cancer

Breast cancer is the most common malignancy among women. Novel pharmacological agents, including hormonal, cytotoxic and biological therapies, are currently being developed and tested in clinical trials and may offer patients more treatment options and an improved chance of long-term survival. Signal transduction inhibitors that block endocrine or growth factor pathways have demonstrated exciting antitumour effects in clinical trials. In addition to new chemotherapeutic drugs, numerous biological agents including growth factor receptor-directed monoclonal antibodies and tyrosine kinase inhibitors that target specific molecular lesions are being examined as potential breast cancer treatments.     

Duration of therapy in metastatic breast cancer: management using Herceptin

Despite progressive developments in therapeutic interventions, including surgery, radiotherapy and chemotherapy, there has been no major improvement in the survival of women with metastatic breast cancer (MBC). Based on knowledge of tumor growth patterns, approaches addressing this issue have included increasing chemotherapy dose or dose density and extending the duration of therapy. However, only the latter approach has resulted in improved clinical benefit, although not survival; and its use is restricted by the cumulative toxicity of chemotherapeutic agents. Therefore, the best hope for improved survival lies with new classes of anticancer drug and particularly biological agents. This review focuses on the first oncogene-targeted therapy for human epidermal growth factor receptor-2 (HER2)+ MBC patients. The humanized anti-HER2 monoclonal antibody Herceptin has proven clinical benefits in HER2+ MBC patients, most importantly improved survival, and is rapidly becoming a standard of care for these patients. In contrast to the fixed number of cycles used for chemotherapeutic agents, Herceptin is administered until disease progression, with some data suggesting that continuation beyond disease progression should be investigated. The preclinical and clinical findings on which the current recommended duration of Herceptin therapy are based are reviewed and alternative strategies are discussed.     

Pharmacological strategies to overcome HER2 cross-talk and Trastuzumab resistance

Approximately 20-30% of breast cancers show increased expression of the HER2 receptor tyrosine kinase. Trastuzumab (Herceptin) is a clinically approved anti-HER2 monoclonal antibody. Many patients with HER2-overexpressing metastatic breast cancer respond to trastuzumab; however, a subset display primary drug resistance. In addition, many patients who initially respond to trastuzumab ultimately develop disease progression. Multiple molecular mechanisms contributing to trastuzumab resistance have been proposed in the literature. These mechanisms include cross-signaling from related HER/erbB receptors and compensatory signaling from receptors outside of the HER/erbB family, including receptors for insulin-like growth factor-I, vascular endothelial growth factor, and transforming growth factor beta. The major downstream signaling pathway activated by HER2 cross-talk is PI3K/mTOR, and a potential integrator of receptor cross-talk is Src-focal adhesion kinase (FAK) signaling. PI3K, Src, and FAK have independently been implicated in trastuzumab resistance. In this review, we will discuss pharmacological inhibition of HER2 cross-talk as a strategy to treat trastuzumab-refractory HER2-overexpresssing breast cancer.     

Maximizing the response to Herceptin therapy through optimal use and patient selection

The aggressiveness of human epidermal growth factor receptor-2 (HER2)-positive breast cancer and the poor prognosis of women with this disease demand the availability of accurate and reliable tests for HER2 status and the optimization of HER2-targeted therapy. The distinctive clinical pattern of HER2-positive breast cancer underlines the importance of testing for HER2 status and efforts are ongoing to validate the two major methods in use-immunohistochemistry (IHC), which measures cell membrane HER2 expression, and fluorescence in situ hybridization (FISH), which measures gene copy number. Clinical trial results demonstrate that there is an association between strong HER2 overexpression (IHC 3+) and optimal response to therapy with the novel recombinant HER2 antibody Herceptin. High levels of concordance between IHC 3+ and FISH-positive status have been observed, and response to treatment with Herceptin is similar for patients whose breast cancers are IHC 3+ and those who are FISH-positive. Observations to date have led to the formulation of an algorithm for HER2 status determination and Herceptin use which recommends that: (i) the HER2 status of all women with breast cancer be determined at presentation, (ii) all IHC 3+ and FISH-positive patients with metastatic disease should receive Herceptin, (iii) Herceptin should be used early in the course of metastatic breast cancer and preferably first line, and (iv) Herceptin therapy should be continued until disease progression.     

Opinion on the use of the antitumor drug trastuzumab (Herceptin) in patients with metastatic breast cancer in the county Mecklenburg-Vorpommern.

The recombinant humanized anti-HER-2 monoclonal antibody trastuzumab (Herceptin) is directed against the human epidermal growth factor receptor on the surface of breast cancer cells. Herceptin was approved in Germany in September 2000 after evaluation in clinical trials involving women with metastatic breast cancer who had tumors overexpressing HER-2/neu. A prerequisite for its use is the diagnosis of the HER-2/neu receptor status in individual patients because trastuzumab is only effective in patients with a high (score +3) overexpression of the HER-2/neu receptor. The only approved diagnostic method is the immunohistochemical DAKO-Hercep test. Clinical experience with this novel biological agent has been obtained in 2 Phase III trials involving 469 and 222 patients, where trastuzumab was used as first- or second-line therapy. The addition of trastuzumab to chemotherapy regimens was associated with longer time to progression, a higher rate and duration of response and longer survival. When used as a single agent in metastatic breast cancer that had progressed after chemotherapy, there was an overall response rate of 15%. The median duration of response was 9.1 months and median survival was 13 months. Unwanted effects included potentially severe cardiotoxicity and in 40% of patients infusion-associated fever and/or shivering that usually occurred only during the first infusion. In patients with moderate HER-2/neu expression, unwanted drug effects outweigh a relatively weak therapeutic effect. In cases of high overexpression, the cancer may go into regression and survival may be prolonged with a relatively small impairment in the life quality. The costs of trastuzumab-therapy are high amounting to an additional 48,000 DM per patient per year. Recommendations for diagnosis and therapy in Mecklenburg-Vorpommern have been formulated in discussions between oncologists, practitioners, scientists and regulatory authorities.     

Efficacy and safety of Herceptin in women with metastatic breast cancer: results from pivotal clinical studies

Amplification of the human epidermal growth factor receptor-2 (HER2) gene and overexpression of the encoded protein are seen in 20-30% of breast cancers, and are associated with aggressive disease and relatively poor prognosis. Thus, HER2 represents an appropriate target for anticancer treatment and the humanized anti-HER2 monoclonal antibody Herceptin has been developed for this purpose. The efficacy of Herceptin has been confirmed in two pivotal trials-a monotherapy study in 222 women with HER2-positive metastatic breast cancer who had already received one or two chemotherapy regimens for metastatic disease and a study comparing Herceptin plus chemotherapy with chemotherapy alone in 469 patients previously untreated for metastatic disease. Herceptin monotherapy was associated with longer median response duration and survival than previous chemotherapy. Addition of Herceptin to chemotherapy increased response rates, time to disease progression and survival duration. Benefit was greatest in patients with high-level HER2 overexpression. Herceptin was well tolerated, with mild to moderate infusion-related reactions, usually seen with the first infusion only, being the most common event. Most patients respond to conventional supportive treatment. Cardiotoxicity, the most serious adverse event observed, occurred mainly in patients exposed to anthracyclines and was generally manageable. Thus, Herceptin represents a significant development in the management of HER2-positive breast cancer.     

Trastuzumab: a review of its use in the management of HER2-positive metastatic and early-stage breast cancer

Trastuzumab (Herceptin) is a humanised monoclonal antibody used in the treatment of breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2), which is associated with clinically aggressive disease and a poor prognosis. The addition of intravenous trastuzumab to first-line chemotherapy improved the time to disease progression, objective response rate, duration of response, and overall survival in randomised, multicentre trials in women with HER2-positive metastatic breast cancer. As such, trastuzumab has become the standard of care in this setting, despite its high acquisition cost and potential for cardiac events, and is licensed for use in combination with paclitaxel (Europe and the US) or docetaxel (Europe). In addition, trastuzumab monotherapy is approved for use in patients with HER2-positive metastatic breast cancer who have previously received chemotherapy for their metastatic disease. Recent data from large phase III trials with trastuzumab in the adjuvant setting revealed significant improvements in disease-free and overall survival. Thus, trastuzumab is also rapidly becoming a standard component of adjuvant therapy for patients with HER2-positive early-stage breast cancer.     

New perspectives on anti-HER2/neu therapeutics

HER2/neu and the epidermal growth factor receptor (EGFR) are significantly overexpressed in several cancer cells. Overexpression of these two receptors accounts for progression of many types of cancer: breast, ovarian, skin, pancreas and brain. In recent years, several approaches to disable the receptor complexes have shown promise. Antibody-based therapy, kinase inhibitors and other inhibitors of signaling molecules are the major approaches. Our group developed the concept that an anti-p185HER2/neu monoclonal antibody might represent a therapeutic for cancer and this has culminated in a clinically useful therapeutic, the humanized monoclonal antibody Herceptin (trastuzumab). We have now developed a small-molecule form of an anti-HER2/neu peptidomimetic (AHNP) that exhibit functions comparable to those of the monoclonal antibody Herceptin. This approach may be considered a new paradigm in receptor-specific tumor therapeutics. A brief review of our approach in developing receptor-specific therapeutic agents for HER2/neu-related cancer is presented.     

Trastuzumab: a pharmacoeconomic review of its use in early breast cancer

Trastuzumab (Herceptin) is a monoclonal antibody approved for the treatment of breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2). Well designed clinical trials in women with early breast cancer have demonstrated that 1 years' therapy with adjuvant intravenous trastuzumab (a loading dose followed by 6 mg/kg every 3 weeks or 2 mg/kg weekly) significantly improves disease-free survival and overall survival compared with observation (subsequent to chemotherapy) or chemotherapy alone in women with HER2-positive disease. In the HERA trial, disease-free survival was estimated to improve by 6.3% at 3 years in the trastuzumab group compared with the observation group. Trastuzumab is generally well tolerated. The most common adverse events are infusion-related symptoms, such as fever and chills, which usually occur with administration of the first dose. Cardiotoxicity occurs in a small proportion of patients receiving trastuzumab, particularly when coadministered with anthracyclines, and cardiac assessment is recommended for all patients at baseline and at 3-monthly intervals. In modelled cost-effectiveness analyses based on data from clinical trials in patients with HER2-positive early breast cancer, adjuvant trastuzumab was predicted to be cost effective from a healthcare payer or societal perspective in several countries. Incremental costs per QALY or life-year gained with trastuzumab administered subsequent to or concurrent with chemotherapy compared with chemotherapy alone were consistently within accepted local thresholds for cost effectiveness. Sensitivity analyses demonstrated that these results remained generally robust to plausible changes in key model assumptions. In conclusion, in patients with HER2-positive early breast cancer, the addition of adjuvant trastuzumab is clinically effective in improving disease-free survival. Available pharmacoeconomic data from several countries, despite some inherent limitations, support the use of adjuvant trastuzumab for 1 year as a cost-effective treatment relative to chemotherapy alone in this patient population.     

Lapatinib: a novel EGFR/HER2 tyrosine kinase inhibitor for cancer

Lapatinib is an oral dual tyrosine kinase inhibitor that targets epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2), both frequently overexpressed in human cancer. Preclinical data have shown that lapatinib is a potent and selective inhibitor of the tyrosine kinase domain of EGFR and HER2, and tumor cells that overexpress these receptors are growth inhibited by lapatinib both in vitro and in vivo. Phase I clinical trials have shown that lapatinib is well tolerated, with mild diarrhea and rash the most frequent toxicities, and early evidence of clinical efficacy has been reported especially in HER2-positive breast cancer. Phase II studies have shown activity for lapatinib in trastuzumab-refractory breast cancer either alone or in combination with trastuzumab. When used as first-line monotherapy for advanced breast cancer, objective tumor responses have been seen in 28% of patients with untreated HER2-positive advanced breast cancer. An extensive phase III program in advanced breast cancer is now in progress both for refractory disease and as first-line therapy in combination with chemotherapy with and without trastuzumab, and with endocrine therapy. Phase II studies have also been conducted in a variety of other tumors, including renal cell cancer. Parallel biomarker studies are starting to elucidate predictive molecular phenotypes that may indicate likelihood of response to lapatinib, and these may direct future trials with this oral tyrosine kinase inhibitor.     

Simultaneous amplification of HER-2 (ERBB2) and topoisomerase IIalpha (TOP2A) genes--molecular basis for combination chemotherapy in cancer

The HER-2 (also known as ERBB2/ErbB2/c-erbB2/HER-2/neu) oncogene is the most frequently amplified oncogene in breast cancer and is also amplified in other forms of cancer. Beside its important role in tumor induction, growth and progression, HER-2 is also a target for new therapeutic approaches such as Herceptin (trastuzumab), a recombinant antibody designed to block signaling through the HER-2 receptor. In addition to Herceptin, which is in a wide clinical use for HER-2 amplified breast cancer, a number of various HER-2 directed immunological and genetic strategies, either targeting the HER-2 receptor, its signaling pathways or both HER-2 and epidermal growth factor receptor (EGFR) simultaneously, have demonstrated promising pre-clinical activity in HER-2 amplified carcinomas. Moreover, the HER-2 amplicon is known to contain more than 30 genes with altered copy numbers that could be therapeutic targets for chemotherapy. The topoisomerase IIalpha gene, TOP2A, is located adjacent to the HER-2 oncogene at the chromosome location 17q12-q21 and is either amplified or deleted (with equal frequency) in a great majority of HER-2 amplified primary breast tumors and also in tumors without HER-2 amplification. Recent experimental as well as numerous, large, multi-center trials suggest that amplification (and/or deletion) of TOP2A may account for both sensitivity or resistance to commonly used cytotoxic drugs, i.e. topoII-inhibitors (anthracyclines etc.), depending on the specific genetic defect at the TOP2A locus. The understanding of HER-2 amplification and its role in the pathogenesis of cancer is expanding, and a number of therapeutic strategies targeting either the HER-2 or its signaling pathways in cancer therapy are being investigated. Combining HER-2 targeting therapies with conventional forms of cytotoxic chemotherapy, where additional diagnostic tests such as those ascertaining TOP2A status, may be helpful for the ideal selection of patients for the combination therapy of an HER-2 targeting drug together with a cytotoxic drug such as topoII-inhibitor especially in the case of TOP2A amplification.     

Distribution of prognostically unfavourable product of c-erbB-2 oncogene and EGF-R in carcinomas of the breast and uterine cervix

A comparative study was undertaken between cancer of the uterine cervix (n = 50) and female breast cancer (n = 50) with reference to the expression of c-erbB-2 oncoprotein (HER-2/neu) and that of epidermal growth factor receptor (EGF-R), both being highly homologous structurally. Expressions of EGF-R and c-erbB-2 oncoprotein were viewed in breast and cervical cancer tissues by immunochemical staining. Cervical cancer cases showed much higher expression of EGF-R which also revealed significant association with the expression of c-erbB-2 oncoprotein and tumour grading. Among breast cancer cases, over-expression of EGF-R correlated significantly with metastasis of lymph node; and expression of c-erbB-2 oncoprotein showed a significant relationship with histological grading of the tumour. Moreover, an association was noticed between the tumour grade and the concomitant immuno positive expression of EGF-R and c-erbB-2. Our study revealed an existence of a conflicting pattern in the expression of EGF-R and c-erbB-2 oncoprotein between carcinomas of the breast and uterine cervix.