Dairy Products and Ovarian Cancer: A Pooled Analysis of 12 Cohort Studies

Jeanine M. Genkinger; David J. Hunter; Donna Spiegelman; Kristin E. Anderson; Alan Arslan; W. Lawrence Beeson; Julie E. Buring; Gary E. Fraser; Jo L. Freudenheim; R. Alexandra Goldbohm; Susan E. Hankinson; David R. Jacobs; Anita Koushik; James V. Lacey; Susanna C. Larsson; Michael Leitzmann; Marji L. McCullough; Anthony B. Miller; Carmen Rodriguez; Thomas E. Rohan; Leo J. Schouten; Roy Shore; Ellen Smit; Alicja Wolk; Shumin M. Zhang; Stephanie A. Smith-Warner

doi:10.1158/1055-9965.EPI-05-0484

DOI: 10.1158/1055-9965.EPI-05-0484 Published February 2006

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Figure 1.
Multivariate adjusted RRs and 95% CI for ovarian cancer according to lactose intake (>30 compared with <10 g/d) by study. Multivariate RRs were adjusted for age at menarche (<13, 13, >13 years), menopausal status at baseline (premenopausal, postmenopausal, dubious), oral contraceptive use (ever, never), hormone replacement therapy use among postmenopausal women (never, past, current), parity (0, 1, 2, >2), BMI (<23, 23 to <25, 25 to <30, ≥30 kg/m²), smoking status (never, past, current), physical activity (low, medium, high), and energy intake (continuously), modeled identically across studies. Black squares and horizontal lines, study-specific RRs and 95% CIs for ≥30 g/d lactose intake compared with <10 g/d. The area of the black squares is proportional to the inverse of the sum of the between-study variance and the study-specific variance, which is related to the sample size, the total number of cases, and the range of variation in intake. Diamond, pooled multivariate RR and the 95% CI. Vertical dashed line, pooled multivariate RR.

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Table 1.

Daily mean intakes of dairy nutrients and foods by cohort study in the ovarian cancer analyses in the Pooling Project of Prospective Studies of Diet and Cancer

Cohort	Follow-up years	Baseline cohort size*	No. cases	Mean (SD) intake
				Dietary calcium (mg/d)	Total calcium^† (mg/d)	Lactose (g/d)	Dietary vitamin D (IU/d)	Total vitamin D^† (IU/d)	Total milk (g/d)^‡	Hard cheese (g/d)^‡	Cottage cheese (g/d)^‡	Yogurt (g/d)^‡	Ice cream (g/d)^‡
AHS	1976-1988	18,402	53	833 (124)	880 (139)	18 (14)	—	—	419 (349)	8 (8)	35 (36)	—	—
BCDDP	1987-1999	32,885	142	862 (369)	1,186 (2,979)	19 (14)	206 (122)	341 (279)	260 (269)	13 (20)	11 (22)	—	19 (36)
CNBSS^§	1980-2000	49,613	223	673 (253)	—	8 (7)	—	—	200 (199)	22 (23)	14 (27)	29 (61)	10 (17)
CPS II	1992-2001	61,202	278	884 (379)	1,136 (584)	19 (13)	197 (119)	342 (258)	277 (265)	11 (14)	—	44 (71)	7 (19)
IWHS	1986-2001	28,486	208	748 (285)	1,029 (483)	15 (11)	223 (111)	382 (292)	275 (265)	11 (13)	19 (31)	12 (39)	11 (19)
NLCS^§	1986-1995	62,412	208	869 (259)	—	14 (7)	—	—	187 (153)	23 (18)	10 (26)	53 (57)	—
NYSC	1980-1987	22,550	77	828 (209)	873 (220)	15 (9)	203 (68)	371 (227)	137 (87)	—	—	—	—
NYU	1985-1998	12,401	65	810 (307)	888 (327)	14 (11)	—	—	202 (243)	17 (22)	15 (26)	38 (61)	19 (32)
NHSa	1980-1986	80,195	120	722 (298)	731 (310)	14 (11)	167 (107)	279 (262)	215 (241)	14 (15)	21 (34)	21 (54)	13 (20)
NHSb	1986-2002	59,538	315	718 (254)	1,056 (492)	13 (10)	182 (100)	319 (243)	221 (230)	13 (13)	17 (25)	28 (55)	13 (18)
NHS II	1991-2002	91,502	52	787 (271)	910 (381)	16 (11)	223 (109)	351 (231)	268 (255)	12 (12)	9 (16)	31 (55)	8 (12)
SMC	1987-2003	61,103	287	913 (255)	—	16 (10)	162 (51)	—	156 (130)	27 (19)	—	104 (108)	7 (10)
WHS	1993-2004	32,466	104	729 (258)	940 (442)	14 (10)	217 (104)	324 (216)	215 (222)	9 (11)	10 (17)	36 (64)	7 (13)

NOTE: Studies that have a “—” did not estimate that nutrient or did not ask on their questionnaire about the consumption of that food item.
Abbreviations: AHS, Adventist Health Study; BCDDP, Breast Cancer Detection Demonstration Project Follow-up Study; CNBSS, Canadian National Breast Screening Study; CPS II, Cancer Prevention Study II Nutrition Cohort; IWHS, Iowa Women's Health Study; NLCS, the Netherlands Cohort Study; NYSC, New York State Cohort; NYU, New York University Women's Health Study; NHSa, Nurses' Health Study (part a); NHSb, Nurses' Health Study (part b); NHS II, Nurses' Health Study II; SMC, Swedish Mammography Cohort; WHS, Women's Health Study.
↵* Baseline cohort size was determined after specific exclusions (i.e., had a prior cancer diagnosis other than nonmelanoma skin cancer at baseline, had a bilateral oophorectomy before baseline, or had log_e-transformed energy intakes beyond 3 SDs from the study-specific log_e-transformed mean energy intake of the population).
↵† Total calcium and vitamin D intake includes dietary and supplemental sources.
↵‡ Milk: 1 8 oz serving is equivalent to 245 g; hard cheese: 1 oz serving is equivalent to 28 g; cottage cheese: 1 0.5 cups serving is equivalent to 105 g; yogurt: 1 cup serving is equivalent to 227 g; ice cream: 1 0.5 cups serving is equivalent to 66g.
↵§ The Canadian National Breast Screening Study and the Netherlands Cohort Study are analyzed as case-cohort studies so the baseline cohort size does not reflect the above exclusions.

Table 2.

Median Pearson correlations for dairy products and nutrients across all studies included in the ovarian cancer analyses in the Pooling Project of Prospective Studies of Diet and Cancer

	Lactose	Total milk	Whole milk	Low-fat milk	Hard cheese	Cottage cheese	Yogurt	Ice cream	Dietary calcium	Total calcium	Dietary vitamin D	Total vitamin D
Lactose	1.00	0.83	0.21	0.67	−0.08	0.08	0.18	0.02	0.90	0.63	0.83	0.40
Total milk		1.00	0.36	0.84	0.03	0.08	0.07	0.03	0.77	0.54	0.71	0.34
Whole milk			1.00	−0.19	0.03	0.00	−0.02	0.06	0.14	0.03	0.13	0.04
Low-fat milk				1.00	0.01	0.09	0.07	0.01	0.69	0.47	0.68	0.33
Hard cheese					1.00	0.09	0.04	0.09	0.17	0.08	−0.10	−0.04
Cottage cheese						1.00	0.15	0.03	0.14	0.10	0.04	0.04
Yogurt							1.00	0.00	0.28	0.23	0.17	0.13
Ice cream								1.00	−0.01	−0.01	−0.02	−0.02
Dietary calcium									1.00	0.70	0.79	0.39
Total calcium										1.00	0.50	0.47
Dietary vitamin D											1.00	0.47
Total vitamin D												1.00

NOTE: Median correlation value was calculated over all studies that measured that dairy food or nutrient. Studies that did not measure that particular food or nutrient were excluded from that specific analysis. For whole milk, New York State Cohort was excluded; for low-fat milk, New York State Cohort was excluded; for hard cheese, New York State Cohort was excluded; for cottage cheese, Cancer Prevention Study II Nutrition Cohort, New York State Cohort, and Swedish Mammography Cohort were excluded; for yogurt, Adventist Health Study, Breast Cancer Detection Demonstration Project Follow-up Study, and New York State Cohort were excluded; for ice cream, Adventist Health Study, the Netherlands Cohort Study, and New York State Cohort were excluded; for total calcium (dietary + supplemental), Canadian National Breast Screening Study, the Netherlands Cohort Study, and Swedish Mammography Cohort were excluded; for dietary vitamin D, Adventist Health Study, Canadian National Breast Screening Study, the Netherlands Cohort Study, and New York University Women's Health Study were excluded; and for total vitamin D, Adventist Health Study, Canadian National Breast Screening Study, the Netherlands Cohort Study, New York University Women's Health Study, and Swedish Mammography Cohort were excluded. All studies measured lactose, total milk, and dietary calcium.

Table 3.

Pooled age and multivariate adjusted RRs and 95% CIs for ovarian cancer according to intake of dairy foods and nutrients

	Categories of intake
Foods
Milk^‡ (g/d)	Range	0	1-69.9	70-124.9	125-249.9	250-499.9	≥500
		Cases	214	305	320	673	321	273
		Age RR	1.00 (Reference)	0.98 (0.81-1.17)	1.07 (0.85-1.34)	1.09 (0.87-1.36)	0.90 (0.73-1.10)	1.10 (0.89-1.36)	0.48	0.20
		MV RR	1.00 (Reference)	0.98 (0.81-1.17)	1.07 (0.84-1.35)	1.09 (0.87-1.36)	0.90 (0.73-1.11)	1.11 (0.87-1.41)	0.30	0.43
Whole^§^,^∥ (g/d)	Range	0	1-124.9	125-249.9	≥250
		Cases	1,120	428	226	145
		Age RR	1.00 (Reference)	0.92 (0.82-1.04)	1.01 (0.87-1.18)	0.93 (0.75-1.16)			0.28	0.83
		MV RR	1.00 (Reference)	0.94 (0.83-1.05)	1.04 (0.88-1.21)	0.95 (0.73-1.24)			0.10	0.99
Low-fat^§ (g/d)	Range	0	1-124.9	125-249.9	≥250
		Cases	818	343	449	373
		Age RR	1.00 (Reference)	1.00 (0.87-1.15)	1.08 (0.93-1.25)	1.07 (0.94-1.23)			0.44	0.38
		MV RR	1.00 (Reference)	0.99 (0.86-1.14)	1.08 (0.93-1.25)	1.07 (0.93-1.23)			0.51	0.38
Hard cheese^¶^,** (g/d)	Range	0	1-24.9	25-49.9	≥50
		Cases	191	1,444	253	139
		Age RR	1.00 (Reference)	1.05 (0.87-1.27)	1.05 (0.74-1.49)	1.24 (0.92-1.68)			0.66	0.51
		MV RR	1.00 (Reference)	1.09 (0.90-1.33)	1.09 (0.77-1.53)	1.30 (0.96-1.78)			0.74	0.38
Cottage cheese^††^,^‡‡ (g/d)	Range	0	1-25.9	26-52.9	≥53
		Cases	542	668	179	75
		Age RR	1.00 (Reference)	0.96 (0.85-1.09)	0.91 (0.75-1.12)	0.88 (0.63-1.23)			0.14	0.31
		MV RR	1.00 (Reference)	0.97 (0.85-1.10)	0.92 (0.75-1.13)	0.88 (0.63-1.23)			0.14	0.33
Yogurt^¶^,^§§ (g/d)	Range	0	1-27.9	28-56.9	57-113.9	≥114
		Cases	800	407	177	197	228
		Age RR	1.00 (Reference)	0.98 (0.87-1.12)	0.89 (0.75-1.05)	0.90 (0.76-1.07)	1.04 (0.87-1.24)		0.80	0.86
		MV RR	1.00 (Reference)	0.97 (0.85-1.10)	0.87 (0.73-1.04)	0.89 (0.75-1.06)	1.04 (0.86-1.24)		0.75	0.89
Ice cream^∥∥ (g/d)	Range	0	1-16.9	17-32.9	33-65.9	≥66
		Cases	561	862	230	67	33
		Age RR	1.00 (Reference)	0.98 (0.88-1.10)	1.07 (0.87-1.32)	1.13 (0.83-1.52)	0.85 (0.59-1.23)		0.67	0.82
		MV RR	1.00 (Reference)	1.02 (0.90-1.14)	1.12 (0.90-1.38)	1.18 (0.85-1.63)	0.91 (0.63-1.32)		0.66	0.55
Nutrients
Dietary calcium^¶¶ (mg/d)	Range	<500	500-699.9	700-899.9	900-1,099.9	1,100-1,299.9	≥1,300
		Cases	287	554	562	354	182	140
		Age RR	1.00 (Reference)	1.02 (0.88-1.18)	1.06 (0.87-1.28)	1.00 (0.78-1.29)	0.98 (0.79-1.21)	1.17 (0.93-1.47)	0.43	0.33
		MV RR	1.00 (Reference)	1.02 (0.88-1.18)	1.05 (0.89-1.24)	1.00 (0.79-1.27)	0.98 (0.79-1.21)	1.17 (0.93-1.47)	0.53	0.38
Total calcium^¶¶^,*** (mg/d)	Range	<500	500-699.9	700-899.9	900-1,099.9	1,100-1,299.9	≥1,300
		Cases	119	251	274	213	169	335
		Age RR	1.00 (Reference)	1.01 (0.85-1.33)	1.10 (0.87-1.40)	1.08 (0.85-1.36)	1.22 (0.95-1.56)	1.18 (0.90-1.53)	0.27	0.11
		MV RR	1.00 (Reference)	1.05 (0.84-1.30)	1.06 (0.85-1.34)	1.04 (0.82-1.32)	1.16 (0.90-1.48)	1.08 (0.84-1.38)	0.37	0.49
Lactose (g/d)	Range	<10	10-19.9	20-29.9	≥ 30
		Cases	785	793	344	210
		Age RR	1.00 (Reference)	1.09 (0.97-1.22)	1.06 (0.91-1.24)	1.21 (1.03-1.42)			0.55	0.17
		MV RR	1.00 (Reference)	1.09 (0.97-1.22)	1.07 (0.91-1.25)	1.19 (1.01-1.40)			0.58	0.19
Dietary vitamin D^†††^,^‡‡‡ (IU/d)	Range	<100	100-199.9	200-299.9	300-399.9	400-499.9	≥ 500
		Cases	226	699	427	136	71	24
		Age RR	1.00 (Reference)	1.05 (0.90-1.22)	1.11 (0.94-1.31)	1.07 (0.84-1.36)	1.60 (1.20-2.13)	1.46 (0.80-2.65)	0.15	0.02
		MV RR	1.00 (Reference)	1.05 (0.90-1.23)	1.10 (0.93-1.30)	1.05 (0.83-1.33)	1.56 (1.17-2.08)	1.37 (0.78-2.40)	0.21	0.04
Total vitamin D^†††^,^‡‡‡ (IU/d)	Range	<100	100-199.9	200-299.9	300-399.9	400-499.9	≥500
		Cases	125	346	252	113	121	339
		Age RR	1.00 (Reference)	1.20 (0.97-1.48)	1.28 (1.02-1.59)	1.11 (0.80-1.54)	1.33 (1.02-1.72)	1.16 (0.94-1.44)	0.49	0.29
		MV RR	1.00 (Reference)	1.20 (0.97-1.48)	1.26 (1.00-1.57)	1.09 (0.79-1.51)	1.27 (0.98-1.64)	1.12 (0.90-1.38)	0.55	0.60

NOTE: Multivariate RRs were adjusted for age at menarche (<13, 13, >13 years), menopausal status at baseline (premenopausal, postmenopausal, dubious), oral contraceptive use (ever, never), hormone replacement therapy use among postmenopausal women (never, past, current), parity (0, 1, 2, >2), BMI (<23, 23-<25, 25-<30, ≥30 kg/m²), smoking status (never, past, current), physical activity (low, medium, high), and energy intake (continuously), modeled identically across studies.
Abbreviation: MV RR, multivariate RR.
↵* P value, test for between-studies heterogeneity is based on the highest category of intake for that food or nutrient.
↵† P value, test for trend.
↵‡ New York State Cohort was not included in the categories 250 to 499.9 and ≥500 g/d of milk because this study had no cases in that category.
↵§ New York State Cohort was not included in the low-fat or whole-milk analyses because they did not measure consumption of these items separately.
↵∥ Nurses' Health Study II was not included in the category ≥250 g/d of whole milk because this study had no cases in that category.
↵¶ New York State Cohort is not included in the hard cheese or yogurt analyses because they did not measure consumption of these food items.
↵** Adventist Health Study, Nurses' Health Study (part a) and Nurses' Health Study II were not included in the category ≥50 g/d of hard cheese because this study had no cases in that category.
↵†† Nurses' Health Study II was not included in the category ≥53 g/d of cottage cheese because this study had no cases in that category.
↵‡‡ Cancer Prevention Study II Nutrition Cohort, New York State Cohort, and Swedish Mammography Cohort were not included in this analysis because they did not measure consumption of this item.
↵§§ Adventist Health Study and Breast Cancer Detection Demonstration Project Follow-up Study are not included in the yogurt analysis because they did not measure consumption of this food item.
↵∥∥ Adventist Health Study, the Netherlands Cohort Study, and New York State Cohort are excluded from the ice cream analyses because they did not measure consumption of this food item. Nurses' Health Study II and Women's Health Study were not included in the category ≥66 g/d of ice cream because this study had no cases in that category.
↵¶¶ Adventist Health Study was not included in the analysis of dietary or total calcium because this study had no cases in the reference group.
↵*** Canadian National Breast Screening Study, the Netherlands Cohort Study, Swedish Mammography Cohort are excluded from the total calcium and vitamin D analyses because they did not have supplement use data available for these nutrients.
↵††† New York State Cohort, Nurses' Health Study (part a) were not included in the category ≥500 g/d of dietary vitamin D because this study had no cases in that category.
↵‡‡‡ Adventist Health Study, Canadian National Breast Screening Study, the Netherlands Cohort Study, New York University Women's Health Study are excluded from the dietary and total (dietary and supplemental) vitamin D analyses because they did not assess vitamin D intake; Swedish Mammography Cohort is excluded from the total (dietary and supplemental) vitamin D analyses because they did not have supplement use data available.

Table 4.

Pooled multivariate adjusted RRs and 95% CIs for histologic subtypes of ovarian cancer according to dairy food and nutrient intake, continuous model

	Increment* (/d)	All ovarian cancer					Endometrioid cancer^†					Mucinous cancer^‡				P^∥
	Increment* (/d)			Case, n	RR (95% CI)^¶	P**	Case n	RR (95% CI)^¶	P**	Case n	RR (95% CI)^¶	P**	Case n	RR (95% CI)^¶	P**	P^∥
Foods
Milk	250 g	2,106	1.02 (0.97-1.08)	0.34	255	1.10 (0.95-1.27)	0.50	120	0.97 (0.77-1.22)	0.40	1,015	1.06 (0.94-1.19)	0.01	0.60
Whole milk^††	250 g	1,919	0.98 (0.88-1.10)	0.09	240	0.91 (0.65-1.27)	0.29	113	1.19 (0.88-1.61)	0.88	930	0.91 (0.76-1.08)	0.19	0.37
Low-fat milk^††	250 g	1,983	1.04 (0.98-1.09)	0.64	249	1.16 (1.00-1.34)	0.81	116	0.93 (0.73-1.20)	0.42	968	1.08 (0.99-1.18)	0.26	0.21
Cheese
Hard cheese^‡‡	25 g	2,027	1.02 (0.93-1.11)	0.17	259	1.11 (0.92-1.35)	0.77	122	1.00 (0.75-1.33)	0.56	982	1.07 (0.97-1.18)	0.69	0.75
Cottage cheese^§§	105 g	1,464	0.82 (0.63-1.08)	0.22	182	0.95 (0.50-1.81)	0.64	87	1.59 (0.92-2.57)	0.53	708	0.90 (0.62-1.32)	0.21	0.05
Yogurt^∥∥	227 g	1,809	0.91 (0.77-1.07)	0.80	239	0.98 (0.64-1.49)	0.83	119	0.83 (0.42-1.64)	0.71	931	0.93 (0.74-1.18)	0.93	0.95
Ice cream^¶¶	66 g	1,753	1.00 (0.84-1.20)	0.49	237	1.13 (0.68-1.87)	0.76	96	0.47 (0.12-1.83)	0.20	869	1.17 (0.94-1.44)	0.85	0.36
Nutrients
Dietary calcium	350mg	2,132	1.03 (0.97-1.09)	0.32	261	1.08 (0.93-1.25)	0.39	122	0.88 (0.70-1.11)	0.70	1,025	1.08 (0.97-1.21)	0.03	0.50
Total calcium***	350mg	1,414	1.01 (0.99-1.02)	0.41	148	1.08 (0.94-1.24)	0.03	59	1.08 (0.89-1.30)	0.48	682	1.00 (0.93-1.07)	0.29	0.53
Lactose	10 g	2,132	1.04 (0.99-1.08)	0.26	261	1.07 (0.95-1.20)	0.63	122	0.97 (0.81-1.16)	0.66	1,025	1.06 (0.97-1.16)	0.02	0.63
Dietary vitamin D^†††	100 IU	1,583	1.06 (1.00-1.12)	0.28	198	1.17 (0.97-1.42)	0.04	81	0.95 (0.73-1.24)	0.22	782	1.04 (0.98-1.12)	0.83	0.84
Total vitamin D^‡‡‡	100 IU	1,296	1.02 (0.99-1.04)	0.31	148	1.08 (1.02-1.15)	0.21	59	0.99 (0.85-1.10)	0.25	647	1.02 (0.94-1.09)	0.85	0.17

↵* Increment for foods is based on the standard serving size and for nutrients is based on the mean of the SD of the mean intake for each nutrient.
↵† Endometrioid analyses additionally exclude Adventist Health Study, New York State Cohort, and New York University Women's Health Study due to small case numbers.
↵‡ Mucinous analyses additionally exclude Adventist Health Study, Breast Cancer Detection Demonstration Project Follow-up Study, New York State Cohort, New York University Women's Health Study, Nurses' Health Study II, and Women's Health Study due to small case numbers.
↵§ Serous analyses additionally exclude Adventist Health Study due to small case numbers.
↵∥ P value for the test for the common effect by histologic types of ovarian cancer (endometrioid, mucinous, and serous).
↵¶ Multivariate RRs were adjusted for age at menarche (<13, 13, >13 years), menopausal status at baseline (premenopausal, postmenopausal, dubious), oral contraceptive use (ever, never), hormone replacement therapy use among postmenopausal women (never, past, current), parity (0, 1, 2, >2), BMI (<23, 23-<25, 25-<30, ≥30 kg/m²), smoking status (never, past, current), physical activity (low, medium, high), and energy intake (continuously), modeled identically across studies.
↵** P value, test for between-studies heterogeneity.
↵†† New York State Cohort is not included in the low-fat or whole-milk analyses because they did not measure consumption of these items separately.
↵‡‡ New York State Cohort is not included in the hard cheese analyses because they did not measure consumption of this food item.
↵§§ Cancer Prevention Study II Nutrition Cohort, New York State Cohort, and Swedish Mammography Cohort are excluded from the cottage cheese analyses because they did not measure consumption of this food item.
↵∥∥ Adventist Health Study, Breast Cancer Detection Demonstration Project Follow-up Study, and New York State Cohort are excluded from the yogurt analyses because they did not measure consumption of this food item.
↵¶¶ Adventist Health Study, the Netherlands Cohort Study, and New York State Cohort are excluded from the ice cream analyses because they did not measure consumption of this food item.
↵*** Canadian National Breast Screening Study, the Netherlands Cohort Study, and Swedish Mammography Cohort are excluded from the total calcium analyses because they did not have supplement use data available.
↵††† Adventist Health Study, Canadian National Breast Screening Study, the Netherlands Cohort Study, New York University Women's Health Study are excluded from the dietary and total vitamin D analyses because they did not assess vitamin D intake.
↵‡‡‡ Swedish Mammography Cohort is excluded from the total vitamin D analyses because they did not have supplement use data available.