Higher serum 25-hydroxy vitamin D3 levels at presentation are associated with improved survival from melanoma, but there is no evidence that later prevailing levels are protective.

TO THE EDITOR: We read with interest the article by NewtonBishop et al, which provides further clinical evidence that vitamin D has an effect on cutaneous melanoma (MM) outcome, as has been suggested by previous studies on vitamin D receptor (VDR) polymorphisms. There is a strong body of epidemiologic evidence that vitamin D status has a protective effect against major systemic cancers. The authors report two studies: the first, a retrospective study, was described as a pilot study for the second prospective study, though surprisingly, there was a long overlap period between the two. The retrospective study involved patients with at least a 3-year, relapse-free period following initial diagnosis of the MM, and serum for 25hydroxyvitamin D3 [25(OH)D3] was taken on patients’ entry onto the study; the median time after diagnosis was 6.5 to 7.5 years. There was no statistically significant difference in serum 25(OH)D3 between patients who did or did not experience relapse (P .3). In the prospective study, serum 25(OH)D3 was estimated at a time close to presentation of the primary MM, and the serum was found to have a protective effect on Breslow thickness and an independent beneficial effect on relapse and survival. The serum 25(OH)D3 at presentation is likely to be a reflection of levels before development of the MM and during early development of the MM; therefore, vitamin D appears to inhibit local invasion and micrometastases during early tumor development. This certainly underlines the need to maintain vitamin D levels in the community. The authors go on to state that “. patients with melanoma who are avoiding sun exposure should take vitamin D3 supplements sufficient to ensure normal levels. ” There are two implications of this: first, the authors believe that the prevailing vitamin D status after excision of the primary MM has an effect on survival in addition to that of the vitamin D status at presentation; and second, vitamin D is still protective during that phase. We would support the first contention, but we believe the second is unjustified. It seems likely that the development of clinical metastases is a function of vitamin D status during early development of the tumor, during local invasion and development of micrometastases, and after presentation, during the phase of growth of micrometastases into clinical metastases. Later vitamin D status was not investigated in the prospective study, but there were limited, relevant data in the retrospective study. In that study, there was no statistically significant difference in serum 25(OH)D3 between patients who experienced relapse and those who did not, and the levels were apparently lower than those at presentation of the MM in the prospective study. This would suggest that, at the time (median 6.6 years after diagnosis), 25(OH)D3 levels were neither protective against nor a risk factor for relapse. However, the group of patients who experienced relapse was atypical in that relapses occurred late for a large majority of patients. The study entry criterion was that a patient had experienced no relapse within 3 years, and the mean time to relapse was 6.6 years, whereas the majority of relapses in an unselected series of MM occurs within 5 years. Thus no information is available for serum 25(OH)D3 levels up to when the large majority of relapses occurs. The fact that later levels in the retrospective study were lower than the levels at presentation of the prospective study might provide some evidence that higher 25(OH)D3 after excision predisposes to relapse. A greater proportion of patients with higher serum levels could have experienced relapse before the entry point of the retrospective study, leaving a population of patients with melanomas with lower levels of 25(OH)D3 still eligible for trial entry. An alternative explanation for lower levels in the retrospective study is that patients avoid sun exposure after diagnosis. Without further evidence, it is not possible to know which explanation is true or whether both are true. It is rather surprising that the authors made no estimate of levels of sun exposure in either study, given that sun exposure is accepted as a more important source of vitamin D than are dietary supplements, which they did investigate extensively. There are strong theoretical reasons for believing that vitamin D status after MM excision may not be protective but may predispose to further progression through immune suppression. The immunosuppressive effects of vitamin D include inhibition of dendritic cells, as mentioned by the authors, and a consequent downregulation of the T-helper cell 1 response and a direct inhibitory effect on T lymphocytes. There have also been reports of downregulation of natural killer cells. The net effect of vitamin D in cancer may be a balance between beneficial anticancer effects on the tumor cells and deleterious effects via the immune system. The authors imply that higher vitamin D levels may favor the immune-inhibitory effects. We are not aware of this, but we would suggest that a loss of expression of the VDR in the tumor cells would critically impair the anticancerous effect of vitamin D, leaving immune suppression unopposed. We have immunohistochemical evidence (unpublished) that VDR protein expression is reduced in MM, particularly in thick tumors, and more so in metastases. Similarly, in more aggressive colon cancer, decreased VDR expression has been reported as well as very low expression in metastases. Furthermore, there is evidence that response to vitamin D is compromised when VDR is poorly expressed in MM cell lines. In conclusion, many previous studies support the hypothesis that vitamin D has a protective effect on the development of cancer. Indeed, the article by Newton-Bishop et al adds weight to this and would suggest a beneficial effect in the early stages of development of cancer. However, we believe it is important not to extrapolate these results to a beneficial effect of the prevailing vitamin D status later (ie, following excision of the primary). There is no evidence from Newton-Bishop et al that, in this phase of metastatic growth, vitamin D is advantageous, and there is reason to suspect that it may be disadvantageous in the presence of downregulated tumor cell VDR. JOURNAL OF CLINICAL ONCOLOGY C O R R E S P O N D E N C E VOLUME 28 NUMBER 27 SEPTEMBER 2