The two studies that led to the licensing of herceptin as treatment for metastatic breast cancer have now been published [4,5]. A re-analysis of data from both these studies supports the preclinical observation of a relationship between HER-2 expression and growth inhibition of tumour cell lines by antibodies to the receptor (Genentech, San Francisco, data held on file).
In the pivotal phase II study, heavily pretreated patients whose tumour overexpressed HER-2 at the 2 and 3+ levels by immunohistochemistry (IHC) were treated with herceptin as a single agent. Following re-analysis by a 'response evaluation committee', the overall response rate in this group was 15% with a median survival of 9.1 months [4]. While this response rate itself appears modest, it is noteworthy that the majority of these patients had already received anthracyclines and taxoids, and about one-quarter of patients had received a high dose regimen of chemotherapy. In addition, those patients who did respond to herceptin had a longer duration of response following treatment, compared with their previous regimen of chemotherapy (9.1 months versus 5.2 months). Retrospective analysis of response rate and median survival restricted to the patients whose tumours overexpress HER-2 at the highest levels (immunohistochemical score, 3+) had a response rate of 18% and a median survival of 16.4 months.
In the pivotal phase III study by Slamon et al. [5], patients were randomised to receive chemotherapy with or without herceptin. Patients were stratified according to whether or not adjuvant chemotherapy contained an anthracycline, such that the majority of patients who did not have adjuvant chemotherapy or whose adjuvant therapy did not contain an anthracycline were randomised to doxorubicin and cyclophosphamide with or without herceptin. In the subgroup of patients who had received an anthracycline in the adjuvant setting, patients were randomised to paclitaxel with or without herceptin.
The principle endpoint of the Slamon et al. study was median time to progression, which for the group as a whole was significantly longer in those patients receiving chemotherapy with herceptin compared with chemotherapy alone (7.4 months versus 4.6 months; P < 0.05). Time to progression was significantly longer in each of the chemotherapy subgroups (cyclophosphamide versus herceptin + cyclophosphamide, 6.1 months versus 7.8 months; paclitaxel versus herceptin + paclitaxel, 2.7 months versus 6.9 months). When both chemotherapy subsets were considered, a survival benefit attributable to herceptin with chemotherapy versus chemotherapy alone was noted (median survival, 25 months versus 20 months). This observed survival difference was despite the fact that nearly three-quarters of patients treated initially with chemotherapy alone crossed over to herceptin as a single agent on progression of disease.
It is therefore possible that any observed survival difference attributable to herceptin has been somewhat underestimated. Interestingly, when the benefits of herceptin were analysed retrospectively in those patients expressing HER-2 at the highest level (immunohistochemical score, 3+), it became apparent that the difference in most parameters (time to progression, response rate and survival) was greater in those patients whose tumours expressed HER-2 at the 3+ level compared with the group as a whole. For example, survival in the HER-2 3+ subgroup was 29 months for those patients receiving chemotherapy with herceptin, compared with 20 months for those receiving chemotherapy alone [6].
The current limitation of herceptin use in combination chemotherapy remains the cardiac dysfunction observed as part of the pivotal phase III study and when herceptin was combined with anthracycline. Some level of cardiac dysfunction was observed in 27% of patients treated with doxorubicin/cyclophosphamide with herceptin, compared with only 7% treated with chemotherapy alone. Cardiac dysfunction reached grade III and IV levels of the New York Heart Association rating in 16% of patients at some point during therapy, reducing to 6% of patients once treatment had been completed. The aetiology of the cardiac dysfunction remains unclear, and combinations of herceptin with other anthracyclines, including epirubicin and liposomal doxorubicin, remain the subject of clinical trials. The license for herceptin in combination with chemotherapy is therefore restricted to its use with paclitaxel, where the addition of herceptin increased median survival from 18 to 25 months.
In summary, herceptin is currently licensed for use as a single agent following anthracycline and taxoid chemotherapy or in those patients for whom such therapies are unsuitable, and also in combination with paclitaxel. In both incidences, the current license restricts its use to those patients who tumours overexpress HER-2 at the highest level (3+) as assessed by IHC.
As well as conventional endpoints, health-related quality of life using the European Organisation for Research and Treatment of Cancer Quality of Life questionnaire QLQ-C30 was administered at baseline, week 8 and every 3 months thereafter. The five primary prospectively defined quality of life domains examined included global quality of life, physical, social and role functioning as well as fatigue. The use of herceptin with chemotherapy was associated with improvements in all these domains when compared with chemotherapy alone [7].