Royal North Shore Hospital
St Leonards NSW
Our understanding of cancer has progressed dramatically in the past two decades, following the discovery that changes in important growth-regulating genes within cells can alter their behaviour and lead to cancer. One such gene, HER2/neu, is amplified in some cases of breast cancer, including about 25-30% of women with advanced breast cancer. Extra copies of the gene lead to the production of extra copies of a receptor on the surface of the cell. Growth factors bind to the receptors, and stimulate tyrosine kinases, leading to unrestrained multiplication of the cell. Breast cancers with excess receptors may behave more aggressively1. Trastuzumab (Herceptin®) is now commercially available in most of the Western world, including Australia, for the treatment of women with advanced breast cancer who overexpress HER2 receptors.
Trastuzumab (Herceptin®) is a recombinant humanised mouse monoclonal antibody that has been developed to bind to the HER2 receptor. It induces immune attack on the cell, blocks receptor function and growth factor binding, and promotes the degradation of the receptor. It also appears to enhance chemotherapy cytotoxicity.
Trastuzumab is administered intravenously over 30-90 minutes, weekly, either alone or together with cytotoxic chemotherapy. An initial loading dose of 4mg/kg is followed by maintainance of 2mg/kg2,3. Third weekly schedules are currently under investigation as the half life is long.
To determine suitability for treatment, over expression of HER2 needs to be determined. HER2 expression is measured on breast cancer cells, usually from a sample stored after initial surgery. There are a number of different methods. Immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) are currently the best methods of measurement. By IHC, HER2 expression is characterised as 0, 1+, 2+, and 3+. Overexpression is defined as moderate (2+) or high (3+) staining. FISH is more sensitive, less observer-dependent, but technically more difficult and less widely available at present. Reference laboratories have been developed to perform FISH when the IHC is equivocal (2+ or patchy). These tests are expensive and do not currently attract a rebate. Data presented at the annual meeting of the American Society of Clinical Oncology in 2001 suggests that FISH positivity is a better predictor of response and survival4.
Side effects of trastuzumab include chills or fever during infusion (40% of patients), usually occurring during the first infusion2,3. These can be managed with paracetamol and antihistamines.
In combination studies neutropaenia is more common with coadministration of trastuzumab3. Cardiac dysfunction, of unknown aetiology, occurs in about 4% of patients treated with trastuzumab alone2, up to 10% of patients treated with trastuzumab + paclitaxel, and up to 28% of patients treated with trastuzumab + anthracyclines (doxorubicin or epirubicin)3. Patients with poor baseline cardiac function and advanced age have a higher risk of cardiac dysfunction when treated with combination therapy6. Cardiac monitoring is recommended prior to commencement of therapy, particularly in patients pretreated with anthracyclines, and at regular intervals. Cardiac dysfunction appears to remit and to respond to ACE inhibitor therapy, and reintroduction of trastuzumab may be possible6. Patients with extensive pulmonary involvement with metastatic breast cancer may experience acute deterioration in respiratory function, presumably due to an acute inflammatory response. Caution is advised in this setting.
In highly HER2 over-expressing patients with advanced breast cancer who had received prior chemotherapy, trastuzumab used alone induced major responses in about 15% of patients, and minor responses or stable disease in a further 10%. The median duration of response was nine months and in all patients treated, the median survival 13 months2. Monotherapy was well tolerated, with only 1% of patients discontinuing because of treatment related adverse events. In studies of trastuzumab alone responses are usually seen within two to three months of starting treatment. First line monotherapy studies are currently underway.
First line controlled studies of trastuzumab plus chemotherapy (paclitaxel or doxorubicin) compared to the same chemotherapy alone have shown that the addition of trastuzumab significantly improves response rate (52% vs 45%), time to progression (7.6 vs 4.6 months), one year survival (78% vs 67%) and overall survival (25 vs 20 months). Survival benefits are probably underestimated as two-thirds of patients receiving initial chemotherapy crossed over to trastuzumab when they progressed. Significantly larger proportions of patients in the combination arms experienced an improvement in quality of life5. Benefits were greater in the HER2 highly over-expressing group but also occurred in the HER2 moderately over-expressing group3. Older patients (>60 year old) had worse overall outcomes but still benefited from the addition of trastuzumab. Patients responding after combination therapy for six months were continued on trastuzumab until progression. Because of the high risk of cardiotoxicity in the anthracycline arm, combinations of anthracyclines and trastuzumab are not recommended.
Current trials are exploring other combinations of trastuzumab and chemotherapy. Combination with Vinorelbine yielded a response rate of 75% in a phase II study in pretreated women7, and preliminary data with docetaxel and cisplatin also appearing promising. Preclinical data suggests that synergy with these agents will occur, rather than the additive benefit with paclitaxel and anthracyclines.
A number of international adjuvant studies are either underway or in final planning stages. Cardiotoxicity will be of greater concern in the adjuvant setting and close monitoring is planned.
2. M Cobleigh, C Vogel, et al. “Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2 overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease”. Journal of Clinical Oncology, 17, 9 (1999):2639-2648.
5. D Osoba, D Slamon, et al. “Effects of treatment with HER2MAB plus chemotherapy versus chemotherapy alone on health related quality of life in women with HER2/neu overexpressing metastatic breast cancer.” Proc ASCO, 20, 109 (2001).