In this study of CA-125 in post-menopausal women with no evidence of ovarian cancer, mean CA-125 level was 11.9, with a very low percentage of women, 1.6%, having values greater than the standard clinical threshold of 35 U/ml. The most striking associations, based on the multivariate parameter estimates (), were for race/ethnicity, corresponding to 19%, 12%, 8% and 11% lower mean CA-125 levels in Black, Hispanic, Asian and Pacific Islander/Native American women relative to White women, hysterectomy (9% lower mean), current smoking (9% lower mean) and to a much lesser degree obesity (3% lower mean). The higher mean CA-125 levels in women who were older (7%), had a history of breast cancer (5%), late menopause (4%), former smokers (1.4%) and users of hormone therapy (3–4%), were modest. Interestingly, the demographic patterns are complementary to incidence patterns for ovarian cancer, with higher incidence in White and older women.[18
The most comparable study we could find was data from 18,748 post-menopausal women in a United Kingdom screening trial.[9
] However, the focus of their analyses was to develop a parsimonious predictive model rather than our approach of including all variables of interest in our models with the purpose of calculating risk estimates for individual variables. While Pauler et al. included women from 40 to 60 years of age, our study subjects were older, with a range from 55–74 years.
Prior studies generally report a decrease in CA-125 levels with increasing age.[9
] It has been consistently demonstrated that CA-125 is higher in pre- versus post-menopausal women,[20
] so it is important to consider that our population was all post-menopausal. Our mean and median values for Whites were identical to those in a reference value study of 938 Dutch post-menopausal women with a mean of 12 U/ml and median of 10 U/ml.[20
] These authors found a slight decrease in age using categories from <45 years to >65 years, but did not consider any other variables. Another study from the Netherlands indicated a dramatic drop in CA-125 between age categories from 60–70 years in a healthy control group of 370 women, again a univariate analysis.[14
] However, Grover et al found no age association in post-menopausal women, and an increase in CA-125 with increasing age in a pre-menopausal and peri-menopausal sample.[22
] Pauler et al. demonstrated a slight reduction in CA-125 levels with increasing age adjusted for some of the same variables we used.[9
] They reported that the decrease by age was attenuated in women with a previous history of cancer. Our results indicating an increase in CA-125 by increasing post- menopausal age category were based on a very large, diverse, and older sample of women and allowed simultaneous adjustment for numerous collected potentially important variables. If valid, this association could possibly be a consequence of aging processes at the cellular and immunological level. Interestingly, when we analyzed CA-125 using results from the original Centocor assay available for 5371 initially enrolled women aged 60 years and older, the values were lower (age 60–64, mean 9.2 and median 8.0; age 65–69, mean 9.2, median 7.7; age 70–74, mean 9.9, median 8.0), and there was no statistical difference by age categories, suggesting that perhaps the assay used could affect results.
While endometriosis has consistently been found to be associated with CA-125 level, which is expected based on the underlying biology, we did not find this association. This may reflect the limitation that a history of endometriosis was based solely on self report. More importantly, endometriosis often resolves after menopause and therefore a post-menopausal CA-125 might not be expected to be related to a historical diagnosis of this condition.
Another striking finding from these PLCO CA-125 analyses is the differences by racial/ethnic group. These results adjusted for education level as a surrogate marker for socioeconomic status and confirm the prior UK study addressing race/ethnicity as a possible factor in CA-125 levels in which only 80 Asian and 89 African women out of a total of 18,748 subjects were evaluated.[9
] Even so, race was a statistically significant variable with mean CA-125 levels slightly lower (by 1.2 U/ml) in Asians and markedly lower (by 5.2 U/ml) in African relative to White women. In the UK study, the Asian group is most probably predominantly from the Indian subcontinent, whereas in the PLCO study the Asian group is largely comprised of women with Japanese, Chinese, and Filipino heritage.
In our data, hysterectomy was associated with decreased mean CA-125, confirming other work.[9
] The finding that current hormone therapy use increased CA-125 only in women with a uterus comports with the premise that hormone therapy resulted in stimulation of CA-125 in the endometrium, which is a known source of CA-125 in healthy women.[17
] Although some women with hysterectomy who reported having their ovaries had likely also had oophorectomy, the concentration of CA-125 in the healthy ovary is small compared to the endometrium and oophorectomy had no significant impact on CA-125 levels in other studies.[17
] CA-125 levels vary during the menstrual cycle, suggesting an influence of ovarian steroid hormones. Kurihara et al. demonstrated in a small study that CA-125 was higher among healthy post-menopausal women using hormone therapy than among non-users.[24
] Two clinical trials examined CA-125 levels in response to initiation of hormone therapy.[25
] In both studies there was no effect of current estrogen therapy on CA-125 levels in women with hysterectomies, which corroborates our data. However, for women with a uterus, Karabacak reported that 100 ug/day transdermal estradiol was associated with a significant increase in CA-125, again consistent with our results.[25
] In contrast, Cengiz et al. reported that current use of combination of estrogen and progestin resulted in lower CA-125 levels in women with a uterus, while Okon et al. saw no change in their 12 month follow-up study.[26
] The type of hormone therapy used was not determined in our study, but it is likely that estrogen-only therapy would predominate in the women with hysterectomy and estrogen-progestogen therapy would predominate in women with a uterus.
It is not obvious why current smoking and obesity are associated with a lower CA-125. It is intriguing that Pauler et al. also found a protective effect of current smoking, which they considered was most likely a fluke or possibly due to an effect on liver enzymes and enhanced metabolic degradation of CA-125.[9
] Perhaps a higher plasma volume, associated with obesity,[28
] dilutes the level of serum CA-125. Why former smoking or hormone therapy use may be associated with increased CA-125 is even less clear. A limitation of the baseline questionnaire used in this study is that “former” was not linked to dates or duration, so we cannot reconstruct histories linking the timing of hysterectomy, smoking, and timing and duration of hormone therapy use as related to the date of CA-125 measurement.
Another limitation is that while this population is unusually large and represents geographic and racial/ethnic diversity, it is comprised of women agreeing to participate in a long term cancer prevention screening trial. Potential subjects were recruited using a multitude of approaches, with random mailings accounting for the majority of enrollees.[30
] It has been demonstrated that the PLCO population has lower mortality rates than the general population, suggesting they are healthier in general.[31
] Analyses of data from one site comparing those enrolled to those invited from within a health care system population demonstrated that 11% of those asked joined the study and suggested that those who were White, in their sixties, with higher income and with fewer co-morbidities were somewhat more likely to participate.[32
] Our analyses are therefore likely subject to some degree of selection (volunteer) bias. Further, although the trial deployed numerous strategies to recruit minority subjects [30
], the percentages of enrolled women in these groups was lower than the percentages these groups represent in the United States, suggesting that volunteer bias and representativeness may be even more of an issue for non-Whites. This is noteworthy since an important result of our analyses is the lower CA-125 values associated with minorities. Additionally, there is always the possibility that our results could be affected by unmeasured confounders such as subclinical chronic disease processes or genetic variation and that characteristics such as age and race are markers for some other factor directly affecting CA-125. Finally, it is possible that a small number of women with sub-clinical ovarian cancer remained in the study population.
In summary, CA-125 levels were found to be associated with a number of demographic and medical factors. A notable finding was substantially lower mean CA-125 levels in minority women relative to White women, with levels 8–19% lower. If CA-125 is incorporated in a screening algorithm, these variables may prove to be important in clinical evaluations. Future analyses will consider changes in CA-125 over time using the baseline and measurements available from five subsequent annual screening exams among women without ovarian cancer in this population.