AS562 - Sex steroid hormones in women and development of primary liver cancer

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Investigator Names and Contact Information

Introduction/Intent

Incidence and mortality rates of liver cancer have been increasing in the United States (U.S.) for over 30 years.  One intriguing characteristic of liver cancer is the male predominance, with a male:female ratio of 2.8:1 in the U.S. [1].  While this may be partially explained by a higher prevalence of known risk factors among men, such as hepatitis B virus (HBV), hepatitis C virus (HCV), excessive alcohol consumption, and cigarette smoking, these factors do not fully explain the sex differences in liver cancer incidence [2, 3].  One hypothesis is that hormones could be responsible for the sex disparity [4].  In animal models, estrogen or castration reduces liver cancer development in male rodents, while testosterone or ovariectomy increases liver cancer development in female rodents [3].  Similarly, in the Liver Cancer Pooling Project (LCPP), an increased risk of liver cancer was seen among women who had an oophorectomy [5].  Additionally, several nested case-control study have found increased serum testosterone levels in liver cancer patients compared to controls [6-9], and a nested case-control study in the European Prospective Investigation into Cancer also found higher levels of sex hormone binding globin increased risk of liver cancer [10].  In a SEER-13 analysis of secondary tumors among males with prostate cancer, an androgen-sensitive tumor normally treated with anti-androgen therapy, the risk of liver cancer was reduced (standardized incidence ratio=0.61, 95% CI: 0.57-0.66) [11].  Thus, both experimental and population-based studies have found that estrogen reduces and testosterone increases the risk of liver cancer.[3, 5-11] However, all studies to date have been performed in a male-only population or include a small sample size of women. Thus, no studies have been able to examine the potential differential effects of sex steroid hormones by sex.Sex steroid hormones can drive cell proliferation, which then facilities the accumulation and fixation of genetic errors leading to a malignant phenotype.[15] Additional epidemiologic and experimental studies need to be conducted to elucidate the role of hormones in the etiology of liver cancer.

In order to study the etiology of liver cancer using a prospective design, the Liver Cancer Pooling Project (LCPP), a pooling project within the NCI Cohort Consortium, was initiated in 2009.  Fourteen U.S. based cohorts are contributing questionnaire data and serum samples to the LCPP.  Questionnaire data from WHI participants, as well as serum for HBV/HCV determinations, have already been approved for this consortia effort.  While known risk factors, such as HBV/HCV and alcohol consumption, have been studied extensively, an examination of other putative factors, such as hormones, might greatly enhance the current understanding of the etiology of liver cancer in the U.S.

As a result, with this application we seek to obtain serum samples from WHI participants who developed liver cancer and from matched controls.  With serum samples from 116 liver cancer cases, WHI is the largest female-only cohort with serum in the pooling project (Table 1).  The serum samples will be used to determine levels of estradiol, testosterone, and sex hormone binding globulin. Free testosterone and free estradiol will be calculated using each of the hormones in conjunction with sex hormone binding globulin. Free estradiol and free testosterone may be a more relevant measurement of estradiol and testosterone, as they are not bound.

Specific Aim:

Determine whether concentrations of total testosterone (T), estradiol (E2), free testosterone and free estradiol, and sex hormone binding globulin (SHBG) are related to the development of liver cancer in a U.S. population.

References

1.         Nordenstedt, H., D.L. White, and H.B. El-Serag, The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis, 2010. 42 Suppl 3: p. S206-14.

2.         Schottenfeld, D. and J.F. Fraumeni, Cancer epidemiology and prevention. 3rd ed. 2006, Oxford ; New York: Oxford University Press. xviii, 1392 p.

3.         Bakiri, L. and E.F. Wagner, Mouse models for liver cancer. Mol Oncol, 2013. 7(2): p. 206-23.

4.         Yeh, S.H. and P.J. Chen, Gender disparity of hepatocellular carcinoma: the roles of sex hormones. Oncology, 2010. 78 Suppl 1: p. 172-9.

5.         McGlynn, K.A., et al., Reproductive factors, exogenous hormone use and risk of hepatocellular carcinoma among US women: results from the Liver Cancer Pooling Project. Br J Cancer, 2015. 112(7): p. 1266-72.

6.         Yuan, J.M., et al., A cohort study of serum testosterone and hepatocellular carcinoma in Shanghai, China. Int J Cancer, 1995. 63(4): p. 491-3.

7.         Yu, M.W., et al., Androgen-receptor gene CAG repeats, plasma testosterone levels, and risk of hepatitis B-related hepatocellular carcinoma. J Natl Cancer Inst, 2000. 92(24): p. 2023-8.

8.         Yu, M.W. and C.J. Chen, Elevated serum testosterone levels and risk of hepatocellular carcinoma. Cancer Res, 1993. 53(4): p. 790-4.

9.         Tanaka, K., et al., Serum testosterone:estradiol ratio and the development of hepatocellular carcinoma among male cirrhotic patients. Cancer Res, 2000. 60(18): p. 5106-10.

10.       Lukanova, A., et al., Prediagnostic plasma testosterone, sex hormone-binding globulin, IGF-I and hepatocellular carcinoma: etiological factors or risk markers? Int J Cancer, 2014. 134(1): p. 164-73.

11.       Davis, E.J., et al., Risk of second primary tumors in men diagnosed with prostate cancer: A population-based cohort study. Cancer, 2014.

12.       Tworoger, S.S., et al., The combined influence of multiple sex and growth hormones on risk of postmenopausal breast cancer: a nested case-control study. Breast Cancer Res, 2011. 13(5): p. R99.

13.       Zhang, X., et al., Postmenopausal plasma sex hormone levels and breast cancer risk over 20 years of follow-up. Breast Cancer Res Treat, 2013. 137(3): p. 883-92.

14.       Fortner, R.T., et al., Premenopausal endogenous steroid hormones and breast cancer risk: results from the Nurses' Health Study II. Breast Cancer Res, 2013. 15(2): p. R19.

15.       Henderson, B.E. and H.S. Feigelson, Hormonal carcinogenesis. Carcinogenesis, 2000. 21(3): p. 427-33.