Abstract
Purpose:
Among healthy postmenopausal women, levels of CA125 and CA15.3 are influenced by demographic and reproductive factors, including race/ethnicity. In this study we sought to examine the interaction between race/ethnicity and other correlates of these biomarkers and whether the racial differences observed are simply determined by other correlates with racial differences.
Methods:
In archived sera from 946 postmenopausal women who participated in the 2001–2002 cycle of the National Health and Nutrition Examination Survey, we measured CA125 and CA15.3 and examined their associations with health survey and examination data available in this cohort. We used multivariable linear regression to examine the association between CA125 and CA15.3 and race/ethnicity. We then calculated geometric means of these markers by demographic and reproductive factors stratified by race/ethnicity and used likelihood ratio tests to evaluate heterogeneity.
Results:
Non-white race was associated with lower CA125, with Non-Hispanic Blacks being associated with −29.0% (95%CI=−42.5%, −12.2%) difference and Mexican Americans being associated with −6.4% (95%CI=−18.1%, 6.9%) difference on average compared to Non-Hispanic Whites. Associations between CA125 and age and parity varied by race/ethnicity. Non-Hispanic Blacks were associated with higher CA15.3 compared to Non-Hispanic Whites, with 17.3% (95%CI=−0.5%, 38.3%) differences on average. Associations between CA15.3 and age, number of births, and age at natural menopause varied by race/ethnicity.
Conclusions:
Among postmenopausal women, Non-Hispanic Blacks were associated with lower CA125 and higher CA15.3 levels compared to Non-Hispanic Whites. Our results support that race/ethnicity should be considered when assigning thresholds for these biomarkers being tested for diagnostic or screening purposes.
Keywords: CA125, CA15.3, racial/ethnic difference, postmenopausal
INTRODUCTION
Cancer Antigen 125 (CA125) and CA15.3 are members of the mucin family of glycoproteins and overexpressed in ovarian and other cancers, and have been investigated as cancer screening biomarkers [1]. CA125 is currently the best biomarker for ovarian cancer diagnosis and follow up [2, 3]. CA125 and CA15.3 have been reported to be associated with demographic and reproductive characteristics among healthy women [4–8]. Specifically, CA125 has been consistently observed to be associated with menopausal status and race/ethnicity in prior studies, with lower CA125 associated with postmenopausal women and non-white race [5–8]. We and others have previously reported the predictors of CA125 differed by menopausal status [4, 7, 8]. However, while we know demographic characteristics differ by race/ethnicity [9], it is not clear if the difference in these biomarker values by race/ethnicity can be explained by racial/ethnic differences in other demographic and reproductive characteristics. Moreover, it has not been investigated whether the correlates of CA125 and CA15.3 are similar or different by race/ethnicity. It is plausible that the reported racial disparities in ovarian cancer incidence could be in part explained by the differences in the “normal” CA125 values across race/ethnicity, leading to underdiagnosis or later diagnosis of ovarian cancer in these understudied population [9, 10].
Here, we measured CA125 and CA15.3 in archived sera from women who participated in the US National Health and Nutrition Examination Survey (NHANES) 2001–2002 and investigated whether CA125 and CA15.3 values differed by race/ethnicity after accounting for previously reported demographic and reproductive characteristics associated with CA125 and/or CA15.3 in postmenopausal women. We also investigated the interaction between race/ethnicity and correlates of these biomarkers using demographic and health data available on this cohort.
MATERIALS AND METHODS
Study population
The National Health and Nutrition Examination Survey (NHANES) is an ongoing series of cross-sectional population-based survey studies designed to assess the health and nutritional status of adults and children in the United States [11]. The NHANES uses a complex, multistage probability sampling scheme to recruit a representative sample of non-institutionalized US population. Participants provided health related information via questionnaire by trained interviewers, physical examination, and biospecimens. We selected women from the NHANES 2001–2002 cycle in order to maximize the potential follow-up data on this cohort while minimizing ethical concerns about whether an elevated CA125 or CA15.3 value observed might require notification. Accordingly, we requested and received permission from the Scientific and Ethics panels of NHANES to obtain archived sera from women in this cohort to measure these biomarkers.
Details on the exclusion criteria and sample size are summarized in Figure 1. Of the 11,039 participants in the NHANES 2001–2002 cohort, we excluded men (n=5,331), those women who were < age 20 (n=2,833), and those with no plasma available for CA125 and CA15.3 measurements (n=350). Among these women, we requested and received permission to receive sera from 2,525 women to measure several biomarkers including CA125 and CA15.3. For the current analyses, we excluded those with outlying CA125 (n=3) or CA15.3 values (n=82), women missing data on the reproductive-health questionnaires (n=212), having unknown menopausal status (n=1), women with prior history of ovarian cancer (n=6), and women categorized as other Hispanic (n=90) or other race (n=80). We excluded premenopausal women (n=1,105) since this report focused on CA125 and CA15.3 levels in postmenopausal women. Women who were excluded due to outlying biomarker values had similar racial/ethnic distributions compared to all women with the biomarker data. Women were categorized as premenopausal if they reported regular periods in the past year or normally irregular cycles at the time of blood draw or were age < 50 at time of survey and reported no periods in the past year because of a hysterectomy without bilateral salpingo-oophorectomy (BSO) or because of a medical condition or treatment; otherwise they were categorized as postmenopausal. In sum, our analysis included a total sample of 946 postmenopausal women.
Fig.1.
Exclusions to determine the analytic population
The study was approved by the scientific and ethics panel of NHANES and by the Partners Human Research Committee.
Exposure variables
We examined demographic and reproductive characteristics that have previously been reported to be associated with CA125 and/or CA15.3 among postmenopausal women [4–7]. Characteristics examined included age at blood draw, body mass index (BMI) which was calculated using weight and height measured by trained health technicians, smoking status (never, former, current), and race/ethnicity. The racial/ethnic groups included: non-Hispanic white, non-Hispanic black, and Mexican Americans. Based on the Hispanic subgroup analysis recommendations in the NHANES Analytic Guidelines 1999–2010 [12], women who were categorized as “other Hispanic” or “other race” were excluded from the analysis. Reproductive characteristics included age at menarche, oral contraceptive (OC) use and duration, parity, number of live births, age at first and last live birth, history of breastfeeding, tubal ligation, hysterectomy, age at natural menopause, menopausal hormone therapy use (never, former, current), and “ovulatory years.” Age at natural menopause was defined as the age at last period for those who either never had a BSO or had a BSO after their periods stopped [13]. Ovulatory years were calculated by the following equation: (age at last period) – (age at menarche) – (years of OC use) – (number of live births) * 0.92 – (number of pregnancies resulting in non-live births) * 0.31 [14].
CA125 and CA15.3 measurements
CA125 and CA15.3 levels were measured in sera from eligible NHANES 2001–2002 participants at the Genital Tract Biology Laboratory (Brigham and Women’s Hospital, Boston, MA). Details are available online https://wwwn.cdc.gov/Nchs/Nhanes/2001-2002/SSCA_B.htm. Briefly, the assays were performed using electrochemiluminescence immunoassay platform (Meso Scale Discovery (MSD) (Gaithersbug, MD, USA) and available kits (CA125: catalog number K151WC, CA15.3: catalog number N45ZA-1) to accommodate the small volume of NHANES sera available [4]. The range of detection for the CA125 assay was 10,000–0.6 U/ml with low limit of detection (LLD) 0.286 U/mL and for the CA15.3 assay was 12,500–0.76 mU/mL (LLD=0.483 mU/mL). All the samples measured were above the LLD for both CA125 and CA15.3. Assay performance was assessed using unblinded quality control samples. For CA125, the inter-plate coefficient of variation (CV) was 13% and the minimum to maximum range the intraplate CV was 0.5%–22% and its mean was 7.0%. Corresponding values for CA15.3 were, 19% interplate CV, 0%–17% intraplate CV range, and mean of 4%. It should be noted that the MSD assays are not equivalent to the commonly used clinical assays such as CA125II (Roache Elecsys) and CA15.3 (Roche). We have previously estimated the correlation between the CA125II assay values with the corresponding MSD assay values in 534 women, 326 of whom were postmenopausal, who participated as controls in the New England Case Control Study [15]. Both assay measurements were highly correlated with Pearson correlation coefficient of 0.90 (95%CI: 0.88–0.91) overall and yielded a mean (and 95% confidence interval) of 12.8 (5.9, 22.8) for CA125II, and a mean of 27.0 (9.2, 56.4) for the MSD assay in postmenopausal women. We have not performed a similar comparative study for CA15.3. However, published values in healthy postmenopausal women cite a mean of 18 U/mL for CA15.3 (Boehringer Mannheim)[16] and 617.6 mU/mL for the MSD assay [4].
These MSD biomarker data on CA125 and CA15.3 measured in this study were made available by NHANES on April 17, 2019 and placed on line on June 27, 2019 and are publicly available at https://wwwn.cdc.gov/Nchs/Nhanes.
Statistical analyses
CA125 and CA15.3 values were log-transformed to achieve normal distribution. Outliers were identified using the extreme studentized deviate many-outlier procedure [17] and excluded from the analysis. Sample weights were applied to the whole dataset using SAS survey procedures (SURVEYMEANS, SURVEYFREQ, and SURVEYREG) with the DOMAIN option for analyzing subpopulations as instructed in the NHANES analytic guidelines [12].
We examined the association between CA125 and race/ethnicity using multivariable model adjusting for factors that differed by race/ethnicity in the univariate analyses with p-value <0.20. In the multivariable adjusted model, we excluded those missing the following adjustment variables: BMI (n=57), smoking (n=2), age at menarche (n=35), breastfeeding (n=1), tubal ligation (n=8), hormone therapy use (n=36), with 820 women included in the multivariable adjusted analysis. We included a missing indicator for those missing age at natural menopause since it had high missingness (44%). Of the 417 women missing age at natural menopause, 96% had surgical menopause. We also conducted a sensitivity analysis restricting to those with complete information on all adjustment variables. Average percent differences in the biomarker levels were calculated as [exp (effect estimate) −1] × 100 compared to the reference group using the effect estimates from the linear multivariable regression model.
To examine the differences by individual demographic and reproductive characteristics and CA125 and CA15.3 by race/ethnicity, we calculated the geometric means and 95% confidence intervals (CIs) using linear regression models adjusted for age for each race/ethnicity subgroups (non-Hispanic white, non-Hispanic black, Mexican Americans) among those with complete information on the exposure of interest. Trend test for exposures in ordinal categories were calculated by modeling the median of each categories as a continuous term. We used likelihood ratio test comparing the model with the cross-product term between the exposure variable and race/ethnicity with the model with main effects only.
We used weighted stepwise linear regression analysis to identify predictors of CA125/CA15.3. First, candidate predictors were selected if any of the univariate analysis results between predictors and CA125 and CA15.3 by race/ethnicity had p-value < 0.20. We conducted a complete case analysis where the analytic population was restricted to those that had complete information on all of the candidate predictor variables. We used weighted stepwise linear regression analysis with p< 0.20 for variable selection and retention into the model to identify predictors of CA125 and CA15.3 from the candidate predictors. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).
RESULTS
Characteristics of all NHANES participants and the three specific racial/ethnic groups are shown in Table 1 with the final column indicating the crude p value comparing the three ethnic groups. There were 946 postmenopausal women included in the analysis; 616 non-Hispanic white women, 166 non-Hispanic black women, and 164 Mexican American women (Table 1). Non-Hispanic white women were older on average, had lower BMI, were more likely to be former smokers, and have used hormone therapy compared to non-Hispanic blacks and Mexican Americans. Non-Hispanic black women had greater BMI and later menarche, were more likely to be parous, and have had tubal ligation or hysterectomy compared to the other groups. Average CA125 values differed between the ethnic groups (ANOVA p-value=0.002). CA125 levels were lower in non-Hispanic black and Mexican American women compared to non-Hispanic white women. Difference in average CA15.3 by ethnicity were less striking (ANOVA p-value=0.08). However, CA15.3 levels were lower in Mexican American women compared to non-Hispanic black women.
Table 1.
Distribution of baseline postmenopausal participant characteristics by race/ethnicity, NHANES 2001–2002 (n=946)
| Characteristics | All (n=946) | Non-Hispanic white (n=616) | Non-Hispanic black (n=l66) | Mexican American (n=164) | p-valuec |
|---|---|---|---|---|---|
| CA125 (U/mL)a | 10.2 (9.6–10.7) | 10.6 (9.9–11.3) | 7.3 (6.3–8.4) | 9.4 (8.4–10.4) | 0.002 |
| CA15.3 (mU/mL)a | 873.7 (821.8–929.0) | 860.9 (806.6–918.8) | 1003.2 (888.8–1132.2) | 871.5 (766.0–991.5) | 0.08 |
| Age at blood draw (years)a | 63.8 (62.6–65.0) | 64.2 (62.9–65.6) | 61.0 (59.4–62.7) | 60.4 (58.0–62.8) | 0.01 |
| Body Mass Index (kg/m2)a | 28.8 (28.2–29.4) | 28.5 (27.8–29.2) | 31.2 (30.1–32.3) | 30.2 (28.6–31.9) | 0.0009 |
| Smoking Status, n (%)b | |||||
| Never | 549 (54) | 332 (52) | 110 (65) | 107 (64) | 0.006 |
| Former | 261 (28) | 189 (29) | 31 (16) | 41 (24) | |
| Current | 134 (18) | 94 (18) | 25 (19) | 15 (12) | |
| Age at menarche (years) | 12.8 (12.7–13.0) | 12.8 (12.6–13.0) | 13.3 (13.0–13.6) | 12.7 (12.4–13.0) | 0.01 |
| Oral contraceptive use, n (%)b | 373 (49) | 236 (49) | 74 (49) | 63 (45) | 0.84 |
| Parous, n (%)b | 840 (88) | 542 (88) | 152 (92) | 146 (89) | 0.21 |
| Breastfeeding, n (%)b | 428 (43) | 268 (43) | 67 (38) | 93 (55) | 0.15 |
| Tubal ligation, n (%)b | 229 (28) | 135 (27) | 56 (38) | 38 (27) | 0.05 |
| Hysterectomy, n (%)b | 437 (46) | 285 (45) | 84 (51) | 68 (42) | 0.37 |
| Hormone therapy use, n (%)b | 428 (56) | 331 (59) | 46 (31) | 51 (33) | <0.0001 |
| Previous history of cancer, n (%)b | 119 (13) | 96 (14) | 10(5) | 13(8) | 0.0003 |
| Age at natural menopause (years)a | 49.1 (48.4–49.8) | 49.2 (48.4–50.0) | 48.6 (47.6–49.6) | 47.2 (46.5–48.0) | 0.02 |
Mean (95% confidence interval); means for CA125 and CA15.3 are geometric.
Unweighted number and weighted percentage
p-value: ANOVA p-value for continuous values, chi-square p-values for categorical values
Number of missing observations: body mass index (n=57), smoking status (n=2), age at menarche (n=35), OC use (n=2), parous (n=1), breastfeeding (n=1), tubal ligation (n=8), hysterectomy (n=3), age at natural menopause (n=417), hormone therapy use (n=36)
We examined the association between CA125 and race/ethnicity using multivariable model adjusting for factors that were significantly different by race/ethnicity in Table 1 with ANOVA p-value <0.20 (i.e. age, BMI, smoking status, age at menarche, breastfeeding, tubal ligation, hormone therapy use, and previous history of cancer, and age at natural menopause) (Table 2). Non-Hispanic Blacks were associated with significantly lower CA125 values compared to Non-Hispanic Whites after multivariable adjustment (−29.0% difference; 95%CI=−42.5%, −12.2%). As for CA15.3, Non-Hispanic Blacks had a suggestively higher CA15.3 values compared to Non-Hispanic Whites (17.3% difference; 95%CI=−0.5%, 38.3%). Biomarker levels in Mexican Americans did not differ compared to Non-Hispanic Whites after multivariable adjustment. The associations were similar in the multivariable model among women with complete information on all adjustment variables.
Table 2.
Multivariable adjusted associations between race/ethnicity and circulating biomarkers of CA125 and CA15.3, NHANES 2001–2002.
| Predictors | Average % differences (95%CI) | p-value | Predictors | Average % Differences (95%CI) | p-value | |
|---|---|---|---|---|---|---|
| Non-Hispanic white | ref | Non-Hispanic white | ref | |||
| Non-Hispanic black | −29.0 (−42.5, −12.2) | 0.004 | Non-Hispanic Black | 17.3 (−0.5, 38.3) | 0.06 | |
| Mexican American | −6.4 (−18.1, 6.9) | 0.3 | Mexican American | 1.3 (−19.0, 26.7) | 0.9 | |
| Age, years | 0.7 (0.2, 1.2) | 0.006 | Age, years | −0.2 (−1.0, 0.5) | 0.42 | |
| BMI, kg/m2 | 0.4 (−1.4, 0.6) | 0.39 | BMI, kg/m2 | −0.2 (−0.9, 0.4) | 0.49 | |
| Smoking status, never | ref | Smoking status, never | ref | |||
| Smoking status, former | −0.4 (−13.7, 14.8) | 0.95 | Smoking status, former | 0.7 (−14.8, 18.9) | 0.93 | |
| Smoking status, current | −9.9 (−26.9, 11.2) | 0.31 | Smoking status, current | −1.8 (−16.3, 15.2) | 0.81 | |
| Age at menarche, years | 0.2 (−2.0, 2.6) | 0.82 | Age at menarche, years | 0.9 (−2.0, 4.0) | 0.51 | |
| Breastfeeding | −4.1 (−14.1, 7.0) | 0.43 | Breastfeeding | 3.6 (−7.3, 15.8) | 0.51 | |
| Tubal ligation | 11.8 (−0.6, 25.7) | 0.06 | Tubal ligation | −6.0 (−18.9, 8.9) | 0.38 | |
| HT use, never | ref | HT use, never | ref | |||
| HT use, former | −10.2 (−20.2, 1.1) | 0.07 | HT use, former | 7.0 (−7.5, 23.7) | 0.34 | |
| HT use, current | −7.8 (−17.5, 3.1) | 0.14 | HT use, current | −4.2 (−17.6, 11.4) | 0.56 | |
| Previous history of cancer | 7.4 (−6.9, 23.9) | 0.3 | Previous history of cancer | 9.2 (−8.8, 30.9) | 0.31 | |
| Age at natural menopause, years | Age at natural menopause, years | |||||
| <46 | ref | <46 | ref | |||
| 46–49 | 4.6 (−16.9, 31.8) | 0.68 | 46–49 | −16.9 (−33.8, 4.2) | 0.10 | |
| 50–52 | 13.5 (−7.6, 39.5) | 0.21 | 50–52 | −9.2 (−30.8, 19.1) | 0.46 | |
| 52≤ | 11.9 (−9.5,38.4) | 0.28 | 52≤ | −24.0 (−36.5, −9.2) | 0.005 | |
| Missinga | −0.2 (−18.3, 21.9) | 0.98 | Missinga | −15.1 (−29.0, 1.6) | 0.07 |
96% had surgical menopause
An expanded list of demographic and reproductive variables and their associations with CA125 examined within categories of the variables is shown in Supplemental Table 1. For each entry the p-value shown at the bottom of the categorized variables indicates whether CA125 levels varied by those categories overall or within the specific ethnic categories. The final column shows the p-value for heterogeneity for that category among the three ethnic groups. Overall, there were few key determinants for CA125, with older age being the only predictor significantly associated with CA125 (p-trend=0.0004). When we examined the association within racial/ethnic groups, we observed differential associations. Older age was associated with higher CA125 only in non-Hispanic white women with a significant trend (p-trend=0.001, p-het=0.03). Older age at menarche was significantly associated with higher CA125 in non-Hispanic black women (p-trend=0.04). Longer duration of OC use was associated with a higher CA125 in Mexican American women (p-trend=0.03). Being parous was associated with a lower CA125 in non-Hispanic white women and Mexican American women but not in non-Hispanic black women (p-het=0.03). Tubal ligation was associated with a higher CA125 in non-Hispanic white women (p-value=0.04).
The same analyses were repeated for CA15.3 in Supplemental Table 2. Overall, there were few key determinants of CA15.3; duration of OC use (p-trend=0.005) and age at natural menopause (p-trend=0.05). We observed varying associations between predictors and CA15.3 by race/ethnicity. Older age was associated with lower CA15.3 among Mexican American women (p-trend=0.02) but suggestively higher CA15.3 in Non-Hispanic Blacks (p-het=0.05). Never smoking was associated with a lower CA15.3 compared to former/current smoking in Mexican American women (p-value=0.03). Increased number of births among parous women was associated with a significantly lower CA15.3 in Non-Hispanic Blacks and Mexican Americans (p-trend=0.04 and 0.02, respectively), but not in Non-Hispanic Whites (p-het=0.01). Older age at natural menopause was associated with a lower CA15.3 in Non-Hispanic Whites (p=0.05) and Mexican Americans (p=0.02), but not in Non-Hispanic Blacks contributing to significant heterogeneity (p-het=0.04).
Table 3 presents the results of a stepwise regression analysis to identify predictors of CA125 and CA15.3 overall and within racial/ethnic groups. Candidate predictors for CA125 and CA15.3 separately were first identified based on the univariate analyses shown in Supplemental Tables 1 and 2. For CA125, selected candidate predictors were age at blood draw, BMI, smoking status (never, current, former), age at menarche, duration of OC use (never users were coded as 0), parous, tubal ligation, hysterectomy, hormone therapy use (never, current, former), previous history of cancer, and age at natural menopause. Ovulatory years was not included because it overlapped with parity and duration of OC use. For CA15.3, selected candidate predictors were age at blood draw, smoking status (never, current, former), duration of OC use (never users were coded as 0), ever breastfeeding, hysterectomy, hormone therapy use (never, current, former), previous history of cancer, and age at natural menopause.
Table 3.
Predictors of CA125 and CA15.3 by race/ethnicity using stepwise regression
| Alla,b | Non-Hispanic white | Non-Hispanic black | Mexican American | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Predictors | Average % differences (95%CI) | p-value | Predictors | Average % differences (95%CI) | p-value | Predictors | Average % differences (95%CI) | p-value | Predictors | Average % differences (95%CI) | p-value |
| Non-Hispanic white | ref | -- | -- | -- | -- | -- | -- | -- | -- | -- | |
| Non-Hispanic black | −27.1 (−38.9, −12.9) | 0.002 | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Mexican American | −3.9 (−14.3, 7.8) | 0.47 | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Age, years | 1.0 (0.6, 1.4) | <.0001 | Age, years | 1.1 (0.7, 1.5) | <.0001 | -- | -- | -- | -- | -- | -- |
| Tubal ligation | 10.3 (−0.8, 22.7) | 0.07 | Tubal ligation | 13.5 (2.1, 26.3) | 0.02 | -- | -- | -- | Tubal ligation | −14.6 (−27.7, 0.8) | 0.06 |
| Hysterectomy | −24.6 (−44.2, 1.9) | 0.06 | Hysterectomy | −12.7 (−23.8, 0.03) | 0.05 | Hysterectomy | −17.8 (−34.4, 2.9) | 0.08 | -- | -- | -- |
| Previous history of cancer | 9.6 (−4.9, 26.3) | 0.19 | Previous history of cancer | 11.6 (−4.1, 29.8) | 0.14 | Age at menarche, years | 4.7 (−0.5, 10.1) | 0.07 | -- | -- | -- |
| Age at natural menopause, years | -- | -- | -- | Smoking status, never | ref | Smoking status, never | ref | ||||
| <46 | ref | -- | -- | -- | Smoking status, former | −0.4 (−12.1, 12.7) | 0.94 | Smoking status, former | 9.7 (−5.1, 26.8) | 0.19 | |
| 46–49 | 3.0 (−18.1, 29.5) | 0.79 | -- | -- | -- | Smoking status, current | −25.8 (−54.0, 19.6) | 0.20 | Smoking status, current | −25.6 (−50.5, 11.7) | 0.14 |
| 50–52 | 16.0 (−6.1, 43.2) | 0.16 | -- | -- | -- | -- | -- | -- | Parous | −20.9 (−40.3, 4.7) | 0.09 |
| 52≤ | 8.9 (−12.1, 34.8) | 0.41 | -- | -- | -- | -- | -- | -- | Duration of OC use, months | 0.4 (0.1, 0.6) | 0.005 |
| Missingd | 27.6 (−6.5, 74.3) | 0.12 | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Alla,c | Non-Hispanic white | Non-Hispanic black | Mexican American | ||||||||
| Predictors | Average % differences (95%CI) | p-value | Predictors | Average % differences (95%CI) | p-value | Predictors | Average % differences (95%CI) | p-value | Predictors | Average % differences (95%CI) | p-value |
| Non-Hispanic white | ref | -- | -- | -- | -- | -- | -- | -- | -- | -- | |
| Non-Hispanic black | 14.2 (−1.2, 32.0) | 0.07 | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Mexican American | −3.7 (−20.6, 16.8) | 0.68 | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Age, years | −0.3 (−0.8, 0.1) | 0.13 | Age, years | −0.3 (−0.9, 0.2) | 0.2 | -- | -- | -- | Age, years | −1.4 (−3.4, 0.6) | 0.16 |
| Duration of OC use, months | −0.1 (−0.2, −0.1) | 0.002 | Duration of OC use, months | −0.2 (−0.2, −0.1) | 0.003 | -- | -- | -- | Duration of OC use, months | −0.4 (−0.7, 0.01) | 0.06 |
| Age at natural menopause, years | -- | -- | -- | HT use, never | ref | -- | -- | -- | |||
| <46 | ref | -- | -- | -- | HT use, former | 20.0 (−17.4, 74.4) | 0.32 | -- | -- | -- | |
| 46–49 | −15.4 (−30.0, 2.2) | 0.08 | -- | -- | -- | HT use, current | −18.6 (−34.5, 1.1) | 0.06 | -- | -- | -- |
| 50–52 | −9.8 (−28.3, 13.4) | 0.35 | -- | -- | -- | -- | -- | -- | Ever breastfeeding | −17.1 (−37.7, 10.3) | 0.18 |
| 52≤ | −19.1 (−32.6, −3.0) | 0.03 | -- | -- | -- | -- | -- | -- | Previous history of cancer | 40.1 (5.7, 85.5) | 0.02 |
| Missingd | −15.1 (−29.4, 2.1) | 0.08 | -- | -- | -- | -- | -- | -- | -- | -- | -- |
Race was forced in the model
Women missing data on candidate predictors for CA125 were excluded: smoking status (n=2), age at menarche (n=35), duration of oral contraceptive (OC) use (n=9), parous (n=1), tubal ligation (n=8), hysterectomy (n=3), hormone therapy (HT)use (n=36)
Women missing data on candidate predictors for CA15.3 were excluded: smoking status (n=2), duration of oral contraceptive (OC) use (n=9), breastfeeding (n=1), hysterectomy (n=3), hormone therapy (HT) use (n=36)
96% had surgical menopause
Stepwise regression was used to identify predictors for CA125 and CA15.3 overall and by ethnicity. Race/ethnicity was a significant predictor of CA125 and CA15.3 in the overall multivariable model. CA125 was significantly lower in Non-Hispanic Blacks with −27.1% (95%CI=−38.9%, −12.9%) average differences compared to Non-Hispanic Whites after adjusting for age at blood draw, tubal ligation, hysterectomy, previous history of cancer, and age at natural menopause (p-value=0.002). CA15.3 was higher in Non-Hispanic Blacks with 14.2% (95%CI= −1.2%, 32.0%) average differences compared to Non-Hispanic Whites after adjusting for age at blood draw, and duration of OC use with borderline significance (p-value=0.07). Different predictors were selected for CA125 and CA15.3 by race/ethnicity. As predictors of CA125, age at blood draw, tubal ligation, hysterectomy, and previous history of cancer were selected for Non-Hispanic Whites whereas age at menarche, hysterectomy, and smoking status were selected for Non-Hispanic Blacks and smoking status, duration of OC use, parity, and tubal ligation were selected for Mexican Americans. As predictors of CA15.3, age and duration of OC use was selected for Non-Hispanic Whites, hormone therapy use was selected for Non-Hispanic Blacks, and age at blood draw, duration of OC use, ever breastfeeding, and previous history of cancer were selected for Mexican Americans. All of the predictors selected for Non-Hispanic Whites were also selected in the overall model. There were only few overlapping predictors between Non-Hispanic Whites and the other two racial/ethnic group. The direction of association for each predictor was similar to that in the univariate analysis.
DISCUSSION
Among postmenopausal women, we observed that Non-Hispanic Blacks were associated with lower CA125 levels and higher CA15.3 levels compared to Non-Hispanic Whites even after multivariable adjustment of lifestyle and reproductive factors. Moreover, this is the first study to our knowledge which examined associations of CA125 and CA15.3 with demographic and reproductive characteristics within different racial/ethnic groups in postmenopausal women. Age and parity were differentially associated with CA125 and age, parity, and age at menopause were differentially associated with CA15.3 by race/ethnicity.
Predictors of CA125 among women without ovarian cancer has been investigated to understand the variance between individuals and improve the utility of these markers as ovarian cancer screening biomarkers [4–6, 8, 15]. It has been consistently observed that non-white women have a lower CA125 compared to white women. However, previous studies were conducted among predominantly white populations with limited sample sizes for non-white women (i.e. Blacks, Hispanics, Asians) [5, 6, 15]. Thus, predictors of CA125 by different racial and ethnic groups had not been well investigated. Our multivariable analysis result was consistent with other two previous studies which observed that race/ethnicity was independently associated with CA125 even after adjusting for demographic and reproductive characteristics [5, 6, 15].
Interestingly, correlates of CA125 differed across racial/ethnic groups. Older age was significantly associated with higher CA125 values in Non-Hispanic Whites whereas in other ethnic groups, age was not selected as predictor of CA125. Although this significant trend may be driven by women in the category of age ≥ 75 years-old having high average CA125 values, older age being positively associated with CA125 values among postmenopausal women in prior studies conducted in predominantly non-Hispanic white population, so our observations are consistent with the literature [4, 7, 18]. On the other hand, being parous was significantly associated with lower CA125 in Mexican Americans but not in other race/ethnic groups. Prior studies reported null [6, 7] or positive [4] associations between parity and CA125. Since there were only 17 nulliparous Mexican American women, this observation could be due to chance. This observation could also be driven by other characteristics that are associated with being nulliparous and CA125 values in Mexican American women. While we acknowledge there could be potential confounders that could explain away this association, parity was selected as one of the final predictors of CA125 in the stepwise regression analysis results for Mexican Americans which suggest that being parous may be an important predictor of CA125 in these women.
As opposed to CA125, there is little information on CA15.3 values across ethnic groups. This is the first study to observe that CA15.3 values differed by race/ethnicity with borderline significance and was lower in Mexican Americans and higher in Non-Hispanic Blacks compared to Non-Hispanic Whites. Although a prior study suggested a positive association between BMI and CA15.3 in white postmenopausal women, we did not observe a significant association which may be due to small sample size [4]. Interestingly, ever breastfeeding was a selected predictor of CA15.3 in Non-Hispanic Blacks and Mexican Americans, which could be influenced by the increased expression of CA15.3 in the mammary gland during pregnancy and lactation [19].
In our stepwise regression analysis, race/ethnicity was associated with CA125 and CA15.3 in the overall model, with lower CA125 and higher CA15.3 being associated with Non-Hispanic Blacks compared to Non-Hispanic Whites. Interestingly, while the overall model only included 5 of the 9 adjustment variables used in the multivariable model in Table 2, the direction and magnitude of associations were similar between race/ethnicity and CA125 and CA15.3. Furthermore, different predictors were selected by race/ethnicity, suggesting predictors of CA125 and CA15.3 may differ by race/ethnicity. For CA125, while there were some overlapping predictors selected between the overall and race/ethnicity specific stepwise regression analysis and the direction of association were similar across race/ethnicity in general, the direction of association between tubal ligation and CA125 differed in Non-Hispanic whites and Mexican Americans. To our knowledge, this is the first to report the association between CA125 and tubal ligation in Mexican American women, and therefore validation in other datasets are needed to confirm this observation. For CA15.3, there were fewer overlapping predictors selected between the overall and race/ethnicity specific stepwise regression analysis, further supporting differences in correlates of CA15.3 by race/ethnicity among postmenopausal women without ovarian cancer. These results further support that race/ethnicity is an important factor associated with CA125 and CA15.3 values in postmenopausal women and the epidemiologic factors that influences these biomarker level may differ by race/ethnicity.
Currently, CA125 is included in all of the blood biomarker panels approved by the Food and Drug Administration (FDA) to assist in the differential diagnosis of a pelvic mass [20–23]. These algorithms take into account menopausal status, circulating CA125 and HE4 values, and imaging features of the pelvic mass. While these panels use different biomarker cutpoints depending on the menopausal status, race/ethnicity is not currently considered when interpreting CA125 (or CA15.3) values despite the fact that there is evidence that CA125 levels are lower in non-whites compared to whites, at least in postmenopausal women [5, 6, 8, 15]. Lack of considering racial/ethnic differences may possibly lead to an increase in false negative results of ovarian cancer detection in non-white population using algorithms including CA125. Similarly, a lower threshold for deciding whether a pelvic mass is malignant may be need in non-Hispanic Blacks. On the other hand, CA15.3 is an extensively studied serum biomarker for breast cancer although past studies indicated that serum CA15.3 is not suitable for early detection and therefore is not currently recommended for use in breast cancer screening [24, 25]. Given our observation that race/ethnicity may influence CA15.3 in postmenopausal women, different threshold may need to be considered when interpreting CA15.3 values by race/ethnicity in the context of a screening biomarker.
To our knowledge, this is the first study that examined predictors of CA125 and CA15.3 by racial/ethnic group separately. The strength of this study was the generalizability given that the data were representative samples of the US. We were also able to examine previously reported predictors of CA125 since we had detailed information on multiple demographic and reproductive factors. While this study presents the largest study of non-white population examining the correlates of CA125 and CA15.3 in postmenopausal women without ovarian cancer to date, we were still limited by sample size which may have influenced the stepwise variable selection procedure to identify predictors within racial/ethnic groups. In addition, since we used stepwise variable selection procedure to potentially highly correlated reproductive variables, we may have missed relevant variables in the variable selection process, and therefore the result needs to be interpreted with caution and independent validation is necessary. When stratified by race/ethnicity, some categories had low numbers of <10 due to the limited sample size of Non-Hispanic Blacks and Mexican Americans, which may yield unstable results in the geometric means. We were also unable to examine other ethnic groups such as Asians and other Hispanics. Furthermore, CA125 and CA15.3 were not measured on clinical assay so our results are not comparable to the traditional cutoffs of CA125 (generally 35 U/mL) and CA15.3 (generally 30 U/mL). Since there are no comparative study to determine the statistical correlations between the CA15.3 values between the MSD assay and clinical assay, interpretations on CA15.3 results may need caution. However, we did observe high correlations between the clinical assay and MSD assay for CA125 and do not anticipate that the differences in assays would change the direction of the associations. For some reproductive/ demographic characteristics, our presentation of the age-adjusted geometric means may be driven by other potential confounders since we only used one adjustment variable. However, the objective of this analysis was to elucidate the association between reproductive/demographic characteristics and circulating CA125 and CA15.3 biomarkers in general and be comparable to previously published literature which were conducted in predominantly white population [4, 6, 7, 18].
In conclusion, we observed that CA125 and CA15.3 values as well as their predictors differed by race/ethnicity in postmenopausal women. Non-Hispanic Blacks had lower CA125 levels and higher CA15.3 levels compared to Non-Hispanic Whites even after multivariable adjustment of lifestyle and reproductive factors. Our report supports that differences in race/ethnicity may need to be considered to optimize and interpret these markers when applying to the general population, such as ovarian cancer screening biomarkers and/or on risk prediction algorithms for the differential diagnosis of pelvic mass.
Supplementary Material
Supplemental Table 1. Average CA125 values in postmenopausal women by demographic and reproductive characteristics stratified by race/ethnicity, NHANES 2001–2002 (n=946)
Supplemental Table 2. Average CA15.3 values in postmenopausal women by demographic and reproductive characteristics stratified by race/ethnicity, NHANES 2001–2002 (n=946)
Acknowledgments:
The authors would like to thank the participants of the National Health and Nutrition Examination Survey for their valuable contribution.
Funding: This work was supported by U.S. National Cancer Institute at the National Institutes of Health under the following award numbers: R01 CA193965 (K.L.T.), R01 CA 158119, R35 CA197605 (D.W.C.), and Minnesota Ovarian Cancer Alliance 2019 National Early Detection Research Grant Award (N.S.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Footnotes
Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.
Conflict of interest: None declared.
Ethics approval: The study was approved by the scientific and ethics panel of NHANES. Because the research involved specimens anonymous to us, it was deemed exempt by the Brigham and Women’s Hospital Human Research Committee.
Availability of data and material: The NHANES datasets are available online [https://www.cdc.gov/nchs/nhanes/index.htm].
Code availability: All statistical analyses were conducted using SAS; programs are available from the corresponding author upon request.
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Associated Data
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Supplementary Materials
Supplemental Table 1. Average CA125 values in postmenopausal women by demographic and reproductive characteristics stratified by race/ethnicity, NHANES 2001–2002 (n=946)
Supplemental Table 2. Average CA15.3 values in postmenopausal women by demographic and reproductive characteristics stratified by race/ethnicity, NHANES 2001–2002 (n=946)