Trastuzumab (Herceptin™) is a recombinant humanised monoclonal antibody that inhibits the proliferation of human tumour cells that overexpress the human epidermal growth factor receptor 2 (HER2). In patients with metastatic breast cancer whose tumours overexpress HER2, trastuzumab is licensed as monotherapy or combination therapy with other chemotherapy or hormonal agents until progression of disease. It is not licensed for use following disease progression.

There is a great deal of controversy and practice variation in the UK regarding the continued use of trastuzumab at the time of disease progression; this may be because there is uncertainty as to the mechanisms of resistance and whether this is partial or absolute.

In their clinical guidance on advanced breast cancer, NICE have recommended that for patients who are receiving treatment with trastuzumab for advanced breast cancer, treatment with trastuzumab should be discontinued at the time of disease progression outside the central nervous system on the basis that there is limited evidence of clinical benefit and there is no robust evidence for its cost effectiveness. If disease progression is within the central nervous system alone, treatment with trastuzumab should be continued. NICE note within the guideline that they were aware of limited, very recent evidence (Von Minckwitz study; not included in NICE evidence appraisal but discussed below) of clinical benefit for the use of trastuzumab on disease progression but made the recommendation on the basis that it would not be appropriate to recommend the use of trastuzumab on disease progression without robust evidence of the cost effectiveness of this high cost treatment.

As NICE note, there are very limited data supporting the continued use of trastuzumab after disease progression. One post-RCT analysis showed that the efficacy and incidence of adverse events were comparable between the group that continued on trastuzumab compared to the group that had trastuzumab for the first time after disease progression.  Results of the von Minckwitz study found the overall response and time to progression to be statistically superior with the combined therapy compared to capecitabine alone with no additional significant toxicity. In this trial the median time to progression in patients continuing to receive trastuzumab (plus capecitabine) was 8.2 months vs 5.6 months – a difference of 2.6 months. However the study was underpowered, there may have been potential for bias in the assessment of response rates by the unblinded investigator, patients in the capecitabine group may have had an on-going exposure to trastuzumab because of the drugs long half-life and the trial did not show that the difference in progression-free survival resulted in a statistically significant impact on overall survival (25.5 months vs 20.4 months). A phase II study and six retrospective case series provide some additional evidence in support of continuing trastuzumab therapy beyond disease progression but because the data are uncontrolled it is difficult to set the results described into clinical context.

NICE estimate that annual savings of £11,717,000 in England and Wales, equating to a saving around £21,500 per 100,000 population, could be realised if trastuzumab was discontinued in women whose disease progresses. This saving is based on an estimate that there are currently 777 patients (or between 1 and 2 per 100,000 population) are being treated every year with trastuzumab for disease that has progressed outside the CNS.

York Health Economics Consortium (YHEC) reviewed a cost-utility analysis, submitted by Roche, of trastuzumab compared to capecitabine monotherapy in post-progression HER2 positive metastatic breast cancer. The model used the clinical survival data from the von Minckwitz study. The results from the model reported an incremental cost per quality adjusted life year (QALY) of £54,137. This is well above the normal threshold of £20,000 to £30,000 per QALY accepted by NICE.  The sensitivity analysis showed the results were robust. YHEC judged that the economic model itself, and the values used to populate it, were in the main acceptable and thus the result was valid to use for decision making purposes.