Vitamin D Receptor Polymorphisms and Cancer.

Increasing scientific evidence supports the link between vitamin D and cancer risk. The active metabolite 1,25(OH)2D exerts its activity by binding to the vitamin D receptor (VDR), an intracellular receptor that mediates transcriptional activation and repression of target genes. The binding of 1,25(OH)2D to VDR is able to regulate hundreds of different genes. VDR is active in virtually all tissues including the colon, breast, lung, ovary, bone, kidney, parathyroid gland, pancreatic b-cells, monocytes, T lymphocytes, melanocytes, keratinocytes, and also cancer cells.The relevance of VDR gene restriction fragment length polymorphisms for various types of cancer has been investigated by a great number of studies.We have carried out a systematic review of the literature to analyze the relevance of more VDR polymorphisms (Fok1, Bsm1, Taq1, Apa1, and Cdx2) for individual malignancies considering ethnicity as a key factor for heterogeneity.Up to December 2018, we identified 176 independent studies with data to assess the risk of breast, prostate, colorectal, skin (melanoma and non-melanoma skin cancer), lung, ovarian, kidney, bladder, gallbladder, esophageal, thyroid, head and neck, liver and pancreatic cancer, oral squamous cell carcinoma, non-Hodgkin lymphoma, multiple myeloma and sarcoma.Significant associations with VDR polymorphisms have been reported for prostate (Fok1, Bsm1, Taq1, Apa1, Cdx2), breast (Fok1, Bsm1, Taq1, Apa1, CdX2), colorectal (Fok1, Bsm1, Taq1, Apa1), and skin cancer (Fok1, Bsm1, Taq1). Very few studies reported risk estimates for the other cancer sites.Conflicting data have been reported for most malignancies, and at present, it is still not possible to make any definitive statements about the importance of the VDR genotype for cancer risk. It seems probable that other factors such as ethnicity, phenotype, 25(OH)D plasma levels, and UV radiation exposure play a role as confounding factors and introduce heterogeneity.To conclude, there is some indication that VDR polymorphisms may modulate the risk of some cancer sites and in future studies VDR genetic variation should be integrated also with assessment of vitamin D status and stratified by ethnicity.

Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial.

Treatment of diabetics with metformin is associated with decreased breast cancer risk in observational studies, but it remains unclear if this drug has clinical antineoplastic activity. In a recent presurgical trial, we found a heterogeneous effect of metformin on breast cancer proliferation (ki-67) depending upon insulin resistance (HOMA index). Here, we determined the associations of additional serum biomarkers of insulin resistance, tumor subtype, and drug concentration with ki-67 response to metformin. Two-hundred non-diabetic women were randomly allocated to metformin (850 mg/bid) or placebo for 4 weeks prior to breast cancer surgery. The ki-67 response to metformin was assessed comparing data obtained from baseline biopsy (ki-67 and tumor subtype) and serum markers (HOMA index, C-peptide, IGF-I, IGFBP-1, IGFBP-3, free IGF-I, hs-CRP, adiponectin) with the same measurements at definitive surgery. For patients with a blood sample taken within 24 h from last drug intake, metformin level was measured. Compared with placebo, metformin significantly decreased ki-67 in women with HOMA > 2.8, those in the lowest IGFBP-1 quintile, those in the highest IGFBP-3 quartile, those with low free IGF-I, those in the top hs-CRP tertile, and those with HER2-positive tumors. In women with HOMA index > 2.8, drug levels were positively correlated with the ki-67 decrease, whereas no trend was noted in women with HOMA < 2.8 (p-interaction = 0.07). At conventional antidiabetic doses, the effect of metformin on tumor ki-67 of non-diabetic breast cancer patients varies with host and tumor characteristics. These findings are relevant to design breast cancer prevention and treatment trials with metformin.

Serum EGFR and serum HER-2/neu are useful predictive and prognostic markers in metastatic breast cancer patients treated with metronomic chemotherapy.

BACKGROUND: Metronomic chemotherapy has been demonstrated to be of value in patients with advanced breast cancer. No reliable markers of response are available. In breast tumor, HER-2/neu is a prognostic factor, whereas no definite data exist for EGFR. The aim of the study was to evaluate the prognostic and predictive role of serum HER-2/neu and serum EGFR in breast cancer patients treated with low-dose chemotherapy. METHODS: Serum levels of HER-2/neu (n = 135) and of EGFR (n = 113) were prospectively determined before the start of chemotherapy, after 2 months of treatment, and when progressive disease was diagnosed. RESULTS: Elevated (>15 ng/mL) serum HER-2/neu before the start of chemotherapy was not associated with response rate, whereas elevated serum HER-2/neu at 2 months was significantly associated with reduced long-term clinical benefit (24 weeks) (P < .001), as well as changes in HER-2/neu levels between baseline and 2 months (P < .0001). Multivariate analysis identified a >or=20% increase of serum HER-2/neu as an independent factor for progression-free survival (PFS). Kinetics of serum HER-2/neu were significantly associated with PFS (P < .0001) and overall survival (OS) (P = .015). Low baseline serum levels of EGFR (<45 ng/mL) were predictive of reduced response rate both at 2 months (P = .031) and after 24 weeks (P = .022). Moreover, they were significantly associated with reduced PFS (P = .016) and OS (P = .015). CONCLUSIONS: Serum HER-2/neu and EGFR may represent useful markers for early prediction of probability of response, PFS, and OS in patients with advanced breast cancer treated with metronomic chemotherapy.