The Tumor Microenvironment and Lymphatic Remodeling in Postpartum Breast Cancer

SUMMARY/ABSTRACT: Pregnancy reduces breast cancer (BC) risk in the long-run but is associated with increased BC known as postpartum breast cancer (PPBC) for at least a decade after delivery. PPBC is often more aggressive with both late stage and higher risk of death compared to non-PPBC. Currently the only available information to inform women of possible ways to reduce PPBC is based on breastfeeding and more recently, a possible role for non- steroidal anti-inflammatories (NSAIDs). In addition to sparse data on how to modify PPBC risk, there is even less information related to risk stratification after PPBC diagnosis to improve outcomes with routine genomic signatures and clinical markers not suited for young women diagnosed with BC. We aim to address these major gaps by examining the intratumoral PPBC environment. Studies suggest that the expansion of the lymphatic vasculature, inflammation, and increased features of immune suppression during postpartum remodeling of the mammary gland is exacerbated in the absence- or early-cessation- of breastfeeding which makes the environment more permissive to tumor growth. This permissiveness contributes directly to the increased risk of tumor invasion and metastasis linked to the rising rates of BC mortality in young women. The tumor infiltrating immune cells, through their type, function, and interactions with the tumor and other stromal elements, provide a measurable pathological signature representative of the tumor microenvironment (TME). Promising data suggests that enrichment for Semaphorin 7A (SEMA7A), CD68, and Podoplanin (PDPN) is associated with poor BC prognosis, with mechanisms unclear. Therefore, we will profile the TME for features of macrophage mediated lymphangiogenesis and immune suppression, as measured by SEMA7A, CD68, PDPN, and PD-L1/PD-1 expression via multispectral quantitative immunofluorescence, in a young women’s BC case-cohort of 152 PPBC cases (diagnosed