Previous studies report conflicting data on outcomes of pregnancy-associated breast cancer (PABC). Our aim was to examine the effect of a postpartum diagnosis on maternal prognosis in a young women’s breast cancer cohort. We conducted a retrospective cohort study of women age ≤45 years, diagnosed with breast cancer (n = 619) during 1981–2011 at the University of Colorado Hospital and The Shaw Cancer Center in Edwards, CO. Breast cancer cases were grouped according to time between giving birth and diagnosis: nulliparous (n = 125), pregnant (n = 24), < 5 years postpartum (n = 136), >5—<10 postpartum (n = 130), and ≥10 years postpartum (n = 147), to examine the clinicopathologic features and the risk of distance recurrence and death. Cases diagnosed after pregnancy, but within five-years postpartum, had an approximate three fold increased risk of distant recurrence (HR 2.80, 95 % CI: 1.12–6.57) and death (HR 2.65, 95 % CI: 1.09–6.42) compared to nulliparous cases. Postpartum cases diagnosed within five years of last childbirth demonstrated a higher five-year distant recurrence probability (31.1 %) and a markedly lower five-year overall survival probability (65.8 %) compared to nulliparous cases (14.8 and 98.0 %, respectively). A diagnosis of breast cancer during the first five-years postpartum confers poorer maternal prognoses after adjustment for biologic subtype, stage, and year of diagnosis. We propose that the definition of PABC should include cases diagnosed up to at least five-years postpartum to better delineate the increased risk imparted by a postpartum diagnosis. Based on emerging preclinical and epidemiologic data, we propose that pregnant and postpartum cases be researched as distinct subsets of PABC to clarify the risk imparted by pregnancy and the events subsequent to pregnancy, such as breast involution, on breast cancer. Further, we highlight the importance of postpartum breast cancer as an area for further research to reduce the increased metastatic potential and mortality of PABC.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-013-2437-x) contains supplementary material, which is available to authorized users.

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Platelet indices, especially PDW, are different between diabetics and controls as well as between diabetics with and without microvascular complications. Discriminant analysis using PDW and MPV could classify majority of patients with diabetic complications.

Women diagnosed with breast cancer within 5 years postpartum have poor survival rates. The process of postpartum mammary gland involution, whereby the lactating gland remodels to its pre-pregnant state, promotes breast cancer progression in xenograft models. Macrophage influx occurs during mammary gland involution, implicating immune modulation in the promotion of postpartum breast cancer. Herein, we characterize the postpartum murine mammary gland and find an orchestrated influx of immune cells similar to that which occurs during wound healing. Further, the normal involuting gland may be in an immunosuppressed state as discerned by the transient presence of Foxp3+ regulatory T cells and IL-10+ macrophages with T cell suppressive function. To determine the influence of the postpartum immune microenvironment on mammary tumor promotion, we developed an immune-competent model. In this model, mammary tumors in the involution group are six-fold larger than nulliparous group tumors, have decreased CD4+ and CD8+ T cell infiltrates and contain a greater number of macrophages with the ability to inhibit T cell activation. Targeting involution with a neutralizing antibody against the immunosuppressive cytokine IL-10 reduces tumor growth in involution group mice but not in nulliparous mice, implicating the involution microenvironment as the primary target of αIL-10 treatment. Relevance to women is implicated, as we find post-lactational human breast tissue has transient high IL-10+ and Foxp3+ immune cell infiltrate. These data show an immune modulated microenvironment within the normal involuting mammary gland suggestive of immunosuppression, that when targeted reduces tumor promotion, revealing possible immune-based strategies for postpartum breast cancer.

Obese postmenopausal women have increased risk of breast cancers with poorer clinical outcomes than their lean counterparts. However, the mechanisms underlying these associations are poorly understood. Rodent model studies have recently identified a period of vulnerability for mammary cancer promotion, which emerges during weight gain after the loss of ovarian function (surgical ovariectomy; OVX). Thus, a period of transient weight-gain may provide a lifecycle-specific opportunity to prevent or treat postmenopausal breast cancer. We hypothesized that a combination of impaired metabolic regulation in obese animals prior to OVX plus an OVX-induced positive energy imbalance might cooperate to drive tumor growth and progression. To determine if lean and obese rodents differ in their metabolic response to OVX-induced weight gain, and whether this difference affects later mammary tumor metabolism, we performed a nutrient tracer study during the menopausal window of vulnerability. Lean animals preferentially deposited excess nutrients to mammary and peripheral tissues rather than to the adjacent tumors. Conversely, obese animals deposited excess nutrients into the tumors themselves. Notably, tumors from obese animals also displayed increased expression of the progesterone receptor (PR). Elevated PR expression positively correlated with tumor expression of glycolytic and lipogenic enzymes, glucose uptake and proliferation markers. Treatment with the anti-diabetic drug metformin during ovariectomy-induced weight gain caused tumor regression and downregulation of PR expression in tumors. Clinically, expression array analysis of breast tumors from postmenopausal women revealed that PR expression correlated with a similar pattern of metabolic upregulation, supporting the notion that PR+ tumors have enhanced metabolic capacity after menopause. Our findings have potential explanative power in understanding why obese, postmenopausal women display an increased risk of breast cancer.

Key Points Question Is there an increased risk for metastasis of breast cancers that are diagnosed in young women post partum that extends beyond 5 years from the last childbirth, and what association do standard clinical prognostic factors have with metastatic risk in these young women when categorized by parity? Findings In a cohort study of 701 women 45 years or younger with breast cancer, those with stage I or II cancer diagnosed up to 10 years post partum had an increased risk for distant metastasis, with both estrogen receptor–positive and estrogen receptor–negative disease significantly affected. Meaning Postpartum status may be a prognostic indicator in young women with breast cancer and should be routinely identified, as up to 45% of women 45 years or younger with breast cancer fall into this category and could be at increased risk for metastasis.

IntroductionA postpartum diagnosis of breast cancer is an independent predictor of metastases, however the reason is unknown. In rodents, the window of postpartum mammary gland involution promotes tumor progression, suggesting a role for breast involution in the poor prognosis of human postpartum breast cancers. Rodent mammary gland involution is characterized by the programmed elimination of the secretory lobules laid down in preparation for lactation. This tissue involution process involves massive epithelial cell death, stromal remodeling, and immune cell infiltration with similarities to microenvironments present during wound healing and tumor progression. Here, we characterize breast tissue from premenopausal women with known reproductive histories to determine the extent, duration and cellular mechanisms of postpartum lobular involution in women.MethodsAdjacent normal breast tissues from premenopausal women (n = 183) aged 20 to 45 years, grouped by reproductive categories of nulliparous, pregnant and lactating, and by time since last delivery were evaluated histologically and by special stain for lobular area, lobular type composition, apoptosis and immune cell infiltration using computer assisted quantitative methods.ResultsHuman nulliparous glands were composed dominantly of small (approximately 10 acini per lobule) and medium (approximately 35 acini per lobule) sized lobules. With pregnancy and lactation, a >10 fold increase in breast epithelial area was observed compared to nulliparous cases, and lactating glands were dominated by mature lobules (>100 acini per lobule) with secretory morphology. Significant losses in mammary epithelial area and mature lobule phenotypes were observed within 12 months postpartum. By 18 months postpartum, lobular area content and lobule composition were indistinguishable from nulliparous cases, data consistent with postpartum involution facilitating regression of the secretory lobules developed in preparation for lactation. Analyses of apoptosis and immune cell infiltrate confirmed that human postpartum breast involution is characterized by wound healing-like tissue remodeling programs that occur within a narrowed time frame.ConclusionsHuman postpartum breast involution is a dominant tissue-remodeling process that returns the total lobular area of the gland to a level essentially indistinguishable from the nulliparous gland. Further research is warranted to determine whether the normal physiologic process of postpartum involution contributes to the poor prognosis of postpartum breast cancer.

We describe a preclinical model that investigates progression of early-stage ductal carcinoma in situ (DCIS) and report that compromised myoepithelial cell differentiation occurs before transition to invasive disease. Human breast cancer MCF10DCIS.com cells were delivered into the mouse mammary teat by intraductal injection in the absence of surgical manipulations and accompanying wound-healing confounders. DCIS-like lesions developed throughout the mammary ducts with full representation of human DCIS histologic patterns. Tumor cells were incorporated into the normal mammary epithelium, developed ductal intraepithelial neoplasia and DCIS, and progressed to invasive carcinoma, suggesting the model provides a rigorous approach to study early stages of breast cancer progression. Mammary glands were evaluated for myoepithelium integrity with immunohistochemical assays. Progressive loss of the myoepithelial cell differentiation markers p63, calponin, and a-smooth muscle actin was observed in the mouse myoepithelium surrounding DCISinvolved ducts. p63 loss was an early indicator, calponin loss intermediate, and a-smooth muscle actin a later indicator of compromised myoepithelium. Loss of myoepithelial calponin was specifically associated with gain of the basal marker p63 in adjacent tumor cells. In single time point biopsies obtained from 16 women diagnosed with pure DCIS, a similar loss in myoepithelial cell markers was observed. These results suggest that further research is warranted into the role of myoepithelial cell p63 and calponin expression on DCIS progression to invasive disease. Clinical evidence is compelling for histologic progression of breast cancer through atypical hyperplasia, ductal carcinoma in situ (DCIS), invasive ductal carcinoma, and metastatic stages. 1 Such histopathologic progression studies and mutational profiling of epithelial cancers 2,3 suggest that acquisition of invasive potential is a relatively late event. However, genomic data analyses have revealed that most tumor cell gene expression changes occur at the transition from normal to DCIS, with few additional changes in expression occurring at the transition from DCIS to overt invasive disease. 4,5 These observations implicate key roles for nonepithelial cells in progression to invasive disease. 6,7 The lack of relevant model systems has hindered our understanding of the DCIS to invasive transition.The clinical definition of invasive breast cancer is spread of malignant tumor cells from the confines of the mammary duct into the adjacent tissue stroma. In the normal mammary gland, epithelial ductal and alveolar structures are