1 Cancer Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI.
2 USC/Norris Comprehensive Cancer Center, Los Angeles, CA.
3 Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI.
Received for publication October 12, 2001; accepted for publication March 14, 2002.
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ABSTRACT |
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calcium; case-control studies; dairy products; diet; lactose; ovarian neoplasms
Abbreviations: Abbreviations: CI, confidence interval; GALT, galactose-1-phosphate uridyltransferase; OR, odds ratio.
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INTRODUCTION |
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While results from past dietary studies are provocative, they indicate a need for a more careful examination of the influence of fat and dairy food consumption on risk of ovarian cancer. Only a few studies (12, 18) have attempted to separate an association between ovarian cancer and fat from an association between ovarian cancer and lactose or other components of dairy food. Furthermore, other dietary correlates of dairy product intake, such as intakes of calcium and vitamin D, have been examined by only a few investigators (12). The objective of this analysis was to examine the hypothesis that intake of dairy products and related compounds is positively associated with the odds of epithelial ovarian cancer.
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MATERIALS AND METHODS |
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Eligible patients included all women with histologically confirmed malignant epithelial carcinoma of the ovary diagnosed in 19931999 whose cases were reported to one of two population-based cancer registries, the Hawaii Tumor Registry and the Los Angeles County Cancer Surveillance Program at the University of Southern California (19). Each of these registries is subject to annual quality-control audits by the National Cancer Institute, and case ascertainment is thought to be more than 99 percent complete (19). Interview information was obtained from 603 (62 percent) of the 972 ovarian cancer patients eligible for participation in the study. Reasons for nonparticipation included physician refusal (n = 69), patient refusal (n = 222), and inability to locate the patient (n = 78). Response rates among eligible cases did not differ substantially by study location (65 percent in Hawaii, 61 percent in Los Angeles) or ethnic group (63 percent among Asian Americans, 65 percent among Pacific Islanders, 60 percent among Caucasians). Thirty-nine cases were excluded because of equivocal histologic classification, and six additional cases were excluded because their dietary information was considered unreliable (defined as having an energy intake more than three standard deviations from the mean based on the control lognormal distribution). Of the 558 ovarian cancer patients included in this analysis, 220 were from Hawaii and 338 were from Los Angeles.
Population controls were matched to cases according to specific ethnicity (e.g., Japanese), age (year of birth ±5 years), and study location. Controls were required to report whether or not they had undergone oophorectomy and, if so, whether one or both ovaries had been removed. Eligible controls had to have at least one intact ovary. In Hawaii, the control pool consisted of lists of female Oahu residents who were interviewed by the Health Surveillance Program of the Hawaii Department of Health (20). Potential controls were randomly selected from the pool so that the ethnic and 5-year age distribution would match that of the case group at a 1:1 ratio. In Los Angeles, over 95 percent of the controls were selected on the basis of a neighborhood walk procedure (21). A total of 907 women meeting these eligibility criteria were contacted to participate in the study. Complete demographic and nutrient information was obtained for 609 (67 percent) of these women. We excluded two control women from the analysis because their dietary data were considered unreliable. Of the 607 controls included in this analysis, 283 were from Hawaii and 324 were from Los Angeles.
The majority of the subjects (>95 percent) were interviewed in their homes by trained interviewers. All interviews were administered according to a standard protocol, regardless of the location of the interview, and took 12 hours to complete. A structured interviewer-administered questionnaire was developed for this investigation. The questionnaire gathered information on diet, including use of nutritional supplements, reproductive and gynecologic history, use of contraceptives and exogenous hormones, medical history, and other lifestyle practices.
The diet questionnaire was modeled after the one used in a multiethnic cohort study of over 215,000 men and women living in California and Hawaii that included the ethnic groups of interest in this study (22). The 256 food items or categories identified for inclusion in the questionnaire were representative of the eating patterns of the ethnic groups in the study and were selected from 3-day measured food records completed by a population-based sample of adults. The dietary reference period was the year before diagnosis for cases and the year before the interview for controls. If there had been a recent change in diet (within 3 years), the dietary reference period was the period before that change. For each food or beverage item, the respondent indicated the usual frequency with which the item was consumed per day, week, or month, with yearly frequencies being recorded for particular seasonal items. Photographs indicating the three most representative serving sizes were used to assist subjects in estimating amounts consumed. Both combination and multiple servings could be selected. Dairy items assessed included milk (whole, low-fat, nonfat, lactose-free, Lactobacillus acidophilus-containing), milk-based drinks, yogurt (regular, low-fat, nonfat), cheese (hard, soft), cottage cheese, ice cream, ice milk, and frozen yogurt. Intakes of alcoholic beverages and dietary supplements (nine categories) were also assessed.
The quantity of each food item consumed on a daily basis was calculated as the product of frequency and serving size. The nutrient content of foods was determined from a customized food composition database (22). The food composition data were compiled largely from US Department of Agriculture Handbook no. 8 (23, 24), with supplementation by laboratory analyses of foods, and other commercial publications (2527). In addition to values for energy and macronutrients, the database includes values for over 90 other nutrients, including lactose, calcium, and vitamin D. Total nutrient intake was calculated as the sum of the nutrients derived from foods and supplements.
In this article, we focus on the relation of macronutrients, dairy products, and related compounds to risk of epithelial ovarian cancer. A preliminary examination of the data included comparisons of cases and controls with respect to several demographic characteristics and risk factors of interest. We used analysis of covariance to compare log-transformed mean intakes of nutrients and foods between cases and controls while adjusting for age, ethnicity, location, and energy intake (28). We calculated partial Pearson correlations (r) for continuous dietary and nondietary variables, adjusting for age, ethnicity, location, and energy intake, to evaluate collinearity.
We evaluated risks associated with different levels of the exposure variables by unconditional logistic regression modeling case/control status (29). We computed odds ratios and 95 percent confidence intervals by exponentiating the coefficients (and confidence intervals) for the binary indicator variables representing the quartile levels of nutrient or food intake. The quartile cutpoints were based on the distribution in the combined population of cases and controls. Adjustment factors included age as a continuous variable, ethnicity as an indicator variable (Caucasian, Asian, other), study location (Hawaii, Los Angeles), education (continuous variable), oral contraceptive use (ever vs. never), parity (ever vs. never), tubal ligation (yes vs. no), and log-transformed energy intake (in dietary analyses). We also considered other potential risk factors as adjustment variables, such as menopausal status and family history, but these did not materially alter the fit of the models. We employed various methods of calorie adjustment, including the standard and residual methods (30). Odds ratios were generally similar for each of the three methods, so we have presented results from the standard method in which calories were introduced as a model covariate. We performed a test for linear trend in the logit of risk by comparing twice the difference in log likelihoods for models with and without a trend variable assigned the median value for each quartile. Similarly, the likelihood ratio test was used to evaluate the effect of interaction between variables on the risk of ovarian cancer. This test compared a no-interaction model containing main-effect terms with a fully parameterized model containing all possible interaction terms for the variables of interest.
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RESULTS |
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When examined across quartiles of intake, macronutrients remained unrelated to ovarian cancer risk (table 2). Likewise, no association was found for protein and fat derived from meat, dairy, or vegetable sources or for percentage of calories derived from fat, protein, or carbohydrate (data not shown). Energy adjustment had little influence on the odds ratios.
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Intakes of lactose and calcium but not intakes of vitamin D or other sugars (data not shown) were significantly inversely associated with the risk of ovarian cancer after adjustment for energy intake and other confounders (table 4). The strong correlation (r = 0.77) between intakes of lactose and calcium suggested overlapping food sources for these nutrients. The trend associated with calcium intake remained significant (p for trend = 0.02) after adjustment for lactose intake, but the relation of lactose to ovarian cancer risk was substantially attenuated by adjustment for calcium (p for trend = 0.68) (data not shown). The odds ratios associated with the top three quartiles of calcium consumption as compared with the lowest quartile were 0.4 (95 percent CI: 0.3, 1.1), 0.3 (95 percent CI: 0.2, 0.6), and 0.5 (95 percent CI: 0.3, 1.2), respectively, among Caucasian women (p for trend = 0.09) and 0.8 (95 percent CI: 0.5, 1.4), 0.5 (95 percent CI: 0.3, 1.0), and 0.4 (95 percent CI: 0.2, 1.0), respectively, among Asian women (p for trend = 0.02).
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A significant inverse association between ovarian cancer risk and calcium derived from dairy sources was found (table 4). We also found a nonsignificant inverse gradient in risk for calcium supplement intake but no relation of nondairy calcium intake to risk. When we limited the calcium analysis to the subset of women who did not report use of calcium supplements (403 cases, 409 controls), odds ratios associated with the top three quartiles of calcium consumption compared with the lowest were 0.7 (95 percent CI: 0.5, 1.1), 0.4 (95 percent CI: 0.2, 0.7), and 0.3 (95 percent CI: 0.2, 0.6), respectively (p = 0.0002).
We modeled the joint association of lactose and dietary calcium intakes (excluding supplements) with risk of ovarian cancer by creating dummy indicator variables consisting of combinations of lactose intake (8.5 g/day vs. >8.5 g/day) and calcium intake (
779 mg/day vs. >779 mg/day), using women with a low intake of both nutrients as the reference category (table 5). Women with high intakes of both calcium and lactose were at significantly decreased risk of ovarian cancer compared with women with low intakes of these nutrients. The inverse association of calcium intake with ovarian cancer risk was modified by lactose intake: Calcium was beneficial among women with a low lactose intake (OR = 0.35/1 = 0.35) but not among women with a high lactose intake (OR = 0.57/0.51 = 1.12). The relation of lactose intake to ovarian cancer was also strongly modified by amount of calcium consumed on a daily basis: Lactose intake was inversely associated with risk among women with a low calcium intake (OR = 0.51/1 = 0.51) but not among women with a calcium intake above the median level (OR = 0.57/0.35 = 1.63). The effect of the interaction between calcium and lactose consumption on the odds ratios for disease was significant (p = 0.0001).
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DISCUSSION |
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This investigation had several notable dietary findings, including an inverse association of lactose intake with risk of epithelial ovarian cancer. An inverse association with lactose was unexpected, since most studies have shown little or no relation of lactose to ovarian cancer risk (48, 10, 12, 15, 18) and we had hypothesized a positive association, if any. Lactose may increase calcium absorption (32) and promote the growth of lactic acid bacteria, which may play a role in the activation or detoxification of heterocyclic aromatic amines (33). A recent investigation found an inverse association between lactose and colon cancer (34). Only one other case-control study, a study of 108 ovarian cancer cases and 108 controls in Washington State, reported a significant inverse relation between dietary lactose intake and ovarian cancer risk (18). Herrinton et al. (18) found an odds ratio of 0.25 (95 percent CI: 0.07, 0.88) among 56 casepopulation-control pairs and an odds ratio of 0.96 (95 percent CI: 0.55, 1.7) among 52 casefriend-control pairs. Harlow et al. (35) proposed that the greatest benefit of oral contraceptive use should appear among women with the highest lactose intakes, because oral contraceptives lower gonadotropin levels. However, we found no effect of an interaction between lactose intake and oral contraceptive use on the odds ratios.
To our knowledge, this is the first study to suggest an inverse relation between dietary calcium intake and ovarian cancer risk, although intakes of calcium and lactose in our population were highly correlated and difficult to distinguish. An interaction model suggested that the inverse associations of calcium and lactose with risk were strongest at low levels of the other dietary component. Indeed, no additional effect of calcium was observed among subjects with a high lactose intake. Dietary calcium has been reported to be inversely related to breast cancer (36) and colon cancer (37) and positively related to prostate cancer (38). Two previous epidemiologic studies examined the potential association of calcium with ovarian cancer (12, 39). In an investigation of 189 ovarian cancer cases and 200 hospital controls in Athens, Greece, Tzonou et al. (39) found no association between calcium intake and ovarian cancer. In the Iowa Womens Health Study, which contained 139 ovarian cancer cases, Kushi et al. (12) reported no association between calcium intake and ovarian cancer risk, although the rate ratios suggested a positive trend rather than an inverse trend.
Our finding of a significant inverse gradient in the odds ratios for low-fat milk but not for whole milk or other dairy products is consistent with the findings of several other studies (3, 5, 7, 16) but inconsistent with a hypothesized relation of calcium or lactose to ovarian cancer. Concentrations of these nutrients are relatively unaffected by reductions in the fat content of milk. The observation that only dairy sources of calcium were related to ovarian cancer might be explained by the lower bioavailability of this nutrient from plants, which contain phytates, oxalates, and other compounds that inhibit calcium absorption (32). We found a strong inverse dose-response gradient in the odds ratios associated with calcium intake among nonusers of supplements, precluding the possibility that the calcium association is a result of dietary supplementation among these women. Neither type of fat consumed, amount of dairy fat consumed, nor percentage of calories derived from fat was related to ovarian cancer in this study. Although some epidemiologic investigators have reported an increased risk of ovarian cancer associated with animal fat and meat intake (3, 4, 6, 7, 11, 14), others have found no association (9, 12, 18, 39). Another component of dairy foods, vitamin D, was unrelated to risk in our investigation and in the Iowa Womens Health Study (12), but dietary vitamin D is a poor measure of total vitamin D exposure.
An inverse association between dietary calcium and ovarian cancer risk is biologically plausible. Calcium down-regulates the production of parathyroid hormone and parathyroid hormone-related protein, both of which reabsorb calcium from bone to regulate hypocalcemia (40, 41). Small-cell carcinoma of the ovary has been associated with hypercalcemia and expression of parathyroid hormone-related protein (42). McCarty (43) hypothesized that parathyroid hormone is a cancer-promoting agent, activating the protein kinase C and phospholipase C signaling pathways, triggering mitosis, and reducing apoptosis. Several laboratory studies have suggested that parathyroid hormone stimulates the production of local levels but not circulating levels of insulin-like growth factors 1 and 2 and transforming growth factor ß1 (40, 41). Insulin-like growth factor and its binding protein may alter susceptibility to cancer through complex interactions with hormones and other growth factors (44). However, results from a random population sample showed an association of insulin-like growth factor 1 with parathyroid hormone among men but not among women (45). Furthermore, we found no association in our study between risk and vitamin D intake, which also down-regulates parathyroid hormone and is inversely related to colon and breast cancer (36, 37).
Use of identical methods and standardization of procedures for subject ascertainment, interviewer training, and data collection in Hawaii and Los Angeles were important components of this investigation. We have focused considerable attention on validating our dietary assessment method against food records (46), and we have demonstrated that our dietary data are reproducible (47). Our dietary assessment method has also been tested in a calibration substudy of the multiethnic cohort that compared diet as reported on the questionnaire with three 24-hour dietary recalls (48). It is unlikely that cases would systematically over- or underestimate their consumption of the many foods included in our questionnaire, although we have no means of examining this possibility. Our interviewers were trained in standardized probing methods that minimized between-interviewer variation. We constructed models that examined location-specific effects of the major dietary exposure variables (e.g., dairy foods, fat) on ovarian cancer risk within ethnic groups. These models were compared by the likelihood ratio test against models with ethnicity-specific effects only and were found to be similar, which suggested that the data could be pooled for statistical analysis. Although the validity of our findings may be somewhat limited by the less-than-optimal response rates in this study (62 percent for cases and 67 percent for controls), these response rates compare favorably with those of other studies of diet and ovarian cancer (511, 18).
In summary, we found that women who consume higher quantities of calcium and lactose were at significantly decreased risk of epithelial ovarian cancer. This result is unique among dietary studies but is not without plausibility. The findings were tempered by a lack of consistency for nondairy sources of calcium, but the results were homogeneous across ethnic groups and study locations. Although these results are intriguing, we cannot rule out the possibility that both calcium and lactose are surrogates for another, unidentified component of dairy foods.
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ACKNOWLEDGMENTS |
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The authors thank the physicians, administrators, and cancer registrars at the following institutions for their support of this study: Castle Memorial Hospital, Kaiser Foundation Hospital, Kapiolani Medical Center for Women and Children, Kuakini Medical Center, Queens Medical Center, Straub Clinic and Hospital, St. Francis Hospital, Tripler Army Hospital, and Wahiawa General Hospital.
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NOTES |
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REFERENCES |
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