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Background FRα overexpression in epithelial ovarian cancer (EOC) may confer a tumor growth advantage. We examined the relation between multivitamin use, a proxy for folic acid intake, with FRα expression in ovarian tumors and assessed whether the association was modified by alcohol intake, a folate agonist. Methods Cases (n=148) aged 20-80 years were seen at Mayo Clinic, MN between 1/00 and 8/04 with suspected EOC. Controls (n=148) without history of cancer and both ovaries intact were frequency matched to cases by age (5 years) and state. Lifestyle, medical and reproductive factors, regular multivitamin (≥ 4 pills per week) and weekly alcohol (≥ 5 vs <5 drinks) intakes over the past year were assessed. Tissue microarray (TMA) slides of tumors were constructed, stained with affinity purified anti-FRα antibody Pu17, digitally imaged and scored for staining intensity. Forty cases were excluded (no/insufficient tumor, or not primary EOC, or negative biopsy), leaving 108 cases available for analysis. Unconditional logistic regression multivariable odds ratios (MOR) and 95% confidence intervals were computed. Results Staining intensity for FRα ranged from none (n=10 [9%]) to weak (n=7 [6%]), moderate (n=25 [23%]) and strong (n=66 [61%]). 1) Case-control analysis showed that, compared to controls, the associations of multivitamin intake with no or weak, moderate and strong staining FRα tumors were 0.14 (0.03-0.71), 0.19 (0.05-0.72) and 0.57 (0.28-1.15), respectively (Ptrend=0.04). For weekly alcohol intake, the associations were 0.32 (0.02-4.01), 0.82 (0.13-5.10) and 1.72 (0.68-4.39), respectively (Ptrend=0.74). The associations were unappreciably altered when both variables were modeled simultaneously. 2) Case-case analysis showed that, compared to no, weak or moderate staining tumors combined (n=42), the MOR associated with strong staining tumors was 2.90 (1.07-7.91) for multivitamin intake and strengthened after control for tumor grade and stage: 4.13 (1.27-13.4). For weekly alcohol intake, the MOR was 1.94 (0.41-9.29). 3) The interaction analysis showed that, compared to EOC cases not taking multivitamins (MV-) and with < 5 weekly drinks (ALC-), the MOR associated with developing a strong staining tumor was 0.37 (0.01-9.33) for MV- / ALC+; 3.32 (0.96-11.5) for MV+ / ALC-; and 8.21 (0.92-73.0) for MV+ / ALC+ (Pinteraction=0.34), however our sample was small. Conclusions Among women without cancer, multivitamin intake is associated with a lower risk of developing a weak or moderate staining FRα ovarian tumor, but protection is lost with strong staining tumors. Among women who develop EOC, multivitamin intake is associated with a 3 to 4-fold increased risk of a strong staining tumor and this risk is 8-fold if cases also consume ≥ 5 weekly alcoholic drinks. Further study of the clinical implications of our findings is needed in a larger sample with biomarkers of folate status.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]