||1R01CA267897-01A1 Interpret this number
||Columbia University Health Sciences
||The Tumor Microenvironment and Lymphatic Remodeling in Postpartum Breast Cancer
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 <5 years from childbirth) matched to 272 non-PPBC cases (diagnosed ≥10 years
from childbirth) on age at diagnosis. We will measure functional-specific TME phenotypes by measuring the
independent and joint associations between protein abundance and spatial proximity to tumor and the lymphatic
vasculature. We will examine each phenotype independently and together to develop TME poly-phenotype
scores. We aim to examine the independent association between the functional-specific TME phenotypes and
the developed TME poly-phenotype score with (1) PPBC status and (2) overall survival. We also (3) examine
the association between prediagnostic lifestyle behaviors (i.e., breastfeeding, NSAID intake, physical activity)
and TME phenotypes and scores. There are no genomic signatures or clinical markers that inform therapeutics
nor prognosis for young women’s BC. Thus, for young women’s BC overall and PPBC specifically, strategies are
needed that define predictive biomarkers and provides insight into the functional biology of modifiable
behaviors. To our knowledge, this is the first study to examine TME features through density and spatial
pathology for young women’s BC and the first to temporally examine lifestyle behaviors and the breast TME.
Stressful Life Events, Social Support, and Incident Breast Cancer by Estrogen Receptor Status.
, McDonald J.A.
, Williams F.
, Shiels M.S.
, Freedman N.D.
, Lin Z.
, Magnani J.W.
Cancer prevention research (Philadelphia, Pa.), 2023-05-01; 16(5), p. 259-267.