Abstract PS8-39: Evidence for reproductive control of liver size with implications for risk of liver metastases in postpartum breast cancer patients

Abstract

Abstract Women diagnosed with breast cancer within 10 years of a completed pregnancy are 2~3x more likely to develop liver metastases than never-pregnant (nulliparous) patients, even after controlling for prognostic variables (Goddard 2017). This finding suggests a unique biology in the postpartum liver, a putative pre-metastatic niche, which makes postpartum patients more susceptible to liver metastases. In rodent models, we previously reported increased liver size, hepatocyte proliferation, and anabolic metabolism during pregnancy and lactation. Within one week post-weaning, the rodent liver returned to its pre-pregnant size via a coordinated cell death and tissue remodeling process we call liver involution (Goddard 2017). We find that this process of involution supports overt liver metastasis using two different mammary tumor cell lines. In women, a liver-breast interaction during pregnancy and weaning, as occurs in rodents, has not been described. To investigate the human liver with pregnancy and weaning, we conducted a prospective, non-interventional clinical trial in healthy pregnant women. 47/77 women completed the pregnancy study visits and 17/47 completed post-wean visits. Participants underwent magnetic resonance imaging (MRI) of their livers, provided blood samples, and completed body metric analyses at each study time point. The majority of women (~70%) had increased liver size and evidence of increased liver function at third trimester compared to first trimester, with liver size returning to pre-pregnancy levels with weaning. In this cohort, the increase in liver size exceeded levels expected if the metabolic demands associated with increased body weight during pregnancy were the primary mediator. Intriguingly, primary bile acid and bile acid synthetic enzyme concentrations correlated with liver size increase during pregnancy. Women whose liver growth did not follow the most often observed pattern of increase with pregnancy and decrease postpartum had unchanged bile acid levels, were more likely to have gestational hypertension, and did not have expected increases in liver glucose production during pregnancy. Combined, this study provides the first description of human liver size increase with pregnancy, and return to pre-pregnant baseline size after weaning, with evidence that women who do not experience these liver changes may be metabolically distinct. Furthermore, these data are consistent with the hypothesis that reproductive alterations to the liver, in particular weaning-induced involution, contributes to the increased risk for liver metastases in women diagnosed with breast cancer postpartum. Reference: Goddard, E. T., Hill, R. C., Nemkov, T., D'Alessandro, A., Hansen, K. C., Maller, O., Mongoue-Tchokote, S., Mori, M., Partridge, A. H., Borges, V. F., & Schedin, P. (2017, Feb). The Rodent Liver Undergoes Weaning-Induced Involution and Supports Breast Cancer Metastasis. Cancer Discov, 7(2), 177-187. https://doi.org/10.1158/2159-8290.CD-16-0822 Citation Format: Alexandra Quackenbush, Erica Goddard, Claire Dorfman, Kimberly Vesco, Jonathan Purnell, Pepper Schedin. Evidence for reproductive control of liver size with implications for risk of liver metastases in postpartum breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-39.