TABLE 2.
HRs of invasive breast cancer associated with cumulative average total vitamin C intake in the NHS (1980–2014; n = 88,041) and NHSII (1991–2013; n = 93,372)1
| All tumors | ER+ tumors | ER− tumors | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Median, mg/d | No. of cases/person-years | HR (95% CI)2 | HR (95% CI)3 | No. of cases/person-years | HR (95% CI)3 | No. of cases/person-years | HR (95% CI)3 | P heterogeneity ER status 4 | |
| NHS | |||||||||
| Quintile 1 | 105 | 1452/480,533 | 1 (ref) | 1 (ref) | 956/480,533 | 1 (ref) | 249/480,533 | 1 (ref) | |
| Quintile 2 | 167 | 1593/499,223 | 1.03 (0.95–1.10) | 0.98 (0.91–1.05) | 1116/499,223 | 1.01 (0.93–1.10) | 262/499,223 | 0.96 (0.81–1.15) | |
| Quintile 3 | 237 | 1621/499,331 | 1.04 (0.97–1.11) | 0.98 (0.91–1.05) | 1136/499,331 | 1.00 (0.92–1.09) | 251/499,331 | 0.91 (0.76–1.09) | |
| Quintile 4 | 371 | 1660/498,641 | 1.06 (0.99–1.14) | 0.98 (0.91–1.05) | 1171/498,641 | 1.00 (0.92–1.09) | 265/498,641 | 0.94 (0.79–1.13) | |
| Quintile 5 | 723 | 1621/474,478 | 1.07 (1.00–1.15) | 0.99 (0.92–1.06) | 1097/474,478 | 0.98 (0.89–1.07) | 263/474,478 | 0.98 (0.82–1.17) | |
| — | — | — | P trend = 0.06 | P trend = 0.97 | — | P trend = 0.46 | — | P trend = 0.92 | 0.68 |
| NHSII | |||||||||
| Quintile 1 | 88 | 663/383,385 | 1 (ref) | 1 (ref) | 436/383,385 | 1 (ref) | 110/383,385 | 1 (ref) | |
| Quintile 2 | 139 | 653/394,836 | 0.96 (0.86–1.07) | 0.92 (0.83–1.03) | 426/394,836 | 0.90 (0.79–1.03) | 104/394,836 | 0.88 (0.67–1.16) | |
| Quintile 3 | 197 | 642/393,514 | 0.95 (0.85–1.05) | 0.90 (0.81–1.00) | 421/393,514 | 0.87 (0.76–1.00) | 107/393,514 | 0.92 (0.70–1.20) | |
| Quintile 4 | 305 | 659/391,260 | 0.97 (0.87–1.09) | 0.92 (0.82–1.02) | 454/391,260 | 0.93 (0.81–1.06) | 110/391,260 | 0.96 (0.73–1.26) | |
| Quintile 5 | 625 | 694/380,880 | 0.99 (0.89–1.11) | 0.92 (0.83–1.03) | 461/380,880 | 0.90 (0.78–1.03) | 114/380,880 | 0.99 (0.75–1.30) | |
| — | — | — | P trend = 0.71 | P trend = 0.47 | — | P trend = 0.42 | — | P trend = 0.73 | 0.51 |
| Pooled | |||||||||
| Quintile 1 | 105 | 2115/863,919 | 1 (ref) | 1 (ref) | 1392/863,919 | 1 (ref) | 359/863,919 | 1 (ref) | |
| Quintile 2 | 167 | 2246/894,059 | 0.99 (0.94–1.06) | 0.95 (0.90–1.01) | 1542/894,059 | 0.97 (0.90–1.04) | 366/894,059 | 0.95 (0.82–1.10) | |
| Quintile 3 | 237 | 2263/892,845 | 1.01 (0.95–1.07) | 0.95 (0.90–1.01) | 1557/892,845 | 0.96 (0.89–1.03) | 358/892,845 | 0.93 (0.80–1.07) | |
| Quintile 4 | 371 | 2319/889,901 | 1.03 (0.97–1.09) | 0.96 (0.90–1.02) | 1625/889,901 | 0.98 (0.91–1.05) | 375/889,901 | 0.93 (0.80–1.08) | |
| Quintile 5 | 723 | 2315/855,358 | 1.05 (0.99–1.11) | 0.97 (0.91–1.03) | 1558/855,358 | 0.95 (0.88–1.02) | 377/855,358 | 0.99 (0.85–1.15) | |
| — | — | — | P trend = 0.05 | P trend = 0.81 | — | P trend = 0.37 | — | P trend = 0.82 | 0.54 |
Vitamin C intake was adjusted for total energy intake using the residual method. Numbers do not add up to total numbers of cases and person-years because of missing values. Abbreviations: AHEI, alternate healthy eating index; ER, estrogen receptor; NHS, Nurses’ Health Study; NHSII, Nurses’ Health Study II.
Unadjusted. Stratified by age and period.
Adjusted for menopausal status and age at menopause (premenopausal; postmenopausal and <45 years at menopause; postmenopausal and 45–49 years at menopause; postmenopausal and 50–52 years at menopause; postmenopausal and ≥53 years at menopause; missing; time-dependent), age at menarche (<12, 12 to <13, 13 to <14, 14 to <15, ≥15 years), parity and age at first birth (nulliparous; 1 child and <25 years at first birth; 1 child and ≥25 years at first birth; ≥2 children and <25 years at first birth; ≥2 children and ≥25 years at first birth; missing; time-dependent), use of oral contraceptive (ever, never; time-dependent), personal history of biopsy-confirmed benign breast disease (yes, no; time-dependent), family history of breast cancer (yes, no; time-dependent), cumulative average alcohol intake (nonusers and quartiles of intakes; time-dependent), BMI at age 18 (<19, 19 to <21, 21 to <23, 23 to <27, ≥27 kg/m2, missing), weight change since age 18 by menopausal status (lost ≥2 kg and premenopausal; lost <2 kg or gained ≤2 kg and premenopausal; gained >2 to 5 kg and premenopausal; gained >5 to 10 kg and premenopausal; gained >10 to 20 kg and premenopausal; gained >20 to 25 kg and premenopausal; gained ≥25 kg and premenopausal; lost ≥2 kg and postmenopausal; lost <2 kg or gained ≤2 kg and postmenopausal; gained >2 to 5 kg and postmenopausal; gained >5 to 10 kg and postmenopausal; gained >10 to 20 kg and postmenopausal; gained >20 to 25 kg and postmenopausal; gained ≥25 kg and postmenopausal; missing; time-dependent), physical activity (quintiles and missing category; time-dependent), recent mammography (yes, no, missing; time-dependent), postmenopausal hormone use (never, past, current, missing; time-dependent), duration of use of postmenopausal hormone therapy with estrogen alone (continuous in months; time-dependent), duration of use of estrogen and progestin postmenopausal hormone therapy (continuous in months), height (<1.60, 1.60 to <1.65, 1.65 to <1.70, 1.70 to <1.75, ≥1.75 meters), total duration of lactation (<12, ≥12 months), and AHEI score without alcohol (quintiles and missing category; time-dependent). Stratified by age and period and additionally stratified by cohort in pooled analyses.
The median value for each quintile of vitamin C cumulative average intake was used as a continuous variable to test for heterogeneity across ER+ and ER- breast tumors.