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Targeted Prevention of Postpartum-Related Breast Cancer (PRBC)

产后相关乳腺癌 (PRBC) 的针对性预防

基本信息

批准号：
10553696
负责人：
Derek C Radisky
金额：
$ 65.39万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553696
关键词：
Address Affect Aftercare Age Algorithms Anti-Inflammatory Agents Arachidonic Acids Area Under Curve Aspirin BCL1 Oncogene BCL2L1 gene BCL2L11 gene Benign Biological Assay Biopsy Birth Blood Breast Breast Cancer Prevention Breast Cancer Risk Factor Breast Diseases Breast biopsy C-reactive protein Characteristics Chemoprevention Childbirth Clinic Clinical Clinical Trials Contralateral DNA Damage Development Dinoprostone Discrimination Eicosanoids Enrollment Epidemiologic Factors Epidemiology Epithelial Cells Estrogen Receptors Estrogens Family history of First Births Freezing Frequencies Gamma-H2AX Immune Immune Targeting Immune response Immunohistochemistry Immunologic Markers Immunooncology Immunosuppression In Situ Inflammation Inflammatory Insulin Knowledge Label Lesion Link Lobule MS4A1 gene Malignant Neoplasms Mammary Gland Parenchyma Mammography Measures Modeling Multiparity Non-Steroidal Anti-Inflammatory Agents North Carolina Nulliparity Operative Surgical Procedures Participant Pathogenesis Pathology Pathway interactions Patients Persons Postpartum Period Pre-Clinical Model Pregnancy Prevention Prevention strategy Prevention trial Preventive Process Prognosis Prostaglandin Production Prostaglandins Proteins Questionnaires RNA Receiver Operating Characteristics Reporting Research Risk Risk Factors Risk Marker Sampling Schedule Serum Severity of illness Site Specimen Stains Testing Time Tissue Banks Tissue Microarray Tissues Universities Urine Weaning Woman adipokines aged biomarker panel breast cancer diagnosis breast cancer progression candidate identification carcinogenicity cyclooxygenase 2 digital early onset efficacy evaluation follow-up improved individualized prevention inflammatory marker innovation malignant breast neoplasm molecular subtypes mouse model nano-string parity parous predictive signature preventive intervention primary endpoint risk prediction secondary endpoint senescence wound healing young woman

项目摘要

Postpartum-related breast cancers (PRBCs), herein defined as breast cancers (BCs) diagnosed within five years after a birth, augur a poor prognosis. Although early age at first birth and multiparity lower risk of late onset BCs, childbirth transiently increases risks of both estrogen receptor (ER)+ and ER- BCs for over two decades, with peak risks at 5 years postpartum (parous vs. nulliparous: HR=1.80, 95%CI=1.63-1.99). Peak risks are even higher among women with a family history of BC (parous vs. nulliparous: HR=3.53, 95%CI=2.91-4.29), and for women whose first birth is at later ages (pinteraction=0.03). In preclinical models, post-partum involution (PPI), a pro-inflammatory process which restores the breast to a non-lactating state after weaning, is linked to activation of cyclooxygenase-2 (COX-2), which increases production of prostaglandins and results in an immune suppressed, pro-carcinogenic “wound healing” microenvironment that drives BC progression; in these models, treatment with non-steroidal anti-inflammatory agents (NSAIDs) inhibits PRBC development. Among women, both postpartum normal breast tissues and BBD biopsies are characterized by significant inflammation. We and others have reported significantly reduced risk of BC among NSAID users with benign breast disease (BBD), suggesting a potential preventive benefit for women at risk of PRBC. We propose 3 aims to test the hypothesis that dysregulated PPI increases risk of BBD and PRBC, and that inhibition of deleterious inflammation following PPI can lower BC risk. In Aim 1, we will define and validate a PPI-specific immune signature score to distinguish normal breast tissues of young nulliparous from parous women (obtained within 5 years of a birth, matched by age) using 240 samples donated to the Komen Tissue Bank (KTB). We will also measure eicosanoids, including prostaglandin E2, in frozen tissues from a subset (n=100) of these women. We will define factors related to PPI immune signature score, hypothesizing that higher scores may indicate increased PRBC risk. In Aim 2, we will refine and independently test whether a PRBC immune signature score based on 8 previously defined markers with a combined AUC=0.76 predicts risk in previously untested BBD biopsies (75 cases and 75 matched controls). We will compare PRBC immune signature scores in 707 BCs from women aged 40 years or less by parity status, molecular subtype, and adjusted for potential confounders. In Aim 3, we will conduct a window of opportunity clinical trial to test if a 6-week course of aspirin 81 mg per day can reduce the deleterious inflammation associated with PRBC risk (i.e., PRBC immune score) and favorably alter other BC risk markers in breast tissues, blood and urine. This significant and innovative proposal seeks to define a unifying mechanism of pathogenesis for PRBC, which will provide the basis for developing a short-term, well-tolerated prevention strategy using immune-targeting and/or anti-inflammatory agents to prevent BC.

产后相关乳腺癌（prbc），这里定义为五年内诊断出的乳腺癌（bc）