Our group was amongst the first in continental Europe to treat patients with fulvestrant as part of a compassionate use programme supported by AstraZeneca. In our institution it is common practice to evaluate tumour marker levels following each month of palliative therapy. During informal analysis of such data in patients receiving fulvestrant, potential differences in tumour marker kinetics were noted within the subgroup of patients responding to therapy and thus a detailed investigation was carried out.
In this study a trend towards increased CA 15-3 levels was noted during the first 3 months in patients responding to fulvestrant treatment. This trend became stronger over time, but still failed to reach statistical significance after 6 months of treatment. This result was unexpected since these patients were responding to fulvestrant therapy. The only occasion in which CEA appeared to have a higher predictive value than CA 15-3 was in the subgroup of patients experiencing a PR, where the observed decrease in CEA levels attained statistical significance after 6 months.
In the group of patients experiencing SD we found a significant increase in CA 15-3 levels at both 3 and 6 months. This was observed both in patients with SD ≥ 6 months but < 9 months and in those experiencing SD ≥ 9 months, thus this observation is unlikely to result from a bias caused by a lead-time effect to actual PD. There are several possible explanations for this early increase in tumour marker levels. First, it may be as a result of the delay in reaching steady-state levels with fulvestrant treatment , although this appears unlikely as these patients were already experiencing CB with fulvestrant. Nonetheless it seems reasonable to ask whether a loading-dose regimen of fulvestrant may be appropriate and this type of dosing is under investigation in ongoing clinical trials . However, as initial increases in CEA and CA 15-3 have also been observed in patients experiencing CB with other breast cancer therapies [8, 22–25], the dose of fulvestrant seems unlikely to be the cause. One explanation is that the increase in tumour markers may result from increased tumour degradation in response to fulvestrant treatment. These data may suggest that, in the absence of radiological detection of PD, fulvestrant treatment should be continued beyond 3 months before response to therapy is assessed. Marker levels in patients with de novo PD increased steadily during fulvestrant treatment as may be expected in the presence of non-responsive disease. As tumour marker levels may rise in both responding and non-responding patients during the first few months of fulvestrant treatment, it may be that an increase in markers following a period of stabilisation may be more predictive of disease progression.
The data presented here suggest that if increased CA 15-3 levels are observed after the first 3 months of fulvestrant treatment this should not be taken as a sign of PD without radiological verification. On the contrary, such an increase may also be observed in patients gaining CB from treatment. Consequently, our results demonstrate that it is inappropriate to change therapy purely based on increased tumour marker levels, as some patients may still be benefiting from fulvestrant treatment.
In our study CEA levels were found to decrease significantly after 6 months in patients experiencing a PR and to increase significantly in those with SD. Significant rises in CEA were also observed in patients experiencing de novo PD.
The predictive value of tumour markers in signalling secondary progression was also prospectively assessed. We found that both CA 15-3 and CEA levels increased significantly during the last 3 months of treatment and so these markers may be valuable in predicting secondary progression. However, both the CEA and CA 15-3 data need to be treated with some caution because of the small number of patients in this study.