Dilution effect of serum CA125 and CA19-9 over a cutoff value,according to obesity

Abstract

The dilution effect of high plasma volume contributes to a lower level of specific tumor marker such as prostate-specific antigen. To date, few studies have focused on this effect of other tumor marker levels. Therefore, we evaluated the dilution effects of a higher plasma volume on lowering the serum concentration of various tumor markers such as CA125 and CA19-9. Data from patients (age ≥40 years) visiting our public health center between March 2007 and March 2013 were gathered. A total of 19,439 male and 11,655 female native Koreans were eligible to have a serum CA125 and CA19-9 screening for ovarian and pancreatic cancer, respectively. CA125 levels in 11,234 women were analyzed. There was a statistically significant trend toward a lower likelihood of having a serum CA125 level >35 U/mL with increased body mass index (BMI), with obese men having a 53.1% lower likelihood than those with a normal BMI. After CA19-9 analysis in 29,978 participants, there was also a significant trend toward a lower likelihood of having a serum CA19-9 level >35 U/mL with increased BMI, with obese men having a 27.0% and obese women having a 32.7% lower likelihood than those with a normal BMI. These results might affect tumor screening efficiency for ovarian and pancreatic cancer using serum CA125 and CA19-9, respectively. Further studies are needed to better define these results in clinical practice.

Keywords

CA125 CA19-9 Obesity Screening Tumor marker

Introduction

Tumor markers are substances produced by a tumor or secreted by tissue in response to a tumor. They may be used in the screening, diagnosis and classification of tumors, as well as in the prognostic assessment and monitoring of recurrence and metastasis in cancer cases (1). Men offered screening for prostate-specific antigen (PSA) (2) had a significant reduction in the rate of death from prostate cancer (3). Recently, a growing body of evidence suggests that obese men may have lower serum PSA (4–5–6–7–8). A proposed mechanism for the relationship between obesity and lower PSA is hemodilution. Banez et al (4) reported that PSA significantly decreased with increasing body mass index (BMI) due to dilution of a fixed amount of PSA in the greater plasma volume in larger-bodied patients. An inverse association could result in fewer screen-detected cancers, causing a decrease in the observed incidence of prostate cancer in obese men (9).

Our previous study showed that there was a statistically significant trend toward a lower likelihood of having a serum total PSA level ≥2.5 ng/mL with increased BMI, with obese men having an 18% lower likelihood than those with normal BMI (10). When this threshold was considered, there was an observable trend of decreasing PSA level with increased BMI, with significant point estimates of risk of an “abnormal” PSA among BMI groups (9).

CA125 is a well-known tumor marker for ovarian cancer, together with ultrasonography. In the last decade, much effort has focused on the performance of CA125 to improve its sensitivity (11). CA19-9 is a potential marker in the early detection of pancreatic cancer when used in the appropriate clinical setting (12).

Current tumor markers including PSA, CA125, CA19-9 and carcinoembryonic antigen (CEA) have common limitations that these markers are not cancer specific but rather disease specific, resulting in low specificity. Nevertheless, to date, there are no substitutable tumor makers for them. In this study, we hypothesized that if the dilution effect of high plasma volume contributes to a lower PSA, this effect may lower other tumor marker levels. Therefore, we evaluated the dilution effects of a higher plasma volume on various tumor markers including CA125 and CA19-9.

Materials and Methods

Data collection and study design

Male and female data (age ≥40 years) from the public health center attached to Soonchunhyang University Seoul Hospital was gathered between March 2007 and March 2013. A total of 19,439 male and 11,655 female native Koreans were eligible to have serum tumor marker tests, including CA125, CA19-9, CEA and α-fetoprotein (AFP) screening for ovarian, pancreatic, colorectal cancer and hepatoma, respectively. CA125 and CA19-9 were estimated using Architect i2000 (Abbott Diagnostic Laboratories, Abbott Park, IL, USA), CEA using Advia Centaur (Siemens Medical Solution, Erlangen, Germany) and AFP using Hitachi 7600-110 (Hitachi Ltd., Tokyo, Japan). The standard diagnostic cutoff values were CA125 (>35 U/mL), CA 19-9 (>35 U/mL), CEA (>5 ng/mL) and AFP (>20 ng/mL). All anthropometric measurements were made by trained observers using standardized techniques. BMI was defined as weight (kg) divided by the square of height (m²). Subjects were then classified as nonobese (BMI <25) or obese (BMI ≥25) according to the Asia-Pacific criteria of obesity (13). This study was approved by our institutional review board.

Statistical analysis

Mean and standard deviation (SD) were used to describe statistical data. All variables were nonparametric variables as determined by the Kolmogorov-Smirnov normality test. A logarithmic transformation of all variables was performed to ensure a more normal distribution and back-transformed for interpretation. A p value was calculated by using the independent t-test for continuous variables and the Pearson chi-square test for categorical variables. Thresholds of tumor markers were used to categorize each value as normal or abnormal for analyses. To describe the association between obesity and the likelihood of a certain serum CA125 or CA19-9 level, logistic regression analyses were used after dichotomizing men as having a CA125 or CA19-9 level >35 U/mL. The odds of having an abnormal CA125 or CA19-9 level for each threshold were then calculated, using men with a normal BMI as the reference group. SPSS 14.0 software (SPSS Inc., Chicago, IL, USA) was used for statistical analyses, and p values <0.05 were considered statistically significant.

Results

CA125

Table I gives the demographics of the CA125 study population. Mean age was 50.9 years (range 40-86), which was significantly younger in the nonobese group than in the obese group. Data from 11,234 of 11,388 total women (98.6%) were analyzed. One hundred four were excluded because of data loss. Among the 11,234 women, 277 (2.47%) had an abnormally high CA125 level (>35 U/mL). Mean CA125 was significantly lower in the obese group than in the nonobese group. Univariate analyses revealed that the likelihood of having a CA125 level >35 U/mL in the nonobese group (2.78%) was significantly higher than in the obese group (1.32%) (p<0.001) (Tab. I). After controlling for age, there was a statistically significant trend toward a lower likelihood of having a serum CA125 level >35 U/mL with increased BMI, with obese men having a 53.1% lower likelihood than those with a normal BMI (Tab. II).

TABLE I

Demographics Of Study Population For Ca125

	Nonobese (n=8,817)	Obese (n=2,417)	p Value
Mean age (SD), years	50.2 (7.6)	53.3 (8.9)	<0.001^*
Mean BMI (SD), kg/m²	21.6 (2.1)	27.4 (2.4)	<0.001^*
Mean CA125 (SD), U/mL	12.43 (13.47)	11.12 (10.17)	<0.001^*
No. (%), CA125 >35 U/mL	245 (2.78%)	32 (1.32%)	<0.001^†

Independent t-test.

†

Pearson chi-square test.

TABLE II

Odds of Having a Serum CA125 >35 U/mL, According to Obesity

Threshold 35 U/mL	OR	95% CI	p Value
Nonobese	Reference
Obese	0.469	0.324-0.680	<0.001^*

OR = odds ratio; CI = confidence interval.

Logistic regression analysis.

CA19-9

Mean age for this study group was 50.8 years (range 40-90). Of the 30,132 total study subjects for CA19-9, 154 were excluded due to insufficient data, for a total of 29,978 participants analyzed (male to female ratio 62.6%/37.4%). Among them, 856 (2.86%) had an abnormally high CA19-9 level (>35 U/mL). The positive rate in women (5.35%) was much higher than that in men (1.37%) (p<0.001). Univariate analyses revealed that the likelihood of having a CA19-9 of >35 U/mL in the nonobese group was significantly higher than in the obese group in both men (p=0.019) and women (p<0.001) (Tab. III). After controlling for age, there was a statistically significant trend toward a lower likelihood of having a serum CA19-9 level >35 U/mL with increased BMI, with obese men having a 27.0% (p=0.018) and obese women having a 32.7% (p<0.001) lower likelihood than those with a normal BMI (Tab. IV).

TABLE III

Demographics Of Study Population For Ca19-9

Men	Nonobese (n=10,939)	Obese (n=7,814)	p Value
Mean age (SD), years	50.8 (7.7)	50.6 (7.6)	0.039^*
Mean BMI (SD), kg/m²	22.7 (1.7)	27.1 (1.9)	<0.001^*
Mean CA19-9 (SD), U/mL	9.12 (18.89)	8.79 (16.67)	0.204^*
No. (%), CA19-9 >35 U/mL	168 (1.54%)	88 (1.13%)	0.019^†
Women	Nonobese (n=8,808)	Obese (n=2,417)
Mean age (SD), years	50.2 (7.6)	53.3 (8.9)	<0.001^*
Mean BMI (SD), kg/m2	21.6 (2.1)	27.4 (2.4)	<0.001^*
Mean CA19-9 (SD), U/mL	12.47 (13.64)	11.60 (20.58)	0.014^*
No. (%), CA19-9 >35 U/mL	505 (5.73%)	95 (3.93%)	<0.001^†

Independent t-test.

†

Pearson chi-square test.

TABLE IV

Odds of Having a Serum CA19-9 >35 U/mL, According to Obesity

Men	OR	95% CI	p Value
Nonobese	Reference
Obese	0.730	0.563-0.947	0.018
Women
Nonobese	Reference
Obese	0.673	0.538-0.842	<0.001

OR = odds ratio; CI = confidence interval.

CEA and AFP

Among 30,738 participants, 285 (0.93%) had a CEA level >5 ng/mL. The chi-square test revealed that there was no difference according to obesity (nonobese 0.95%, obese 0.88%, p=0.570) in the likelihood of having an abnormal CEA. AFP showed a very low positive rate (41/30,631 participants, 0.13%) over cutoff value, which was statistically insignificant.

Discussion

Obese men are known to have a significantly higher rate of prostate cancer deaths but lower serum PSA concentrations compared with nonobese men (14, 15). It has been suggested that obese men experience a prostate cancer detection bias due to hemodilution of PSA that can result in delayed prostate cancer diagnosis and subsequent delay in treatment (4). Yang showed that there was a statistically significant trend toward a lower likelihood of having a serum PSA level ≥2.5 ng/mL with increasing BMI and that obese men had an 18% lower likelihood compared with men with a normal BMI (10). If obesity leads to a clinically significant decrease in PSA, this would suggest that the PSA thresholds used in clinical practice should be adjusted based on BMI. Likewise, the current study revealed that there was a significantly lower likelihood of having “abnormal” serum CA125 or CA19-9 levels with increased BMI, than in those with a normal BMI.

CA125 is a tumor antigen that is elevated in the majority of ovarian cancers and has shown increases in some women with early stage disease (16). Few data have been published concerning the association of CA125 concentration and obesity. CA125 has been reported to be inversely correlated with the presence of metabolic syndrome and the numbers of metabolic syndrome components such as obesity (16, 17). The possible mechanism is assumed to be that subjects with a greater BMI have larger plasma volumes, which could lead to hemodilution of soluble tumor markers, a similar phenomenon with PSA (17). Johnson et al attempted to elucidate the usual pattern of CA125 levels among populations of women without ovarian cancer (16). Among women 55 to 74 years of age not diagnosed previously with ovarian cancer, the odds ratio (OR) of obese patients having an elevated CA125 level was significantly decreased (OR=0.53, 95% confidence interval [95% CI], 0.39-0.71) compared with the normal weight group, similar to the results from our current study (OR=0.469, 95% CI, 0.324-0.680) (16). In the same study, the mean CA125 level was 11.9 U/mL, with a very low percentage of women (1.6%) having values greater than the standard clinical threshold of 35 U/mL, while the current study demonstrated a higher mean CA125 (12.15 U/mL) and higher positive rate (2.47%) over cutoff. The reason for these differences is not clear. Besides obesity, CA125 level is influenced by a number of factors, including race/ethnicity, age, hysterectomy, smoking, etc. Therefore, we believe that the different age distribution and/or different ethnicity between the 2 study groups may have affected the results.

So far, CA19-9 is the standard tumor marker for pancreatic cancer. CA19-9 has proven to be useful in differentiating benign and malignant pancreatic disease (12). Among our study population, 2.86% had an abnormally high CA19-9 level (>35 U/mL), and the positive rate in women (5.35%) was significantly higher than that in men (1.37%). However, regardless of sex, there was a significantly lower likelihood of having an abnormal CA19-9 value with increased BMI, with obese men having a 27.0% and obese women having a 32.7% lower likelihood than those with a normal BMI. Chang et al revealed that a higher BMI was significantly associated with lower CA19-9 levels in a screened Korean male population (18).

In our current study, the positive rates of CEA and AFP were very low (0.93% and 0.13%, respectively); therefore, it was difficult to assess the relation between obesity and these markers due to the weak statistical power. Colon cancer and hepatoma are the second and fourth most prevalent cancer in Korean men (19). We believe that these tumor markers were inappropriate to use for screening the normal population.

In this study, there were several limitations. First, as we have documented before, these tumor markers are not cancer specific but rather disease or organ specific. Hence, benign conditions which cause the elevation of those tumor markers should be considered. However, in our study we did not consider those confounding factors, because we wanted to investigate only the casualty of dilutional effect of obesity in those tumor markers. PSA can be affected by benign conditions such as prostatitis, and CA125 can be affected by menstruation and endometriosis or greatly by pregnancy (20, 21). CA19-9 is affected by pancreatitis, too (20, 22). Second, this study was not considered for cancer status, which is the fundamental part of a tumor-screening study. However, this study is based on the data by screening population, and real cancer status could not be discerned if a serial workup for the national cancer network was not done. Moreover, the results are taken from an electronic medical recording system and no data are available about the analytical variations of the employed methods during the course of the study. Lastly, the International Association for the Study of Obesity has proposed a criterion for obesity as a BMI ≥30 based on data from a white population. In contrast, for people from the Asia-Oceania region, for whom the main form of energy intake is carbohydrates, obesity has been defined as a BMI ≥25 (13). This difference in BMI cutoff is quite large and could have had an effect on the study results. If we had used the Western criteria for obesity in the CA19-9 study population, only 3.0% (890 of 29,978) of the participants would have been classified as obese. Therefore, we believe our results might not be applicable to populations in other countries. The current study was not community-based, and we had no additional evidence as to whether these men were perfectly healthy. These points highlight limitations of our study.

Conclusions

In our study, obese women had a 53.1% lower likelihood of having a CA125 level >35 U/mL compared with nonobese women in a screened Korean population. Also, there was a significant trend toward a lower likelihood of having a serum CA19-9 level >35 U/mL with increased BMI, with obese men having a 27.0% and obese women having a 32.7% lower likelihood than those with a normal BMI.

Footnotes

Financial support: This work was supported in part by the Soonchunhyang University Research Fund.

Conflict of interest: The authors declare that they have no competing interests.

References

Tatsumi

Kawano

Takubo

Nakamura

Tsuda

External quality control results for hormones, tumor markers and CRP testing.

Southeast Asian J Trop Med Public Health 1999 30Suppl 3 105–109

Fedorchenko

Zhila

Sapsai VI Volkov

Chernenko

[Postgraduate training and ways of improving it in a department of urology] [article in].

Klin Khir 1986 10 48–50

Schroder

Hugosson

Roobol

Tammela

Ciatto

Nelen

Screening and prostate-cancer mortality in a randomized European study.

N Engl J Med 2009 360(13): 1320–1328

Banez

Hamilton

Partin

Vollmer

Sun

Rodriguez

Obesity-related plasma hemodilution and PSA concentration among men with prostate cancer.

JAMA 2007 298(19): 2275–2280

Fowke

Matthews

PSA and body composition by dual X-ray absorptiometry (DXA) in NHANES.

Prostate 2010 70(2): 120–125

Liu

Wang

Zhu

Wan

Body mass index and serum lipid profile influence serum prostate-specific antigen in Chinese men younger than 50 years of age.

Asian J Androl 2011 13(4): 640–643

Loeb

Carter

Schaeffer

Ferrucci

Kettermann

Metter

Should prostate specific antigen be adjusted for body mass index? Data from the Baltimore Longitudinal Study of Aging.

J Urol 2009 182(6): 2646–2651

Price

Hamilton

Robertson

Butts

Freedland

Body mass index, prostate-specific antigen, and digital rectal examination findings among participants in a prostate cancer screening clinic.

Urology 2008 71(5): 787–791

Culp

Porter

The effect of obesity and lower serum prostate-specific antigen levels on prostate-cancer screening results in American men.

BJU Int 2009 104(10): 1457–1461

10.

Yang

The likelihood of having a serum PSA level of ≥2.5 or ≥4.0 ng ml(-1) according to obesity in a screened Korean population.

Asian J Androl 2013 15(6): 770–772

11.

Timms

Menon

Devetyarov

Early detection of ovarian cancer in samples pre-diagnosis using CA125 and MALDI-MS peaks.

Cancer Genomics Proteomics 2011 8(6): 289–305

12.

Lee

Chung

Park

Song

Chung

Serum CA 19-9 and CEA levels as a prognostic factor in pancreatic adenocarcinoma.

Yonsei Med J 2013 54(3): 643–649

13.

Kanazawa

Yoshiike

Osaka

Numba

Zimmet

Inoue

Criteria and classification of obesity in Japan and Asia-Oceania.

World Rev Nutr Diet 2005 94 1–12

14.

Calle

Rodriguez

Walker-Thurmond

Thun

Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.

N Engl J Med 2003 348(17): 1625–1638

15.

Rodriguez

Patel

Calle

Jacobs

Chao

Thun

Body mass index, height, and prostate cancer mortality in two large cohorts of adult men in the United States.

Cancer Epidemiol Biomarkers Prev 2001 10(4): 345–353

16.

Johnson

Kessel

Riley

The epidemiology of CA-125 in women without evidence of ovarian cancer in the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial.

Gynecol Oncol 2008 110(3): 383–389

17.

Joo

Kim

Serum CA125 concentration has inverse correlation with metabolic syndrome.

J Korean Med Sci 2011 26(10): 1328–1332

18.

Chang

Ahn

Han

Kim

Myung

The clinical significance in healthy men of the association between obesity related plasma hemodilution and tumor marker concentration.

J Urol 2009 181(2): 567–572 [discussion: 572-573]

19.

Jung

Won

Kong

Seo

Lee

Cancer statistics in Korea: incidence, mortality, survival and prevalence in 2010.

Cancer Res Treat 2013 45(1): 1–14

20.

Erbagci

Yilmaz

Kutlar

Menstrual cycle dependent variability for serum tumor markers CEA, AFP, CA 19-9, CA 125 and CA 15-3 in healthy women.

Dis Markers 1999 15(4): 259–267

21.

Han

Lotgerink

Gziri

Van Calsteren

Hanssens

Amant

Physiologic variations of serum tumor markers in gynecological malignancies during pregnancy: a systematic review.

BMC Med 2012 10 86

22.

Talar-Wojnarowska

Gasiorowska

Olakowski

Lekstan

Lampe

Malecka-Panas

Clinical value of serum neopterin, tissue polypeptide-specific antigen and CA19-9 levels in differential diagnosis between pancreatic cancer and chronic pancreatitis.

Pancreatology 2010 10(6): 689–694