Association Between Postpartum Breast Cancer Diagnosis and Metastasis and the Clinical Features Underlying Risk

Goddard, Erica T.; Bassale, Solange; Schedin, Troy; Jindal, Sonali; Johnston, Jeremy C.; Cabral, Ethan; Latour, Emile; Lyons, Traci R.; Mori, Motomi; Schedin, Pepper; Borges, Virginia F.

doi:10.1001/jamanetworkopen.2018.6997

Cited by 83 publications

(110 citation statements)

References 48 publications

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“…Additionally, it has long been recognized that increased breast density increases risk for developing breast cancer. Thus, our results also suggest that SEMA7A expression on the mammary epithelium during involution may promote the increased collagen deposition observed, which may play a role for the increased risk for developing breast cancer that can be attributed to recent pregnancy 1,4,7,39,44-46 . Furthermore, in the normal breast, collagen is typically organized into structures that run parallel to the epithelium.…”

Section: Discussionsupporting

confidence: 57%

“…Finally, it has long been recognized that increased breast density, primarily driven by collagen, increases risk for developing breast cancer(49, 50). Thus, our results suggest that SEMA7A expression on the mammary epithelium during involution may promote the increased collagen deposition observed, which may play a role for the increased risk for developing breast cancer that can be attributed to recent pregnancy (1, 4, 7, 26, 50-52).…”

Section: Discussionmentioning

confidence: 69%

“…Postpartum breast cancer patients diagnosed within five years of most recent childbirth have been described as a high risk population for relapse and metastasis and comprise nearly 30% of all breast cancers diagnosed in women aged <40 in both US and Norwegian cohorts(1). Recent results extend the risk for metastasis to 10 years postpartum, which makes the percentage of young breast cancer patients who are considered postpartum and as such at high risk for metastasis nearly 50%(26). A recent publication by Welch and Hurst defines the hallmarks of metastasis as motility and invasion, modulation of the microenvironment, plasticity and colonization(27).…”

Section: Discussionmentioning

confidence: 99%

“…Finally, in tamoxifen resistant breast cancer cell lines AKT activity also results in upregulation of fibronectin, which in turn promotes therapeutic resistance. Thus, patients in our postpartum cohort with estrogen receptor positive breast cancer, who do not appear to respond favorably to anti-endocrine therapy as they show survival rates as low as those with triple-negative breast cancer 39 , may develop resistance to anti-endocrine therapy through a SEMA7A dependent mechanism. This SEMA7A dependent mechanism may be more broadly at play in other female hormone-dependent cancers as our signature of high SEMA7A, COX-2 and FN also predicts poor survival in ovarian cancer, which often develops chemotherapeutic resistance, especially to cisplatin, and estrogen resistance (refs).…”

Section: Discussionmentioning

confidence: 99%

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Postpartum breast cancer progression is driven by semaphorin 7a mediated invasion and survival

Tarullo

Hill

Hansen

et al. 2019

Preprint

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Breast cancer (BC) remains the second leading cause of cancer related deaths in women in the US --mainly due to metastatic disease. Thus, understanding how BC progresses is of the utmost importance to developing new strategies to block metastasis. Young women diagnosed with BC generally have poor prognosis due to increased rates of metastasis. Additionally, women who are within 5 years of most recent child-birth at diagnosis are ~3 times more likely to develop metastasis than age and stage matched nulliparous women. We define these cases as postpartum breast cancers (PPBC) and propose that the unique biology of the postpartum mammary gland drives tumor progression and metastasis. Semaphorin 7a (SEMA7A) is a unique member of the Semaphorin family as it is the only GPI-anchored member that can be shed into the extracellular environment. Our published results show that SEMA7A expression is associated with decreased overall survival in BC patient cohorts and revealed roles for SEMA7A in breast tumor cell growth, motility, invasion, and tumor associated-lymphangiogenesis all of which are also increased in pre-clinical models of PPBC. However, whether primary SEMA7A driver PPBC progression remains largely unexplored. We utilized a pre-clinical of PPBC with breast cancer cells where we silenced or overexpressed SEMA7A. Our results show that silencing of SEMA7A decreases tumor growth in postpartum hosts while overexpression increases growth in nulliparous hosts to rates closer to those observed in postpartum hosts. Further, we show that SEMA7A effects multiple pro-metastatic tumor attributes such as cell survival, tumor associated COX-2 expression, fibronectin deposition, and fibroblast-mediated collagen deposition in the tumor microenvironment regardless of whether the host is nulliparous or postpartum. Finally, we show that co-expression of SEMA7A/Collagen/COX2/FN mRNA predicts for increased metastasis in breast and ovarian cancer cohorts. These studies suggest SEMA7A as a key mediator of general BC progression and that targeting SEMA7A alone or in combination may open avenues for novel therapeutic strategies to prevent BC progression to metastasis. INTRODUCTION:Postpartum breast cancers (PPBC), or breast cancers diagnosed within 5-10 years of last childbirth, are nearly three times as likely to become metastatic and result in death from breast cancer 1-3 . Specifically, PPBC patients diagnosed within five years of last competed pregnancy exhibit 70% distant metastasis free five-year survival (DMFS) rates 1 that are further decreased to 50% after ten years 2 . Using this definition, PPBC may account over half of breast cancers diagnosed in women aged <45 in two independent cohorts. Using a pre-clinical model of PPBC we have shown that noninvasive breast tumor cells, MCF10DCIS, become invasive and metastatic if they are implanted into mouse mammary tissues during the normal physiological process of postpartum mammary gland involution 4 . The MCF10DCIS model closely resembles ductal carcinoma in situ (DCIS) and progresse...

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Postpartum breast cancer progression is driven by semaphorin 7a mediated invasion and survival

Tarullo

Hill

Hansen

et al. 2019

Preprint

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“…However, some women who experience pregnancy at an early age do develop breast cancer (Box 1). Breast cancer patients that developed breast cancer within 10 years post-partum (pregnancy-induced), had a higher rate of TNBC and increased levels of infiltrating lymphocytes in their tumors [61], as well as an ER-independent, increased risk for metastasis [62].…”

Section: Pregnancy-associated Breast Cancer Preventionmentioning

confidence: 99%

Pregnancy and Breast Cancer: Pathways to Understand Risk and Prevention

Slepicka

Cyrill

Santos

2019

Trends in Molecular Medicine

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Several studies have made strong efforts to understand how age and parity modulate the risk of breast cancer. A holistic understanding of the dynamic regulation of the morphological, cellular, and molecular milieu of the mammary gland offers insights into the drivers of breast cancer development as well as into potential prophylactic interventions, the latter being a longstanding ambition of the research and clinical community aspiring to eradicate the disease. In this review we discuss mechanisms that react to pregnancy signals, and we delineate the nuances of pregnancyassociated dynamism that contribute towards either breast cancer development or prevention. Further definition of the molecular basis of parity and breast cancer risk may allow the elaboration of tools to predict and survey those who are at risk of breast cancer development. Parity: A Perspective for Therapeutic and Prophylactic InterventionBreast cancer is the most frequently diagnosed malignance in women. It strikes >1.6 million women worldwide, and about one in eight 8 women in the USA will develop breast cancer in their lifetime (Box 1 and Table 1). Most breast cancers arise because of dysfunction of cells in mammary ducts (50-70% of tumors) or lobules (10-15% of breast cancers), which categorizes these tumors as carcinomas, specifically adenocarcinomas. Some breast tumors are sarcomas, originating in the stroma or muscle. Other types and subtypes of breast cancer are less frequent, and a single diagnosis of breast cancer may refer to a combination of different tumors (www.breastcancer.org) (Box 1).Parity is known to have a dual effect on breast cancer risk. In many ways, breast tumorigenesis mimics several mechanisms that are commonly activated during pregnancy, including augmented cell proliferation, alterations in cell shedding, reduced cell apoptosis, altered gene expression, and extracellular matrix (ECM) modifications. On the other hand, epidemiological studies have provided evidence of the cancer-preventive benefits of pregnancy wherein an early age of pregnancy decreases the risk of breast cancer development. Although understanding the molecular mechanisms underlying these phenomena is still in its infancy, their elucidation will open new avenues to target breast cancer. Mammary Gland Composition and DevelopmentThe mammary gland is a complex and highly adaptive organ whose main function, in female mammals, is to produce milk during lactation for the sustenance of young offspring. The gland is composed of a variety of cell types, including fibroblasts, adipocytes, epithelial, endothelial, and immune cells. The epithelial cells can be further subdivided into multiple cell types that, together, form the branching structure of the gland and constitute the secretory alveoli during lactation. Two main epithelial cell compartments can be distinguished in the mammary gland: the luminal compartment [the inner cell layer, localized between the lumen (see Glossary),and the basal compartment] and the basal compartment (the outer layer surrounding ...

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Young-Onset Breast Cancer Outcomes by Time Since Recent Childbirth in Utah

et al. 2022

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ImportanceBreast cancer diagnosed within 5 to 10 years after childbirth, called postpartum breast cancer (PPBC), is associated with increased risk for metastasis and death. Whether a postpartum diagnosis is an independent risk factor or a surrogate marker of cancer features associated with poor outcomes remains understudied.ObjectiveTo determine whether diagnostic temporal proximity to childbirth is associated with features of breast cancer associated with poor outcomes, including tumor stage, estrogen receptor (ER) status, and risk for distant metastasis and breast cancer–specific mortality, using a population database from the state of Utah.Design, Setting, and ParticipantsThis population-based cohort study using the Utah Population Database (UPDB) included individuals with stage I to III breast cancer diagnosed at age 45 years or younger between 1996 and 2017, followed-up until February 2020. Participant data were analyzed from November 2019 to August 2022.ExposureThe primary exposures were no prior childbirth or time between most recent childbirth and breast cancer diagnosis. Patients were grouped by diagnoses within less than 5 years, 5 to less than 10 years, or 10 years or more since recent childbirth.Main Outcomes and MeasuresThe 2 primary outcomes were distant metastasis–free survival and breast cancer–specific death. Cox proportional hazard models were used to investigate associations between exposures and outcomes adjusting for diagnosis year, patient age, tumor stage, and estrogen receptor (ER) status.ResultsOf 2970 individuals with breast cancer diagnosed at age 45 years or younger (mean [SD] age, 39.3 [5.0] years; 12 Black individuals [0.4%], 2679 White individuals [90.2%]), breast cancer diagnosis within 5 years of recent childbirth was independently associated with approximately 1.5-fold elevated risk for metastasis (hazard ratio [HR], 1.5; 95% CI, 1.2-2.0) and breast cancer–specific death (HR, 1.5; 95% CI, 1.1-2.1) compared with nulliparous individuals. For cancers classically considered to have tumor features associated with good outcomes (ie, stage I or II and ER-positive), a postpartum diagnosis was a dominant feature associated with increased risk for metastasis and death (eg, for individuals with ER-positive disease diagnosed within &lt;5 years of childbirth: age-adjusted metastasis HR, 1.5; 95% CI, 1.1-2.1; P = .01; age-adjusted death HR, 1.5; 95% CI, 1.0-2.1; P = .04) compared with nulliparous individuals. Furthermore, liver metastases were specifically increased in the group with diagnosis within 5 years postpartum and with positive ER expression (38 of 83 patients [45.8%]) compared with the nulliparous (28 of 77 patients [36.4%]), although the difference was not statistically significant. Overall, these data implicate parity-associated breast and liver biology in the observed poor outcomes of PPBC.Conclusions and RelevanceIn this cohort study of individuals with breast cancer diagnosed at age 45 years or younger, a postpartum breast cancer diagnosis was a risk factor associated with poor outcomes. Irrespective of ER status, clinical consideration of time between most recent childbirth and breast cancer diagnosis could increase accuracy of prognosis in patients with young-onset breast cancer.

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Association Between Postpartum Breast Cancer Diagnosis and Metastasis and the Clinical Features Underlying Risk

Cited by 83 publications

References 48 publications

Postpartum breast cancer progression is driven by semaphorin 7a mediated invasion and survival

Postpartum breast cancer progression is driven by semaphorin 7a mediated invasion and survival

Pregnancy and Breast Cancer: Pathways to Understand Risk and Prevention

Young-Onset Breast Cancer Outcomes by Time Since Recent Childbirth in Utah

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