Postpartum breast cancer: mechanisms underlying its worse prognosis, treatment implications, and fertility preservation

Abstract

Breast cancers that occur in young women up to 5 to 10 years' postpartum are associated with an increased risk for metastasis and death compared with breast cancers diagnosed in young, premenopausal women during or outside pregnancy. Given the trend to delay childbearing, this frequency is expected to increase. The (immuno)biology of postpartum breast cancer is poorly understood and, hence, it is unknown why postpartum breast cancer has an enhanced risk for metastasis or how it should be effectively targeted for improved survival. The poorer prognosis of women diagnosed within 10 years of a completed pregnancy is most often contributed to the effects of mammary gland involution. We will discuss the most recent data and mechanistic insights of the most important processes associated with involution and their role in the adverse effects of a postpartum diagnosis. We will also look into the effect of lactation on breast cancer outcome after diagnosis. In addition, we will discuss the available treatment strategies that are currently being used to treat postpartum breast cancer, keeping in mind the importance of fertility preservation in this group of young women. These additional insights might offer potential therapeutic options for the improved treatment of women with this specific condition.

Keywords: carcinoma; gynecology; neoplasm metastasis.

Figure 1

Hypothetical model depicting potential mechanisms during involution and lactation that might explain the poor prognosis of postpartum breast cancer patients. during pregnancy and lactation, Proliferation and differentiation of the mammary gland occurs. It is hypothesized that longer periods of lactation (>12 months) give rise to terminal differentiation of the majority of mammary cells.During mammary gland involution, these mammary epithelial cells are subsequently removed by apoptosis, in order to return the mammary gland to its pre-pregnant state. Besides extensive apoptosis, the involution process can be characterized by infiltration of leukocytes and repopulation of adipocytes (upper panel). Fully differentiated cells are considered to be immune-presenting and might lead to an influx of antigen-presenting macrophages, CTLs, and NK cells.These infiltrated immune cells might rid the mammary gland of these pro-tumorigenic cells and reduce the risk of aggressive postpartum tumor cell formation. In contrast, a lack or short duration of breastfeeding (<12 months) could give rise to less differentiated cells that are less targeted by apoptosis during the subsequent involution process.Survival and expansion of these less differentiated cells might suppress the immune microenvironment associated with normal involution, which might lead to the formation of aggressive tumors with increased invasiveness (lower panel). Resistance to cell death plays an important role in tumor initiation, as it results in the propagation of potentially harmful mutations that allow unregulated growth and division. These surviving cells are thought to produce a multitude of immunosuppressive factors that might lead to the production of an immunosuppressive microenvironment comprizing neutrophils, Tregs, TAMs, and cancer-associated fibroblasts.As these cells are known to modulate the immune system to an immunosuppressive state, they might become more motile and invasive, increasing the risk for metastases. increased extracellular matrix stiffening, collagen deposition, and cross-linking during mammary gland involution, mediated by the infiltration of several of these immune-related cells, has been shown to provide a structural network for tumor cell migration, which further promotes tumor cell invasion and metastasis. Extracellular matrix proteolytic fragments have also been shown to directly promote growth, motility, and invasion.: PPBC, postpartum breast cancer; CTLs, cytotoxic CD8 +T cells; NK cells, natural killer cells; Tregs, regulatory T cells; TAMs, tumor-associated macrophages; CAFs, cancer-associated fibroblasts; ECM, extracellular matrix.