HER2-Positive Breast Cancer

Tykerb (lapatinib, GlaxoSmithKline) has received US Food and Drug Administration approval in combination with Xeloda (capecitabine, Roche) for the treatment of locally advanced or metastatic breast cancer in patients whose tumors over-express the HER2 receptor and who have previously received other cancer drugs, including an anthracycline, a taxane, and trastuzumab (Herceptin).

The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) have published a clinical practice guideline on improving the accuracy of human epidermal growth factor receptor 2 (HER2) testing for breast cancer patients.

AVEO Pharmaceuticals, Inc., has begun enrolling patients with advanced solid tumors in a phase I clinical study of AV-412, a next-generation oral tyrosine kinase inhibitor of EGFR and HER2. In preclinical studies, AV-412 has shown activity in various tumor models, has a toxicity profile similar to other molecules in its class, and has shown preclinical activity against tumor cells that are resistant to first-generation tyrosine kinase inhibitors, the company said in a press release.

GlaxoSmithKline's New Drug Application for Tykerb (lapatinib), an oral small molecule dual inhibitor of EGFR and HER2, has been granted priority review by the FDA. The designation requires that the agency decide on a drug application no longer than 6 months after submission, which was September 18, 2006, for Tykerb. The Tykerb application is for treatment of advanced or metastatic HER2-positive breast cancer in combination with capecitabine (Xeloda) for patients who have received prior treatment.

One of the best examples of the "bench to bedside" process is the development of trastuzumab (Herceptin) for HER2-overexpressed breast tumors. From the identification of the neu oncogene in 1984[1] and its subsequent cloning,[2] to the development of a humanized monoclonal antibody targeting HER2 that improved outcome not only in the metastatic setting[3] but also in the adjuvant setting[4-7] has been a long yet fruitful journey.

Up to 25% of patients diagnosed with breast cancer have tumors that overexpress HER2. HER2-positive breast cancer is highly proliferative, difficult to treat, and confers a poor prognosis. The advent of the anti-HER2 monoclonal antibody trastuzumab (Herceptin) has markedly altered the clinical course of both early and advanced HER2-driven breast cancer. Despite the use of trastuzumab, however, patients with HER2-positive breast cancer still experience disease progression. Overcoming that resistance to therapy is our next challenge. This review examines the current understanding of HER2 biology, the mechanisms of action of and resistance to trastuzumab, as well as new therapies on the horizon.

The oral small-molecule lapatinib (Tykerb), a reversible dual tyrosine kinase inhibitor of HER1 (epidermal growth factor) and HER2 receptors (see mechanism of action image on page 1), produced clinical responses in some women with inflammatory breast cancer (IBC), a rare but aggressive form of the disease that is not usually detected by mammograms or ultrasound.

Bayer HealthCare announced findings from a study using Bayer Diagnostics' serum HER2/neu test that demonstrated metastatic breast cancer patients whose serum HER2/neu levels decreased by less than 20% experienced decreased benefit from trastuzumab (Herceptin)-based therapy.

GlaxoSmithKline (GSK) announced results from a large, randomized, pivotal phase III study of its investigational small-molecule dual kinase inhibitor lapatinib ditosylate (Tykerb). In this study, the combination of lapatinib and capecitabine (Xeloda) vs capecitabine alone nearly doubled time to progression (36.9 weeks in the combination arm vs 19.7 weeks with capecitabine alone, P = .00032) in women with refractory advanced or metastatic HER2 (ErbB2)-positive breast cancer whose disease had progressed following treatment with trastuzumab (Herceptin) and other cancer therapies.

Young, black breast cancer patients are much more likely than young white patients to have tumors that lack receptors for estrogen, progesterone, and HER2, according to a new, population-based study in about 500 women. This means that many breast cancer patients, including almost half of young black patients, "have tumors for which there is no targeted therapy," said lead author Mary Jo Lund, PhD, assistant professor of epidemiology, hematology, and oncology, Rollins School of Public Health and Winship Cancer Institute, Emory University, Atlanta.

Lapatinib (Tykerb), an oral small-molecule reversible dual inhibitor of HER1 (EGFR) and HER2 tyrosine kinases, is emerging as a promising option for HER2-positive breast cancer patients, investigators of phase II and III trials reported at the 42nd Annual Meeting of the American Society of Clinical Oncology (ASCO). Clinical evidence suggests that lapatinib, unlike trastuzumab (Herceptin), can cross the blood-brain barrier to treat brain metastases, which develop in about one-third of HER2-positive breast cancer patients.

The first interim results from the BCIRG 006 phase III trial showed that trastuzumab (Herceptin) combined with docetaxel (Taxotere)-based regimens significantly improved disease-free survival (DFS) in early HER2-positive breast cancer. Genetic studies further delineated a subgroup of patients for whom truly targeted therapy may be applied in the future.

SAN ANTONIO—GlaxoSmithKline has announced the initiation of a global multicenter phase II trial (known as EGF 105084) to evaluate Tykerb (lapatinib) for the treatment of ErbB2 (HER2)-overexpressing breast cancer that has metastasized to the brain. Tykerb is an orally bioavailable small molecule that potently inhibits two receptors, ErbB2 and ErbB1. It is currently in development as a first-line treatment for ErbB2-overexpressing breast cancer.

The past 2 decades of systemic therapy for breast cancer have beena period of monumental change, in terms of both theory and technology.Adjuvant therapy developed from two strands of research-one insystemic chemotherapy and one in hormonal therapy-both of whichwere aided by the application of higher statistical methodology to clinicaltrials. The agent with the single greatest public health impact inoncology has been tamoxifen, but problems with tamoxifen therapy ledto the development of the aromatase inhibitors, and further researchled to the use of hormonal therapy in a chemopreventive capacity. Theevolution of systemic chemotherapy for breast cancer has been an interplaybetween theory-driven approaches and new agents. By the late1980s, accumulating data revealed that overexpression of HER2 (erbB2)played an important role in a substantial portion of breast cancers,which prompted the development of trastuzumab (Herceptin), an agenttargeting HER2-positive disease. Determining HER2 status proved essentialto assessing patient eligibility for trastuzumab therapy. Decodingof the human genome and application of bioinformatics furtherrevolutionized the possibilities in breast cancer treatment.

The epidermal growth factor (EGF) receptor HER2 is a transmembranereceptor tyrosine kinase that plays a crucial role in the regulationof cell proliferation and survival. The overexpression of HER2correlates strongly with prognosis in breast cancer. The targeted blockadeof HER2 activity with monoclonal antibodies (eg, trastuzumab[Herceptin]) and small-molecule tyrosine kinase inhibitors (eg,lapatinib) results in the inhibition of tumor growth in HER2-positivecancers. Anti-HER2 therapies have also shown efficacy in combinationwith chemotherapy in clinical trials in patients with HER2-positive breast cancer. Their efficacy may, however, be limited bymolecular mechanisms that compensate for HER2 suppression (eg,activity of EGF receptor) or mechanisms of resistance (eg, loss ofPTEN). HER2 continues, however, to be overexpressed by the cancercells, and the continued suppression of HER2 may be required formaximum antitumor effect. It should be noted that in the absence ofdefinitive data from randomized trials showing an absence or presenceof benefit, the use of anti-HER2 agents such as trastuzumab in multiplesequential regimens has become the standard of care. CombiningHER2 blockers with agents that overcome the compensatory or resistancemechanisms may increase the efficacy of anti-HER2 therapies.In addition, anti-HER2 therapies can have synergy with common chemotherapyregimens and remain effective through multiple lines oftherapy. Optimizing the use of therapies that target HER2 signalingwill lead to further advances in the treatment of breast cancer.

EDMONTON, Canada-Two docetaxel (Taxotere)-based chemotherapy regimens in combination with the monoclonal antibody trastuzumab (Herceptin) given after surgery significantly improved disease-free survival (DFS) in women with early-stage HER2-positive breast cancer, according to interim results of a phase III trial announced by the Breast Cancer International Research Group (BCIRG) and Sanofi-Aventis. The BCIRG 006 trial compared a standard treatment arm of four cycles of doxorubicin (Adriamycin) and cyclophosphamide followed by docetaxel (AC-T) with two trastuzumab-containing regimens: AC-T plus trastuzumab (AC-TH) and docetaxel plus carboplatin plus 1 year of trastuzumab (TCH) given concomitantly with chemotherapy.

ORLANDO-Interim findingsfrom two large randomized phaseIII studies-a North American jointanalysis and an international trial-have changed the standard of care for

Trastuzumab (Herceptin) is an effective treatment in patients withHER2-overexpressing metastatic breast cancer. Risk of trastuzumabinducedcardiotoxicity raises concerns regarding combined use withanthracyclines or other potentially cardiotoxic agents followinganthracycline treatment. We characterized interactions betweentrastuzumab and gemcitabine (Gemzar) and the combination ofgemcitabine and cisplatin or carboplatin (Paraplatin) as such combinationsmight help reduce the risk of cardiotoxicity. Multiple drugeffect/combination index isobologram analysis was used to study theefficacy of chemotherapeutic drug plus trastuzumab combinations inHER2-overexpressing breast cancer cell lines. Combination index valueswere derived from parameters of the median effect plots, and statisticaltests were used to determine whether the mean combinationindex at multiple effect levels significantly differed from a combinationindex value of 1.0 (values < 1.0 indicate synergy; values > 1.0,antagonism; values equal to 1.0, additivity). At a wide range of clinicallyachievable drug concentrations, interactions between trastuzumaband gemcitabine were synergistic at low concentrations of gemcitabineand antagonistic at high concentrations. A consistent synergistic interactionwas observed with the three-drug combination of trastuzumabplus gemcitabine plus carboplatin or cisplatin. Available clinical dataon the use of trastuzumab plus gemcitabine, and trastuzumab plusgemcitabine/paclitaxel, as well as clinical data on the use ofgemcitabine/cisplatin in breast cancer, are discussed. These findingsindicate that trastuzumab plus gemcitabine and trastuzumab plusgemcitabine plus cisplatin or carboplatin are rational combinations toevaluate in clinical trials.

Trastuzumab (Herceptin) is a therapeutic monoclonal antibody specificfor the human epidermal growth factor receptor type 2 (HER2), acell-surface tyrosine kinase receptor overexpressed by 25% to 30% ofbreast cancers. The drug is now regarded as one option for standardtherapy in HER2-overexpressing metastatic breast cancers. It is associatedwith a moderate response rate as a single agent, and in combinationwith standard chemotherapy, can produce greater response ratesand prolong the survival of women with advanced breast cancer. Itsactivity in metastatic breast cancer has led to active clinical trials examiningits potential role in the neoadjuvant and adjuvant settings.The successful clinical development of trastuzumab provides furtherproof of principle that biologically targeted therapies can have a profoundimpact on the management of breast cancer. Here we review theclinical development of this novel agent, emphasizing the potential fortherapeutic synergy when trastuzumab is combined with both standardchemotherapy and innovative molecularly targeted and biologic agents.

As a result of the availability and clinical efficacy of trastuzumab (Herceptin), clinicians are now faced with a dilemma regarding the accurate identification of patients with HER2 overexpression. In the October 2002 issue of ONCOLOGY,

Received approval from the US Food and Drug Administration (FDA) to include information about Abbott’s PathVysion-a fluorescence in situ hybridization (FISH) test-in the product insert for trastuzumab (Herceptin). FISH is used to detect human

The emerging era of targeted cancer therapies has focused laboratory scientists and clinicians on the need to define and understand molecular targets of novel drugs. For breast cancer patients and doctors, this trend is not news-efforts have been under way for decades to identify the estrogen and progesterone receptors and define the value of these markers as predictors of response to hormonal therapy.

The need for accurate detection of HER2 status is becoming more apparent, as therapeutic decisions are influenced by this information in both the adjuvant and advanced-stage setting. Since the US Food and Drug

The emerging era of targeted cancer therapies has focused laboratory scientists and clinicians on the need to define and understand molecular targets of novel drugs. For breast cancer patients and doctors, this trend is not news-efforts have been under way for decades to identify the estrogen and progesterone receptors and define the value of these markers as predictors of response to hormonal therapy.

Results from three retrospective studies demonstrated that fluorescence in situ hybridization (FISH) testing of tumor tissue for HER2 gene amplification is an effective method of selecting women with HER2-positive metastatic breast cancer who will

HER2 is a member of the type I tyrosine kinase growth factor receptor family and participates in normal growth control mechanisms. It is overexpressed or amplified in 20% to 30% of breast cancers, as well as other carcinomas. HER2 overexpression is associated with adverse prognostic indicators in primary breast cancer, and a number of reports have shown that HER2-overexpressing breast cancer is linked to an increased rate of recurrence/metastases, and therefore, decreased disease-free and overall survival rates.

The degree of pathologic response of tumor to primary chemotherapy is of considerable prognostic importance in patients with breast cancer. The addition of docetaxel (Taxotere) to an anthracycline-based primary chemotherapy regimen has been shown to result in significantly improved pathologic breast cancer response. The identification of predictors of treatment response will permit cytotoxic regimens to be tailored to individual patient requirements and permit pathologic response rates to be improved.

Data presented at the annual meeting of the American Society of Clinical Oncology further validated ChromaVision Medical Systems’ automated cellular imaging system (ACIS). The data from a collaborative study conducted by the United States National Institutes of Health, the Institute of Pathology in Basel, Switzerland, and two diagnostic companies, DAKO A/S and Vysis, Inc, documented that results of the ACIS HER2 immunohistochemical test correlate strongly with overall patient survival. Tests that provide information to help predict both the time and likelihood of survival are vital to clinicians in guiding critical treatment decisions.

NEW YORK-A new regimen of weekly paclitaxel (Taxol) plus the monoclonal antibody trastuzumab (Herceptin) produced an overall response rate of 60% among metastatic breast cancer patients, regardless of HER2 status, according to a study presented at the ASCO meeting.

PLANTATION, Florida-The humanized anti-HER2 antibody trastuzumab (Herceptin) produced an overall response rate of 26% when used as first-line therapy in women with metastatic breast cancer whose tumors overexpress HER2.