Abstract ES2-2: Breast cancer's metastatic moment: How postpartum tissue involution facilitates progression
Authors: P Schedin
Journal: Cancer Research (2019)

Abstract Virginia F. Borges* and Pepper J. Schedin*# Young Women's Breast Cancer Translational Program, University of Colorado, Anschutz Medical Campus, Aurora, Colorado*, and Knight Cancer Institute, Oregon Health &amp; Sciences University, Portland, Oregon#. Young women diagnosed with breast cancer (YWBC) have worse outcomes than older women, however the reasons remain poorly understood. The two dominant hypotheses, centered on tumor cell intrinsic and extrinsic biology respectively, appear in conflict. One hypothesis emphasizes the role of poor prognostic factors increased in young patients, such as ER-, PR- and Her2- disease. A second theory posits that host biology related to reproductive history drives poor outcomes, independent of tumor biologic subtype or size. However, studies addressing the roles of pregnancy in breast cancer risk and outcomes can appear discordant. Consequently, metrics of reproductive history are not always included in standard risk assessment tools, nor utilized to optimize treatment strategies. This education session is focused on bridging the gap between these two theories. Specifically, our data shows that tumor intrinsic risk factors for breast cancer progression are significantly modulated by reproductive biology and support the incorporation of reproductive history into clinical care decisions. There is a strong connection between reproductive history and risk of metastasis in breast cancer. Epidemiologic studies find a recent, but not concurrent, pregnancy to be an independent risk factor for breast cancer metastasis. Our own studies find a ∼3 fold increase in metastases in patients diagnosed postpartum (PPBC). Further, we and others find the postpartum risk-window persists for ≥10 years after child birth. Finally, interactions between breast cancer subtype and pregnancy history are observed, supporting roles for both tumor cell intrinsic and extrinsic biology in driving metastasis in young women. To investigate the mechanism of postpartum host biology on tumor progression, we developed rodent models of PPBC. We find the physiologic process of weaning-induced mammary gland involution to support immune suppression, tumor cell dissemination, and tumor cell access to vasculature — concerted processes that lead to breast cancer metastasis. In a prospective clinical trial, we developed a cohort of healthy, recently nursing women, and find similar tumor-promotional hallmarks in the human breast. Newly identified postpartum liver biology may also shed insight into metastasis in young women. We recently reported weaning-induced involution in the rodent liver. Further, the rodent involuting liver is highly permissive to breast cancer outgrowth. Potential relevance to women is suggested by a first-site-of-metastasis study in YWBC patients. Postpartum patients were at increased risk for liver metastasis, but not lung, brain or bone. Finally, our data showing normal mammary gland involution to be a COX-2 mediated process has led to preclinical modeling of NSAID based PPBC prevention and treatment strategies. Translating NSAID interventions to young women is potentially high-impact, as ∼50% of all YWBC patients are diagnosed within 10 years of their last pregnancy, putting them into an under-recognized, high risk, poor prognostic group. Citation Format: Schedin P. Breast cancer's metastatic moment: How postpartum tissue involution facilitates progression [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES2-2.