Table 3.
Associations between pre-diagnostic plasma osteoprotegerin quartiles and invasive breast cancer, stratified by reproductive, anthropometric, hormonal, and tumor characteristics: results from a matched case-control study nested within the Nurses’ Health Study II.1
| Menopausal Status at Diagnosis/Index Date2 | ||||||
|---|---|---|---|---|---|---|
| Premenopausal |
Postmenopausal |
|||||
| Osteoprotegerin (pmol/L) | No. of Cases |
No. of Controls |
Odds Ratio (95% CI)3 | No. of Cases |
No. of Controls |
Odds Ratio (95% CI)3 |
| Quartile 1 (0.4-3.1) | 63 | 55 | Reference | 17 | 15 | Reference |
| Quartile 2 (3.1-3.6) | 60 | 55 | 1.05 (0.61, 1.79) | 12 | 13 | 0.75 (0.22, 2.59) |
| Quartile 3 (3.7-4.3) | 56 | 54 | 0.99 (0.58, 1.70) | 11 | 12 | 0.99 (0.27, 3.63) |
| Quartile 4 (4.3-10.0) | 39 | 50 | 0.72 (0.40, 1.31) | 13 | 17 | 0.82 (0.24, 2.86) |
| P-trend4 | 0.29 | 0.86 | ||||
| P-interaction5 | 0.95 | |||||
| BMI at Blood Collection | ||||||
| BMI < 25kg/m2 |
BMI ≥ 25kg/m2 |
|||||
| Quartile 1 (0.4-3.1) | 46 | 45 | Reference | 39 | 30 | Reference |
| Quartile 2 (3.1-3.6) | 62 | 48 | 1.47 (0.81, 2.70) | 18 | 26 | 0.45 (0.19, 1.07) |
| Quartile 3 (3.7-4.3) | 44 | 44 | 1.05 (0.56, 1.98) | 28 | 30 | 0.58 (0.26, 1.30) |
| Quartile 4 (4.3-10.0) | 31 | 44 | 0.91 (0.46, 1.81) | 29 | 30 | 0.63 (0.28, 1.42) |
| P-trend4 | 0.54 | 0.34 | ||||
| P-interaction5 | 0.21 | |||||
| Luteal Estradiol at Blood Collection6 | ||||||
| < Median (124.4 pg/mL) |
≥ Median (124.4 pg/mL) |
|||||
| Quartile 1 (0.4-3.1) | 25 | 20 | Reference | 38 | 32 | Reference |
| Quartile 2 (3.1-3.6) | 30 | 26 | 1.04 (0.43, 2.55) | 33 | 30 | 0.95 (0.46, 1.96) |
| Quartile 3 (3.7-4.3) | 21 | 35 | 0.47 (0.19, 1.19) | 32 | 21 | 1.06 (0.48, 2.34) |
| Quartile 4 (4.3-10.0) | 16 | 29 | 0.36 (0.13, 1.00) | 26 | 25 | 0.88 (0.40, 1.96) |
| P-trend4 | 0.02 | 0.82 | ||||
| P-interaction5 | 0.17 | |||||
| Luteal Progesterone at Blood Collection6 | ||||||
| < Median (1403.3 ng/dL) |
≥ Median (1403.3 ng/dL) |
|||||
| Quartile 1 (0.4-3.1) | 36 | 38 | Reference | 30 | 22 | Reference |
| Quartile 2 (3.1-3.6) | 32 | 27 | 1.33 (0.61, 2.91) | 37 | 32 | 0.81 (0.36, 1.81) |
| Quartile 3 (3.7-4.3) | 24 | 28 | 0.92 (0.41, 2.05) | 33 | 33 | 0.78 (0.35, 1.74) |
| Quartile 4 (4.3-10.0) | 18 | 25 | 0.71 (0.30, 1.69) | 26 | 31 | 0.64 (0.28, 1.48) |
| P-trend4 | 0.39 | 0.31 | ||||
| P-interaction5 | 0.84 | |||||
| Percent Mammographic Density | ||||||
| < Median (43.3%) |
≥ Median (43.3%) |
|||||
| Quartile 1 (0.4-3.1) | 27 | 31 | Reference | 29 | 27 | Reference |
| Quartile 2 (3.1-3.6) | 19 | 29 | 1.23 (0.51, 2.94) | 35 | 21 | 1.84 (0.81, 4.16) |
| Quartile 3 (3.7-4.3) | 22 | 28 | 1.06 (0.46, 2.45) | 29 | 27 | 1.02 (0.45, 2.34) |
| Quartile 4 (4.3-10.0) | 18 | 18 | 1.18 (0.45, 3.09) | 25 | 31 | 0.86 (0.37, 2.00) |
| P-trend4 | 0.80 | 0.42 | ||||
| P-interaction5 | 0.48 | |||||
| Tumor Estrogen Receptor (ER) Status | ||||||
| ER + |
ER − |
|||||
| Quartile 1 (0.4-3.1) | 66 | 75 | Reference | 19 | 75 | Reference |
| Quartile 2 (3.1-3.6) | 63 | 74 | 1.08 (0.66, 1.78) | 12 | 74 | 0.67 (0.29, 1.56) |
| Quartile 3 (3.7-4.3) | 57 | 74 | 0.99 (0.60, 1.64) | 13 | 74 | 0.73 (0.32, 1.66) |
| Quartile 4 (4.3-10.0) | 45 | 74 | 0.77 (0.45, 1.31) | 12 | 74 | 0.77 (0.33, 1.80) |
| P-trend4 | 0.31 | 0.57 | ||||
| P-heterogeneity7 | 0.99 | |||||
| Tumor Progesterone Receptor (PR) Status | ||||||
| PR + |
PR − |
|||||
| Quartile 1 (0.4-3.1) | 58 | 75 | Reference | 24 | 75 | Reference |
| Quartile 2 (3.1-3.6) | 54 | 74 | 1.07 (0.64, 1.79) | 23 | 74 | 1.08 (0.54, 2.19) |
| Quartile 3 (3.7-4.3) | 54 | 74 | 1.08 (0.65, 1.82) | 16 | 74 | 0.73 (0.34, 1.54) |
| Quartile 4 (4.3-10.0) | 41 | 74 | 0.80 (0.46, 1.39) | 15 | 74 | 0.77 (0.35, 1.66) |
| P-trend4 | 0.46 | 0.36 | ||||
| P-heterogeneity7 | 0.61 | |||||
Cases and controls were matched on case diagnosis date, age at blood collection (+/− 2 years), time of blood collection (month [+/− 1 month] and time of day [+/− 2 hours]), fasting at blood collection (<2, 2-4, 5-7, 8-11, ≥12 hours since last meal), menopausal status at blood collection and in the questionnaire cycle before cancer diagnosis/control index date (premenopausal, postmenopausal, unknown), and self-reported race/ethnicity (white, non-white). In addition, women who gave a blood sample timed in the menstrual cycle (n=470) were matched on luteal day.
Menopausal status in the questionnaire cycle immediately preceding breast cancer diagnosis or control index date.
Odd ratios produced using unconditional logistic regression adjusted for matching factors and a priori potential confounders: age at menarche (continuous: years); parity/age at first birth (categorical: nulliparous, 1-2 pregnancies/age first birth<25, 1-2 pregnancies/age first birth ≥25, ≥3 pregnancies/age first birth <25, ≥3 pregnancies/age first birth≥25); ever breastfed (categorical: yes, no); family history of breast cancer (categorical: yes, no); history of biopsy-confirmed benign breast disease (categorical: yes, no); BMI at age 18 (continuous: kg/m2); weight change between age 18 and blood collection (continuous: kg); average alcohol consumption from 1991 and 1995 questionnaires (continuous: grams/day); and average physical activity from 1989, 1991, and 1997 questionnaires (continuous: Metabolic Equivalent of Task [MET]-hrs/week).
P-trend modeling the median of each quartile as a continuous variable, testing for linearity using the Wald test.
P-interaction for multiplicative effect modification, assessed using a likelihood ratio test comparing models with vs. without an interaction term between the stratification variable and OPG (quartiles).
Luteal estradiol and luteal progesterone measured from the same plasma sample as osteoprotegerin.
P-heterogeneity assessed using unconditional nominal polytomous logistic regression adjusted for matching factors and confounders, testing for heterogeneity using the Wald test and allowing the effects of covariates to vary by tumor characteristics.
Abbreviations: CI=confidence interval; LRT=likelihood ratio test; BMI=body mass index; ER=estrogen receptor; PR=progesterone receptor.