There is a clear need for an effective adjuvant therapy for patients at high risk of recurrence from melanoma. To date the only treatment licensed for use as adjuvant therapy in melanoma has been interferon a2b which followed the publication o f the results of the ECOG 1684 trial. However interferon is a costly and toxic drug and the survival benefits demonstrated by the ECOG 1684 trial have not been replicated by any other clinical trials. The use o f interferon as adjuvant therapy in melanoma is therefore now controversial.
The mechanisms by which interferon exerts its effects are not fully established. A number of studies have demonstrated that the growth inhibitory effects of interferon are associated with c-myc down-regulation. Furthermore, interferon is also known to up-regulate cell surface HLA expression, either directly or via c-myc down- regulation. This can be expected to lead to more effective anti-tumour activity by cell-mediated immunity. It can therefore be postulated that c-myc down-regulation plays a pivotal role in the anti-tumour activity of interferon. However the worst prognosis primary and metastatic melanoma tumours are known to express the highest levels of the c-myc oncogene (Grover et al. 1997, Ghana et al. 1998, Ross et al. 1998). This may potentially render them relatively resistant to the anti-tumour effects of interferon. To investigate the relationship between tumour c-myc expression and interferon sensitivity, these two parameters were measured in a series of 45 uveal melanomas.
The overall c-myc expression of the whole series o f tumours was uniformly high - the mean c-myc positivity was 85.1% and the median value was 92%. This was significantly higher than the mean c-myc positivity o f 70.2% which was demonstrated in a series of 71 uveal melanomas by the previous RAFT fellow (Jagdeep Ghana MD thesis 1998).
A trend towards higher tumour c-myc positivity was observed in tumours o f male patients. Tumours of larger diameter and those of mixed cell type demonstrated higher c-myc positivity levels, although this was not statistically significant. No relationship was shown between c-myc positivity and these factors in the previous study. The relationship between tumour c-myc expression and prognosis could not be assessed in this series of uveal melanoma tumours due to the short period of patient
follow-up. The future analysis of this relationship in this tumour series will be of interest as the previous series of uveal melanomas analysed by Jagdeep Ghana showed high c-myc expression to be associated with an improved prognosis (Jagdeep Ghana MD thesis 1998). This is in contrast to all other studies performed in other types o f melanoma and other cancers. The reasons for this inverse relationship were not clear but may be related to the failure o f conventional antibodies to detect abnormal tumour c-myc molecules in the poorest prognosis uveal melanoma tumours.
When the factors affecting tumour interferon sensitivity were assessed, age was found to be a statistically significant factor in predicting sensitivity to interferon as measured by the maximum inhibitory percentage. A trend towards increased sensitivity in younger patients was observed when the interferon sensitivity index was used to measure the interferon sensitivity. Both the larger tumours and those of mixed tumour cell type were associated with decreased interferon sensitivity by both measures of assessing interferon sensitivity although this didn’t reach statistical significance. Older melanoma patients are known to have a poorer prognosis when compared to younger patients with tumours of the same size. Tumour diameter and cell type have also been shown to be prognostic factors for uveal melanoma. These factors were related to interferon sensitivity in this series but without statistical significance, although it is epithelial rather than mixed cell type tumours that are thought to have the worst prognosis.
When the c-myc positivity was correlated with the maximum inhibitory percentage a marginally statistically significant relationship was demonstrated at the 5% degree of significance. The tumours expressing the highest levels o f c-myc were the least sensitive to interferon. A similar relationship was found when the interferon sensitivity index was used to assess interferon sensitivity, although this did not reach statistical significance. In addition, the observation that the group of tumours as a whole expressed high levels of the c-myc oncogene (mean = 80.5%) and were resistant to interferon (interferon sensitivity index = 617.5) lends further weight to the c-myc-interferon sensitivity link. Furthermore, the larger tumours and those of mixed cell type were associated with both higher c-myc positivity and interferon resistance.
These results support the concept that c-myc down-regulation is associated with the cell growth inhibition produced by interferon They also demonstrate that interferon
resistance is associated with tumour c-myc overexpression. Therefore not only is c- myc over-expression associated with poor prognosis in the majority of melanoma types, in addition to a number of other cancers, but this study appears to show that it is also associated with resistance to interferon. This has important implications for the use of interferon as adjuvant therapy for melanoma. The patient group which would gain most from effective adjuvant therapy, that is those with the worst prognosis and the highest c-myc expression levels, are the least sensitive to interferon. This may explain why the efficacy o f interferon as an adjuvant agent in melanoma has been questioned. It suggests that the use of interferon alone as adjuvant therapy in melanoma is likely to be o f no benefit as has been demonstrated by all the clinical trials except one - ECOG 1684.
More importantly, perhaps, the link between c-myc over-expression and interferon resistance suggests that the use of therapeutic strategies to block the effects o f the c- myc gene, such as by the use of antisense gene therapy, may potentially overcome tumour resistance to interferon. The combination o f these two therapies may therefore offer a potential method to increase the efficacy o f interferon and offer the prospect of more successful adjuvant therapy in the future. This is therefore the subject of the next chapter in this thesis.