Severe vitamin D deficiency associated with BRAF ‐mutated melanoma

Abstract

DEAR EDITOR, Low levels of vitamin D are associated with poorer prognosis, thicker tumours, ulceration and increased inflammation in primary melanoma. 1 In the U.K., testing is recommended by the National Institute of Clinical Excellence for any new patient diagnosed with melanoma, but not for those with already established or metastatic disease. Driver mutations in BRAF are found in approximately 50% of melanomas and play an important role in cell proliferation and metastases, and also increase inflammation by promoting secretion of proinflammatory cytokines, including interleukin (IL)-6 and IL-8. 2 Inflammation aids proliferation, survival of cancer cells, angiogenesis and metastasis. However, the relationship between BRAF and vitamin D has not been previously examined in patients with melanoma.We conducted a retrospective study to determine levels of 25-hydroxy vitamin D in patients with primary and metastatic melanoma, and make comparisons according to age, sex, stage, season and BRAF status. Classification of vitamin D deficiency (often defined as ≤ 50 nmol L À1 ) remains controversial; however, this is dependent on the type of laboratory testing used. Therefore, we defined deficiency as ≤ 70 nmol L À1 and severe deficiency as ≤ 30 nmol L À1 , as per our laboratory standards. We tested 124 patients (65 men, 59 women; age range 23-85 years) who attended dermatology and oncology clinics from May 2016 to October 2017. Any patients taking vitamin D supplements were excluded. BRAF status was measured in patients with stage III or IV melanoma (American Joint Committee on Cancer, 7th edn). Overall, 104 patients (84%) were vitamin D deficient, 32 of whom (31%) were severely deficient. Four patients were classified as stage 0 melanoma (3%), 18 patients were stage I (14%), seven were stage II (6%), 16 were stage III (13%) and 79 were stage IV (64%). Of the patients with stage IV melanoma, 69 (87%) were vitamin D deficient. There was no variation in patient's levels of vitamin D with regard to the seasons, sex or age. BRAF status was established in 93 patients, 59 of whom (63%) were positive for BRAF mutation. Of these, 22 patients (37%) were severely vitamin D deficient compared with three (9%) BRAF wild-type (P = 0Á006). Of the 43 patients who died, 37 (86%) were vitamin D deficient; 14 of the 43 deceased patients (33%) were severely vitamin D deficient and 11 of these 14 patients (79%) were positive for BRAF mutation.Studies have demonstrated a threefold increased risk of death for higher-risk tumours harbouring NRAS or BRAF mutations compared with wild-type melanomas, after adjusting for other prognostic factors. 3 Further studies are required to investigate the association of severe vitamin D deficiency with BRAF-mutated melanoma, especially as low vitamin D levels may impact and increase the incidence of immune-related adverse events in patients receiving immunotherapy. 4 In this study, over 80% of patients with melanoma were vitamin D deficient; therefore, we recommend testing for all patients with melanoma reg...

Low Vitamin D Status Predicts Poor Clinical Outcome in Advanced Melanoma Treated With Immune Checkpoint or BRAF/MEK Inhibitors: A Prospective Non-Interventional Side-by-Side Analysis

“…Driver mutations in BRAF are found in approximately 50% of melanomas, play an important role in cell proliferation and metastases, and also increase inflammation by promoting secretion of pro-inflammatory cytokines, including interleukin (IL)‐6 and IL‐8 ( 5 ). Inflammation aids proliferation, survival of cancer cells, angiogenesis, and metastasis.…”

“…A retrospective study determined levels of serum 25(OH)D in patients with primary and metastatic melanoma and made comparisons according to age, sex, stage, season, and BRAF status ( 5 ). In that study, BRAF status was established in 93 patients, 59 of whom (63%) were positive for BRAF mutation.…”

“…Consequently, there is urgent need to characterize the molecular mechanisms that exert the therapeutic efficacy of these new treatment modalities and to identify factors that show promise to further optimize melanoma treatment. It has been shown that low levels of vitamin D are associated with poorer prognosis, thicker tumors, ulceration, and increased inflammation in primary melanomas ( 5 , 6 ). Several independent lines of investigation have supported the hypothesis that 25(OH)D serum concentration (s.c.) may be associated with the risk and prognosis of melanoma.…”

MicroRNA-21-Enriched Exosomes as Epigenetic Regulators in Melanomagenesis and Melanoma Progression: The Impact of Western Lifestyle Factors

“…Delivery of exosomal anti-miR-21 may be a promising new option for MM treatment [ 367 , 368 , 369 , 370 ]. The fact that VD/VDR signaling attenuates miR-21 expression [ 305 , 306 , 307 ] suggests that VD deficient individuals should be given oral VD supplementation, and questions extensive use of sunscreens for MM prevention. Obviously, there should be an appropriate balance between UV-induced exosomal miR-21 expression and UV-stimulated vitamin D/VDR-mediated attenuation of miR-21 expression.…”

“…Vitamin D (VD) deficiency has been associated with a poorer outcome in MM [ 282 , 283 ], and has been correlated with BRAF-mutated MM [ 305 ]. Higher 25-hydroxyvitamin D 3 (25OHD 3 ) levels are associated with lower Breslow thickness at diagnosis and are independently protective of relapse and death of MM [ 306 ], whereas patients with low 25OHD 3 concentrations are associated with greater Breslow thickness and reduced survival [ 307 , 308 ].…”