Association of Dairy Products, Lactose, and Calcium with the Risk of Ovarian Cancer

Marc T. Goodman1, Anna H. Wu2, Ko-Hui Tung1, Katharine McDuffie1, Laurence N. Kolonel1, Abraham M. Y. Nomura1, Keith Terada3, Lynne R. Wilkens1, Suzanne Murphy1 and Jean H. Hankin1

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.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Epidemiologic findings have been inconsistent regarding the association of dietary fat, dairy products, and lactose with risk of ovarian cancer. The authors conducted a case-control study in Hawaii and Los Angeles, California, to examine several dietary hypotheses regarding the etiology of ovarian cancer in a population with a broad range of dietary intakes. A total of 558 patients with ovarian cancer diagnosed in 1993–1999 and 607 controls were interviewed regarding their diet. Consumption of all dairy products, all types of milk, and low-fat milk, but not consumption of whole milk, was significantly inversely related to the odds of ovarian cancer. Similar inverse gradients in the odds ratios were obtained for intakes of lactose and calcium, although these nutrients were highly correlated (r = 0.77). The odds ratio for ovarian cancer was 0.46 (95% confidence interval: 0.27, 0.76) among women in the highest quartile of dietary calcium intake versus the lowest (p for trend = 0.0006). The significant dietary association was limited to dairy sources of calcium (p for trend = 0.003), although a nonsignificant inverse gradient in risk was also found in relation to calcium supplement intake. These results suggest that intake of low-fat milk, calcium, or lactose may reduce the risk of ovarian cancer. Am J Epidemiol 2002;156:148–57.

calcium; case-control studies; dairy products; diet; lactose; ovarian neoplasms

Abbreviations: Abbreviations: CI, confidence interval; GALT, galactose-1-phosphate uridyltransferase; OR, odds ratio.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Data compiled by the National Cancer Institute have indicated that rates of ovarian cancer in the United States are approximately 60 percent greater among Caucasian women than among Asian women (1, 2). Aside from differences in reproductive factors, dietary differences might account for some of the ethnic variation in ovarian cancer rates. In several case-control studies, investigators have reported a positive association of dietary fat with risk of ovarian cancer (3–7), although others have failed to reproduce this result (8–10). In accordance with the findings on animal fat, a positive relation between ovarian cancer and consumption of dairy products has been shown in some studies (3, 5, 7, 11–13) but not in others (8, 14–17). Although some investigators have reported associations between ovarian cancer and intakes of specific types or components of dairy food—such as butter (3, 11), whole milk (3, 5, 7), skim milk (12), yogurt (7, 13), cottage cheese (13), and ice cream (7)—inverse associations with intakes of all milk (14), skim/low-fat milk (3, 5, 7, 16), and cheese (17) have also been found.

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.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We initiated a case-control study of ovarian cancer in Hawaii and Los Angeles, California, to explore several dietary hypotheses regarding the etiology of epithelial ovarian cancer. Eligibility criteria for participation included 1) residency in Hawaii or Los Angeles County for at least 1 year prior to diagnosis (cases) or interview (controls); 2) age >=18 years; 3) Caucasian, Asian (Japanese, Chinese, Filipino, Korean), or other (including Pacific Islander or Hispanic) ancestry; and 4) no prior history of ovarian cancer.

Eligible patients included all women with histologically confirmed malignant epithelial carcinoma of the ovary diagnosed in 1993–1999 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 1–2 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 (25–27). 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.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The ovarian cancer patients included in the study population were generally of European or Asian ancestry. The ethnic category "other" included largely Native Hawaiian women and English-speaking, non-Caucasian Hispanic women (table 1). The average age of cases and controls was 54.8 years. Cases were not as well educated as controls (mean years of education: cases, 13.0 years; controls, 13.4 years), and they tended to have lower family incomes (mean annual income: cases, $54,389; controls, $60,711). Seventy-nine percent of cases and 76 percent of controls had ever been pregnant, and pregnancy reduced the risk of ovarian cancer by 41 percent (95 percent confidence interval (CI): 0.4, 0.8) (data not shown). An inverse gradient in risk (p for trend < 0.0001) was associated with an increasing number of pregnancies. Oral contraceptives were used by 43 percent of cases and 56 percent of controls (odds ratio (OR) = 0.6, 95 percent CI: 0.4, 0.8), with an inverse dose-response relation between risk and increasing years of use (p for trend < 0.0001). Other significant risk factors included history of tubal ligation and family history of breast or ovarian cancer.


View this table:
[in this window]
[in a new window]
 
TABLE 1. Odds* ratios for the association between selected nondietary variables and risk of ovarian cancer, Hawaii and Los Angeles, California, 1993–1999
 
We found no significant difference between cases and controls in crude or covariate-adjusted mean intakes of any of the major macronutrients, including fat, carbohydrate, and protein (data not shown). Adjusted mean energy intake was 1,997 kcal/day for cases and 1,960 kcal/day for controls. Age-standardized average daily energy consumption among controls differed substantially between Native Hawaiian (2,335 kcal), Caucasian (2,082 kcal), and Japanese (1,885 kcal) women. Daily intake of dairy products was lower among cases (mean = 146.7 g) than among controls (mean = 179.9 g) after adjustment for covariates (data not shown). This difference in mean values was significant (p = 0.0008).

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.


View this table:
[in this window]
[in a new window]
 
TABLE 2. Odds ratios* for the association between quartiles{dagger} of dietary macronutrient intake and ovarian cancer risk, Hawaii and Los Angeles, California, 1993–1999
 
Consumption of all dairy products, all types of milk, and low-fat milk was significantly inversely related to risk of ovarian cancer (table 3, model 1), but consumption of whole milk was not. Women with the highest intake of butter (>75th percentile) were at significantly reduced risk of ovarian cancer compared with women with the lowest intake (<=25th percentile), but the trend in the odds ratios was not significant. No relations were found between ovarian cancer risk and intakes of yogurt, cheese, and ice cream. Associations were generally homogeneous within each ethnic group. Odds ratios associated with the top three quartiles of all dairy food consumption compared with the lowest quartile were 0.7 (95 percent CI: 0.4, 1.2), 0.6 (95 percent CI: 0.3, 1.1), and 0.7 (95 percent CI: 0.4, 1.2), respectively, for Caucasians (p for trend = 0.21); 1.0 (95 percent CI: 0.6, 1.6), 0.6 (95 percent CI: 0.4, 1.1), and 0.5 (95 percent CI: 0.3, 1.0), respectively, for Asians (p for trend = 0.03); and 0.8 (95 percent CI: 0.3, 2.1), 0.5 (95 percent CI: 0.2, 1.3), and 0.4 (95 percent CI: 0.2, 1.3), respectively, for persons of "other" ethnicity (p for trend = 0.09).


View this table:
[in this window]
[in a new window]
 
TABLE 3. Odds ratios for the association between quartiles* of dairy product intake and ovarian cancer risk, Hawaii and Los Angeles, California, 1993–1999
 
The age-, race-, and location-adjusted correlations between intakes of dairy products and lactose (r = 0.96) and intakes of dairy products and calcium (r = 0.83) underscore the difficulty of identifying independent relations between these dietary exposures and ovarian cancer risk. In table 3, we report odds ratios for ovarian cancer associated with the consumption of dairy products after adjustment for calcium intake (model 2) or lactose intake (model 3). Adjustment for either calcium or lactose tended to attenuate the odds ratios so that the trend in risk associated with dairy product intake was no longer statistically significant.

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).


View this table:
[in this window]
[in a new window]
 
TABLE 4. Odds ratios for the association of quartiles* of lactose, calcium, and vitamin D intake with ovarian cancer risk, Hawaii and Los Angeles, California, 1993–1999
 
Milk drinking was the most common source of calcium among both Caucasian women (22 percent of daily intake) and Asian women (20 percent) (data not shown). Dairy foods were ranked in the top 10 sources of calcium among Caucasian women. In addition to dairy food, among Asian women the top 10 sources of calcium included tofu (accounting for 4 percent of daily calcium intake), oranges (3 percent), and broccoli (2 percent). A slightly greater amount of calcium in the diet was from dairy food sources (42 percent among cases, 40 percent among controls) than from nondairy food sources (38 percent among cases, 35 percent among controls), with a lesser percentage of calcium being obtained from supplements (19 percent among cases, 24 percent among controls). Twenty-eight percent of cases and 33 percent of controls used calcium supplements.

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).


View this table:
[in this window]
[in a new window]
 
TABLE 5. Odds ratios* for the joint association of dietary calcium and lactose intakes with ovarian cancer risk, Hawaii and Los Angeles, California, 1993–1999
 
We also modeled the two-way interaction of dietary calcium or lactose intake (greater than median vs. median or less) and oral contraceptive use (never vs. ever), parity (never vs. ever), and menopausal status (premenopausal vs. postmenopausal) with risk of ovarian cancer (table 6). We found no significant effect of an interaction between these factors on disease risk. Women who had used oral contraceptives and who had high calcium intakes were at particularly low risk of ovarian cancer (OR = 0.34, 95 percent CI: 0.23, 0.52) in comparison with women who had never used oral contraceptives and who had nutrient intakes below the median. Calcium and lactose intakes were inversely related to ovarian cancer regardless of oral contraceptive use, parity, or menopausal status.


View this table:
[in this window]
[in a new window]
 
TABLE 6. Odds ratios* for the joint association of calcium or lactose intake and oral contraceptive use, parity, and menopausal status with ovarian cancer risk, Hawaii and Los Angeles, California, 1993–1999
 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
It has been a more than decade since Cramer et al. (13) hypothesized that galactose, a component sugar of lactose, was positively associated with ovarian cancer through increases in gonadotropin levels. Hypogonadism or ovarian failure in association with gonadotropin stimulation has been found in galactosemic women who are deficient in the enzyme galactose-1-phosphate uridyltransferase (GALT) (31). In an analysis of a case-control study of 235 cases and 239 controls conducted in the Boston, Massachusetts, area between 1983 and 1987, Cramer et al. initially reported that GALT activity was significantly lower among cases (13). A significant positive trend in risk associated with the ratio of lactose intake to GALT activity was also found. However, in a subsequent study of 563 ovarian cancer cases and 523 community controls conducted in New Hampshire and Massachusetts between 1992 and 1997, Cramer et al. found no relation between ovarian cancer risk and lactose or dairy product intake or GALT activity (10).

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 (4–8, 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 case–population-control pairs and an odds ratio of 0.96 (95 percent CI: 0.55, 1.7) among 52 case–friend-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 Women’s 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 Women’s 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 (5–11, 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.


    ACKNOWLEDGMENTS
 
This investigation was supported in part by US Public Health Service grant RO1-CA-58598. Incident cancer cases in Hawaii were collected by the Hawaii Tumor Registry, which is supported under contract by the Hawaii Department of Health. Incident cancer cases in Los Angeles County were collected by the University of Southern California Cancer Surveillance Program, which is supported under contract by the California Department of Health. Both registries are also part of the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program, under contracts NO1-CN–67001 and NO1-CN–25403 from the National Institutes of Health.

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, Queen’s Medical Center, Straub Clinic and Hospital, St. Francis Hospital, Tripler Army Hospital, and Wahiawa General Hospital.


    NOTES
 
Reprint requests to Dr. Marc T. Goodman, Cancer Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, 1236 Lauhala Street, Honolulu, HI 96813 (e-mail: marc{at}crch.hawaii.edu). Back


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Parkin DM, Muir CS, Whelan SL, et al, eds. Cancer incidence in five continents. Vol VI. (IARC Scientific Publication no. 120). Lyon, France: International Agency for Research on Cancer, 1992.
  2. Miller BA, Kolonel LN, Bernstein L, et al, eds. Racial/ethnic patterns of cancer in the United States 1988–1992. Bethesda, MD: National Cancer Institute, 1996. (NIH publication no. 96-4104).
  3. Cramer DW, Welch WR, Hutchison GB, et al. Dietary animal fat in relation to ovarian cancer risk. Obstet Gynecol 1984; 63:833–8.[Abstract]
  4. Shu XO, Gao YT, Yuan JM, et al. Dietary factors and epithelial ovarian cancer. Br J Cancer 1989;59:92–6.[ISI][Medline]
  5. Mettlin CJ, Piver MS. A case-control study of milk drinking and ovarian cancer risk. Am J Epidemiol 1990;132:871–6.[Abstract]
  6. Risch HA, Jain M, Marrett LD, et al. Dietary fat intake and risk of epithelial ovarian cancer. J Natl Cancer Inst 1994;86:1409–15.[Abstract]
  7. Webb PM, Bain CJ, Purdie DM, et al. Milk consumption, galactose metabolism and ovarian cancer (Australia). Cancer Causes Control 1998;9:637–44.[ISI][Medline]
  8. Engle A, Muscat JE, Harris RE. Nutritional risk factors and ovarian cancer. Nutr Cancer 1991;15:239–47.[ISI][Medline]
  9. Slattery ML, Schuman KL, West DE, et al. Nutrient intake and ovarian cancer. Am J Epidemiol 1989;130:497–502.[Abstract]
  10. Cramer DW, Greenberg ER, Titus-Ernstoff L, et al. A case-control study of galactose consumption and metabolism in relation to ovarian cancer. Cancer Epidemiol Biomarkers Prev 2000;9:95–101.[Abstract/Free Full Text]
  11. La Vecchia C, Decarli A, Negri E, et al. Dietary factors and the risk of epithelial ovarian cancer. J Natl Cancer Inst 1987; 79:663–9.[ISI][Medline]
  12. Kushi LH, Mink PJ, Folsom AR, et al. Prospective study of diet and ovarian cancer. Am J Epidemiol 1999;149:21–31.[Abstract]
  13. Cramer DW, Harlow BL, Willett WC, et al. Galactose consumption and metabolism in relation to the risk of ovarian cancer. Lancet 1989;2:66–71.[Medline]
  14. Mori M, Harabuchi I, Miyake H, et al. Reproductive, genetic, and dietary risk factors for ovarian cancer. Am J Epidemiol 1988;128:771–7.[Abstract]
  15. Risch HA, Jain M, Marrett LD, et al. Dietary lactose intake, lactose intolerance, and the risk of epithelial ovarian cancer in southern Ontario (Canada). Cancer Causes Control 1994;5: 540–8.[ISI][Medline]
  16. Bertone ER, Hankinson SE, Newcomb P, et al. A population-based case-control study of carotenoid and vitamin A intake and ovarian cancer (United States). Cancer Causes Control 2001;12:83–90.[ISI][Medline]
  17. Bosetti C, Negri E, Franceschi S, et al. Diet and ovarian cancer risk: a case-control study in Italy. Int J Cancer 2001;93:911–15.[ISI][Medline]
  18. Herrinton L, Weiss NS, Beresford SA, et al. Lactose and galactose intake and metabolism in relation to the risk of epithelial ovarian cancer. Am J Epidemiol 1995;141:407–16.[Abstract]
  19. Ries LA, Eisner MP, Kosary CL, et al, eds. SEER cancer statistics review, 1973–97. Bethesda, MD: National Cancer Institute, 2000. (NIH publication no. 00–2789).
  20. Oyama N, Johnson DB. Hawaii Health Surveillance Program survey methods and procedures. (Research and Statistics report no. 54). Honolulu, HI: Research and Statistics Office, Hawaii State Department of Health, 1986.
  21. Pike MC, Peters RK, Cozen W, et al. Estrogen-progestin replacement therapy and endometrial cancer. J Natl Cancer Inst 1997;89:1110–16.[Abstract/Free Full Text]
  22. Kolonel LN, Henderson BE, Hankin JH, et al. A multiethnic cohort study in Hawaii and Los Angeles: baseline characteristics. Am J Epidemiol 2000;151:346–57.[Abstract]
  23. Nutrient Data Laboratory, Agricultural Research Service, US Department of Agriculture. USDA Nutrient Data Base for Standard Reference. Release no. 10. Riverdale, MD: US Department of Agriculture, 1993.
  24. Nutrient Data Laboratory, Agricultural Research Service, US Department of Agriculture. Nutrient Data Base for Nationwide Food Surveys. Release no. 7. Riverdale, MD: US Department of Agriculture, 1991.
  25. Pennington JA. Bowes and Church’s food values of portions commonly used. 16th ed. Philadelphia, PA: J. B. Lippincott Company, 1994.
  26. Holland B, Welch AA, Unwin ID, et al. McCance and Widdowson’s the composition of foods. 5th ed. Cambridge, United Kingdom: Royal Society of Chemistry and Ministry of Agriculture, Fisheries and Food, 1991.
  27. Kagawa R. Standard tables of food composition in Japan. Tokyo, Japan: Women’s University, 1995.
  28. Snedecor GW, Cochran WG. Statistical methods. Ames, IA: Iowa State University Press, 1967.
  29. Breslow NE, Day NE. Statistical methods in cancer research. Vol 1. The analysis of case-control studies. (IARC Scientific Publication no. 32). Lyon, France: International Agency for Research on Cancer, 1980.
  30. Willett WC, Howe GR, Kushi LH. Adjustment for total energy intake in epidemiologic studies. Am J Clin Nutr 1997; 65(suppl):1220S–8S.[Abstract]
  31. Kaufman FR, Kogut MD, Donnell GN, et al. Hypergonadotropic hypogonadism in female patients with galactosemia. N Engl J Med 1981;304:994–8.[Abstract]
  32. Gueguen L, Pointillart A. The bioavailability of dietary calcium. J Am Coll Nutr 2000;19(suppl):119S–36S.[Abstract/Free Full Text]
  33. Knasmuller S, Steinkellner H, Hirschl AM, et al. Impact of bacteria in dairy products and of the intestinal microflora on the genotoxic and carcinogenic effects of heterocyclic aromatic amines. Mutat Res 2001;480:129–38.[ISI]
  34. Jarvinen R, Knekt P, Hakulinen T, et al. Prospective study on milk products, calcium and cancers of the colon and rectum. Eur J Clin Nutr 2001;55:1000–7.[ISI][Medline]
  35. Harlow BL, Cramer DW, Geller J, et al. The influence of lactose consumption on the association of oral contraceptive use and ovarian cancer risk. Am J Epidemiol 1991;134:445–53.[Abstract]
  36. Lipkin M, Newmark HL. Vitamin D, calcium and prevention of breast cancer: a review. J Am Coll Nutr 1999;18(suppl):392S–7S.
  37. Martinez ME, Willett WC. Calcium, vitamin D, and colorectal cancer: a review of the epidemiologic evidence. Cancer Epidemiol Biomarkers Prev 1998;7:163–98.[Abstract]
  38. Giovannucci E, Rimm EB, Wolk A, et al. Calcium and fructose intake in relation to risk of prostate cancer. Cancer Res 1998; 58:442–7.[Abstract]
  39. Tzonou A, Hsieh C-C, Polychronopoulou A, et al. Diet and ovarian cancer: a case-control study in Greece. Int J Cancer 1993;55:411–14.[ISI][Medline]
  40. Linkhart TA, Mohan S. Parathyroid hormone stimulates release of insulin-like growth factor-I (IGF-I) and IGF-II from neonatal mouse calvaria in organ culture. Endocrinology 1989;125: 1484–91.[Abstract]
  41. Pfeilschifter J, Laukhuf F, Muller-Beckmann B, et al. Parathyroid hormone increases the concentration of insulin-like growth factor-I and transforming growth factor beta 1 in rat bone. J Clin Invest 1995;96:767–74.[ISI][Medline]
  42. Matias-Guiu X, Prat J, Young RH, et al. Human parathyroid hormone-related protein in ovarian small cell carcinoma: an immunohistochemical study. Cancer 1994;73:1878–81.[ISI][Medline]
  43. McCarty MF. Parathyroid hormone may be a cancer promoter—an explanation for the decrease in cancer risk associated with ultraviolet light, calcium, and vitamin D. Med Hypoth 2000;54:475–82.[ISI][Medline]
  44. Yu H, Levesque MA, Khosravi MJ, et al. Associations between insulin-like growth factors and their binding proteins and other prognostic indicators in breast cancer. Br J Cancer 1996;74: 1242–7.[ISI][Medline]
  45. Landin-Wilhelmsen K, Wilhelmsen L, Lappas G, et al. Serum insulin-like growth factor I in a random population sample of men and women: relation to age, sex, smoking habits, coffee consumption and physical activity, blood pressure and concentrations of plasma lipids, fibrinogen, parathyroid hormone and osteocalcin. Clin Endocrinol 1994;41:351–7.[ISI][Medline]
  46. Hankin JH, Wilkens LR, Kolonel LN, et al. Validation of a quantitative diet history method in Hawaii. Am J Epidemiol 1991;133:616–28.[Abstract]
  47. Hankin JH, Nomura AM, Lee J, et al. Reproducibility of a diet history questionnaire in a case-control study of breast cancer. Am J Clin Nutr 1983;37:981–5.[Abstract]
  48. Stram DO, Hankin JH, Wilkens LR, et al. Calibration of the dietary questionnaire for a multiethnic cohort in Hawaii and Los Angeles. Am J Epidemiol 2000;151:559–70.