Introduction 1 2 3 3 19 15 16 20 21 14 17 22 25 26 27 29 30 31 32 33 34 35 1 36 37 Methods Study population 38 39 42 n n n n n n n n n n n 43 Alcohol assessment Participants reported average weekly consumption of beer, wine/champagne, and cocktails/liquor at ages 18–22 years, at ages 30–35 years, and in the year prior to baseline. Available response categories for average number of drinks per week were none, ≤ 3, 4–10, 11–17, 18–24, and ≥ 25. A typical drink was defined as one bottle, can, or glass of beer; one glass of wine, champagne, or wine cooler; or one cocktail, shot, or mixed drink of liquor. A single drink of beer, wine, or liquor was assumed to contain 13.2, 11.1, or 15.0 grams of alcohol, respectively. Based on these standards, daily intake of grams of alcohol from each type of drink was calculated for each woman during each time period. Alcohol intake in the cohort was reproducible (r = 0.87) and valid compared to multiple 24–hour recalls (r = 0.74) (Pamela Horn-Ross, unpublished data). 36 37 37 Residence-based measures 44 44 45 Follow-up 46 Date and cause of death are ascertained through linkages with the California state mortality file and the national Social Security Administration death master file, as well as reports from relatives. Address changes are obtained through annual mailed newsletters, notifications by participants, and record linkages with the California Department of Motor Vehicles, the US Postal Service National Change of Address database, and other sources. Statistical analysis p 47 Hazard rate ratios, presented as relative risks (RR), and corresponding 95% confidence intervals (CI) were estimated for each type of alcoholic beverage, comparing categories of consumption to non-drinkers of that alcohol type as the reference group. Tests for linear trend across exposure categories were conducted using the median of each category coded as an ordinal variable. The median of the highest category of beer, wine, or liquor intake was equal to the lower boundary because most women in those categories reported consuming one drink per day. 43 n 48 Results 1 2 P trend Table 1 n Characteristic n (%) Age at baseline (years)     <35 10,456 (11.6%)     35–44 18,546 (20.5%)     45–54 28,275 (31.3%)     55–64 16,229 (18.0%)     65–74 11,496 (12.7%)     75–84 5,369 (5.9%) Race/ethnicity     White 78,468 (86.8%)     Non-white 11,266 (12.5%)     Unknown 637 (0.7%) Parity (full-term pregnancies)     None 23,810 (26.3%)     1–2 43,674 (48.3%)     ≥3 21,412 (23.7%)     Unknown 1,475 (1.6%) Oral contraceptive use (years)     None 26,643 (29.5%)     <5 27,608 (30.5%)     ≥5 32,463 (35.9%)     Unknown 3,657 (4.0%) Lifetime strenuous physical activity (average hours/week)     <0.5 25,254 (27.9%)     0.5–3.9 49,467 (54.7%)     ≥4.0 15,293 (16.9%)     Unknown 357 (0.4%) Menopausal status     Pre-menopausal 42,204 (46.7%)     Peri-menopausal 2,202 (2.4%)     Post-menopausal 39,744 (44.0%)     Unknown 6,221 (6.9%) Hormone therapy (HT) use (peri-/post-menopausal women only)     None 12,968 (30.9%)     Combination estrogen + progestin HT 14,235 (33.9%)     Estrogen-only HT, ≤5 years 4,342 (10.4%)     Estrogen-only HT, >5 years 4,899 (11.7%)     Estrogen-only HT, unknown duration 332 (0.8%)     Mixed combination and estrogen-only HT 4,776 (11.4%)     Unknown 394 (0.9%) a     Greater San Francisco Bay Area 18,444 (20.4%)     Southern Coastal/Los Angeles Area 35,388 (39.2%)     Other areas 36,483 (40.4%)     Unknown 56 (0.1%) Type of residence     Rural 12,677 (14.0%)     Town 3,136 (3.5%)     Small city 16,135 (17.9%)     Metropolitan suburban 48,278 (53.4%)     Metropolitan urban 9,038 (10.0%)     Unknown 1,107 (1.2%) a     ≤49th 18,962 (21.0%)     50–59th 10,199 (11.3%)     60–69th 12,620 (14.0%)     70–79th 14,508 (16.1%)     80–89th 16,864 (18.7%)     90–99th 16,076 (17.8%)     Unknown 1,142 (1.3%) Smoking history     Never 60,868 (67.4%)     Former 24,989 (27.7%)     Current 4,428 (4.9%)     Unknown 86 (0.1%) Alcohol drinking in the year prior to baseline     None 31,024 (34.3%)     Beer only 2,222 (2.5%)     Wine only 19,365 (21.4%)     Liquor only 2,868 (3.2%)     Beer and liquor only 1,005 (1.1%)     Wine and beer/liquor 33,887 (37.5%) a Table 2 Relative risks (RRs) and 95% confidence intervals (CIs) for associations between intake of specific types of alcohol at various ages and risk of ovarian cancer Alcohol type Time period Daily intake (g/day) Median (g/day) n a a b b Total alcohol  Year before baseline   None 0.0 77 1.00 (reference) —    <10.0 4.5 81 1.04 (0.76, 1.42) —    10.0– < 20.0 11.8 72 1.47 (1.06, 2.03) —    ≥20.0 28.2 23 1.15 (0.71, 1.84) —       P trend    c   None 0.0 67 1.00 (reference) —    <10.0 7.3 101 1.14 (0.83, 1.56) —    10.0– < 20.0 11.8 47 1.08 (0.74, 1.59) —    ≥20.0 29.7 16 0.99 (0.56, 1.71) —       P trend    d   None 0.0 131 1.00 (reference) —    <10.0 4.5 62 0.76 (0.55, 1.03) —    10.0– < 20.0 11.8 36 1.26 (0.86, 1.84) —    ≥20.0 28.8 9 1.00 (0.50, 1.99) —       P trend   Beer  Year before baseline   None 0.0 199 1.00 (reference) 1.00 (reference)   <13.2 4.0 51 0.96 (0.70, 1.31) 0.89 (0.64, 1.24)   ≥13.2 13.2 3 0.58 (0.19, 1.84) 0.54 (0.17, 1.70)      P trend P trend  c   None 0.0 180 1.00 (reference) 1.00 (reference)   <13.2 4.0 45 0.81 (0.58, 1.13) 0.75 (0.53, 1.06)   ≥13.2 13.2 6 0.72 (0.32, 1.64) 0.73 (0.32, 1.69)      P trend P trend  d   None 0.0 179 1.00 (reference) 1.00 (reference)   <13.2 4.0 46 0.95 (0.68, 1.32) 0.93 (0.65, 1.33)   ≥13.2 13.2 13 1.21 (0.68, 2.16) 1.30 (0.70, 2.39)      P trend P trend Wine  Year before baseline   None 0.0 91 1.00 (reference) 1.00 (reference)   <11.1 3.3 99 1.08 (0.81, 1.43) 1.09 (0.80, 1.50)   ≥11.1 11.1 63 1.50 (1.08, 2.09) 1.57 (1.11, 2.22)      P trend e P trend e  c   None 0.0 90 1.00 (reference) 1.00 (reference)   <11.1 3.3 112 1.19 (0.90, 1.59) 1.26 (0.92, 1.71)   ≥11.1 11.1 29 1.21 (0.78, 1.86) 1.38 (0.87, 2.19)      P trend P trend  d   None 0.0 167 1.00 (reference) 1.00 (reference)   <11.1 3.3 63 1.11 (0.82, 1.50) 1.17 (0.84, 1.63)   ≥11.1 11.1 8 1.42 (0.69, 2.91) 1.63 (0.76, 3.50)      P trend P trend Liquor  Year before baseline   None 0.0 169 1.00 (reference) 1.00 (reference)   <15.0 4.5 68 1.09 (0.82, 1.45) 1.06 (0.78, 1.44)   ≥15.0 15.0 16 0.87 (0.52, 1.47) 0.82 (0.48, 1.39)      P trend P trend  c   None 0.0 124 1.00 (reference) 1.00 (reference)   <15.0 4.5 93 1.07 (0.81, 1.41) 1.04 (0.77, 1.40)   ≥15.0 15.0 14 0.77 (0.44, 1.35) 0.75 (0.42, 1.36)      P trend P trend  d   None 0.0 164 1.00 (reference) 1.00 (reference)   <15.0 4.5 69 0.99 (0.74, 1.32) 0.94 (0.68, 1.29)   ≥15.0 15.0 5 0.62 (0.25, 1.52) 0.49 (0.19, 1.26)      P trend P trend a b c d e p p  p  3 n P trend Table 3 Relative risks (RRs) and 95% confidence intervals (CIs) for associations between patterns of drinking specific types of alcohol and risk of ovarian cancer Alcohol type Time period Drinking pattern n a a b b Total alcohol  c   Never 49 1.00 (reference) —    Steady moderate 118 1.25 (0.89, 1.76) —    Decreasing 29 1.06 (0.67, 1.68) —    Increasing 27 1.10 (0.68, 1.77) —    Steady heavy 8 1.32 (0.62, 2.82) —   d   Never 55 1.00 (reference) —    Steady moderate 70 1.07 (0.74, 1.53) —    Decreasing 24 1.06 (0.65, 1.72) —    Increasing 86 1.30 (0.92, 1.84) —    Steady heavy 3 1.87 (0.58, 6.04) —   Year before baseline   0 days/week 77 1.00 (reference) —    1 to 4 days/week 98 1.25 (0.92, 1.69) —    5 to 7 days/week, ≤ 20 g/day 30 1.36 (0.88, 2.08) —    5 to 7 days/week, > 20 g/day 18 1.14 (0.68, 1.93) —  Beer  c   Never 163 1.00 (reference) 1.00 (reference)   Steady moderate 26 0.80 (0.53, 1.21) 0.73 (0.47, 1.13)   Decreasing 25 0.94 (0.62, 1.44) 0.88 (0.57, 1.38)   Increasing 17 1.08 (0.65, 1.79) 0.99 (0.59, 1.66)   Steady heavy 0 —  —   d   Never 159 1.00 (reference) 1.00 (reference)   Steady moderate 24 1.06 (0.68, 1.64) 1.02 (0.64, 1.62)   Decreasing 34 0.95 (0.65, 1.38) 0.92 (0.61, 1.37)   Increasing 21 0.77 (0.49, 1.22) 0.71 (0.44, 1.14)   Steady heavy 0 —  —   e   0 days/week 199 1.00 (reference) 1.00 (reference)   1 to 4 days/week 40 0.98 (0.70, 1.39) 0.79 (0.53, 1.16)   5 to 7 days.week 1 0.33 (0.05, 2.37) 0.36 (0.05, 2.59)     P trend P trend Wine  c   Never 60 1.00 (reference) 1.00 (reference)   Steady moderate 65 1.15 (0.80, 1.64) 1.19 (0.80, 1.77)   Decreasing 34 1.25 (0.82, 1.92) 1.32 (0.82, 2.11)   Increasing 53 1.25 (0.86, 1.82) 1.29 (0.86, 1.93)   Steady heavy 19 1.54 (0.91, 2.62) 1.75 (1.00, 3.04)  d   Never 71 1.00 (reference) 1.00 (reference)   Steady moderate 29 0.98 (0.63, 1.52) 1.01 (0.62, 1.63)   Decreasing 20 1.48 (0.89, 2.45) 1.73 (1.00, 2.99)   Increasing 113 1.29 (0.95, 1.74) 1.38 (0.99, 1.92)   Steady heavy 5 2.47 (0.99, 6.19) 2.76 (1.09, 7.00)  e   0 days/week 91 1.00 (reference) 1.00 (reference)   1 to 4 days/week 97 1.19 (0.89, 1.60) 1.23 (0.89, 1.71)   5 to 7 days.week 37 1.34 (0.91, 1.98) 1.45 (0.96, 2.20)     P trend P trend Liquor  c   Never 110 1.00 (reference) 1.00 (reference)   Steady moderate 47 1.13 (0.80, 1.60) 1.12 (0.76, 1.63)   Decreasing 50 1.04 (0.74, 1.46) 0.97 (0.67, 1.41)   Increasing 21 1.11 (0.69, 1.77) 1.04 (0.63, 1.70)   Steady heavy 3 0.49 (0.15, 1.54) 0.46 (0.15, 1.49)  d   Never 126 1.00 (reference) 1.00 (reference)   Steady moderate 32 1.12 (0.76, 1.66) 1.10 (0.71, 1.69)   Decreasing 35 0.84 (0.57, 1.23) 0.76 (0.50, 1.15)   Increasing 44 0.98 (0.69, 1.38) 0.92 (0.64, 1.33)   Steady heavy 1 0.80 (0.11, 5.77) 0.69 (0.10, 5.04)  e   0 days/week 169 1.00 (reference) 1.00 (reference)   1 to 4 days/week 57 1.13 (0.83, 1.53) 1.10 (0.78, 1.55)   5 to 7 days.week 13 1.00 (0.57, 1.78) 0.73 (0.35, 1.51)     P trend P trend a b c d e The lack of an association with total alcohol, beer, or liquor intake, as well as the persistence of the association between wine intake and risk of ovarian cancer after adjustment for alcohol consumption, suggested that determinants of wine drinking, or ingredients of wine other than alcohol, were responsible for the observed positive association. After mutual adjustment, older age (up to ages 65–69 years), White race, higher total caloric intake, nulliparity, ever-use of oral contraceptives, more physical activity, ever-use of HT, higher SES or median family income, residence in the Greater San Francisco Bay Area, lower body mass index, ever-smoking of cigarettes, and higher intake of coffee and/or tea were significantly associated with drinking at least one daily glass of wine, compared to none (data not shown). However, the positive association between wine consumption and risk of ovarian cancer remained statistically significant even after adjustment for these characteristics (data not shown). 4 P trend P trend Table 4 Stratified relative risks (RRs) and 95% confidence intervals (CIs) for associations between wine intake in the year before baseline and risk of ovarian cancer within participant subgroups Characteristic (at baseline) Alcohol consumption from wine P trend P heterogeneity  None  < 11.1 g/day ≥ 11.1 g/day Cases a Cases a a Cases a a Age ≤Median (50 years) 23 1.00 27 1.07 (0.58, 1.99) 12 1.43 (0.67, 3.04) 0.34  >Median 68 1.00 72 1.10 (0.76, 1.57) 51 1.62 (1.09, 2.39) 0.01 0.95 Parity Nulliparous 18 1.00 26 1.34 (0.69, 2.62) 13 1.56 (0.71, 3.40) 0.31  Parous 71 1.00 73 1.05 (0.73, 1.50) 48 1.57 (1.06, 2.34) 0.02 0.61 Oral contraceptive use Never 45 1.00 39 1.00 (0.62, 1.61) 29 1.70 (1.02, 2.82) 0.03  Ever 22 1.00 14 0.76 (0.37, 1.58) 14 1.78 (0.85, 3.72) 0.09 0.54 Lifetime strenuous physical activity ≤Median (1.4 hours/week) 61 1.00 58 1.07 (0.72, 1.59) 40 1.68 (1.09, 2.59) 0.01  >Median (1.4 hours/week) 30 1.00 41 1.11 (0.66, 1.86) 23 1.39 (0.77, 2.50) 0.26 0.55 Menopausal status Pre-menopausal 21 1.00 20 0.83 (0.42, 1.65) 10 1.24 (0.55, 2.83) 0.53  Peri-/Post-menopausal 66 1.00 72 1.16 (0.80, 1.66) 51 1.72 (1.16, 2.55) 0.01 0.86 Hormone therapy (HT) use b 21 1.00 22 1.27 (0.64, 2.51) 9 1.20 (0.51, 2.78) 0.73  b 23 1.00 18 0.69 (0.35, 1.37) 16 1.17 (0.58, 2.34) 0.45  b 16 1.00 19 1.27 (0.62, 2.61) 15 2.03 (0.95, 4.35) 0.06 0.37 Region of residence Greater Bay/Southern Coastal regions 45 1.00 62 1.20 (0.79, 1.84) 38 1.69 (1.06, 2.71) 0.02  Other California regions 46 1.00 37 0.94 (0.59, 1.52) 25 1.46 (0.87, 2.48) 0.12 0.41 Type of residence Rural/town/small city 35 1.00 34 1.23 (0.74, 2.06) 23 1.77 (1.01, 3.11) 0.05  Metropolitan suburban/urban 54 1.00 65 1.04 (0.70, 1.55) 40 1.51 (0.97, 2.37) 0.05 0.77 c Lower 75%  57 1.00 50 1.09 (0.72, 1.67) 24 1.35 (0.81, 2.27) 0.25  Upper 25%  32 1.00 49 1.16 (0.72, 1.88) 39 1.96 (1.19, 3.24) 0.004 0.43 Body mass index 2 33 1.00 46 1.31 (0.81, 2.11) 32 1.64 (0.97, 2.76) 0.07  >Median 53 1.00 52 0.97 (0.63, 1.49) 27 1.48 (0.89, 2.45) 0.10 0.69 Cigarette smoking status Never 66 1.00 61 1.05 (0.71, 1.56) 36 1.77 (1.13, 2.78) 0.01  Ever 25 1.00 38 1.19 (0.69, 2.03) 27 1.42 (0.80, 2.50) 0.24 0.57 Dietary folate intake d 23 1.00 21 0.73 (0.37, 1.43) 13 1.15 (0.54, 2.44) 0.55  d 21 1.00 23 1.16 (0.60, 2.24) 10 1.17 (0.51, 2.66) 0.75 0.74 Total folate intake e 43 1.00 46 1.07 (0.68, 1.70) 25 1.34 (0.78, 2.30) 0.27  e 41 1.00 48 1.20 (0.77, 1.89) 37 2.07 (1.29, 3.35) 0.002 0.43 a b c d i.e. e i.e. In secondary analyses, we examined the associations between alcohol consumption and risk of ovarian cancer among only women who were peri- or post-menopausal at baseline (46% of the study population, 75% of cases). In this group, we observed the same lack of a significant association with total alcohol, beer, or liquor intake, along with a significant positive association with baseline wine intake. Likewise, when we restricted the case population to invasive ovarian cancer (90% of cases) or to serous ovarian cancer (45% of cases), baseline intake of alcohol from wine, but not from other sources, was associated with significantly increased risk of ovarian cancer. Discussion 3 18 19 In contrast, average consumption of at least one glass per day of wine in the year before baseline was associated with elevated risk of ovarian cancer, while wine intake at ages 30–35 years or 18–22 years was associated with nonsignificantly increased risk. The positive association with baseline wine intake persisted after adjustment for total alcohol intake, suggesting that the apparent effect of wine on ovarian cancer risk was independent of alcohol content. The association was also unchanged by further adjustment for characteristics and behaviors associated with wine drinking in this cohort, and was not significantly modified by reproductive characteristics, demographic factors, or folate intake. However, there was a significant positive association between wine consumption and ovarian cancer risk among peri-/post-menopausal women who used unopposed estrogen HT, whereas there was no such association among peri-/post-menopausal women who did not use HT or used combined estrogen-progestin HT. Wine consumption was also associated with increased ovarian cancer risk among women of high SES, but not among women of relatively low SES. 15 49 14 24 17 13 18 19 19 24 16 17 25 14 15 3 12 19 24 1 50 51 52 54 37 In summary, given the lack of association between overall alcohol consumption and ovarian cancer risk in our study, further investigations are necessary to determine whether ingredients of wine, but not beer or liquor, foster ovarian cancer development; whether correlates of wine drinking not measured or imperfectly measured in our study population are associated with ovarian cancer risk; or if an association is largely due to the apparent interaction between wine consumption and unopposed estrogen HT use and/or other characteristics of women of high SES. If the observed association between wine drinking and ovarian cancer risk is due to confounding, then there may exist an as-yet unidentified ovarian cancer risk factor that is also associated with wine drinking. On the other hand, if the interactions with estrogen HT use and SES are confirmed, there may be a biological basis for the increased risk of ovarian cancer among wine drinkers with high endogenous and exogenous estrogen levels. However, if alcohol consumption is indeed unrelated to ovarian cancer development but positively associated with the risk of breast cancer, then differences in the hormonal and non-hormonal triggers between these two malignancies may help us understand the carcinogenic effects of alcohol on hormonally responsive tissue. Further understanding of the complex relationships among steroid hormone levels, metabolism of alcohol and wine, and carcinogenesis will help clarify what role, if any, alcohol and wine play in the development of ovarian cancer.