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Project

Postpartum breast cancer diagnosed during the post-weaning period: a distinct entity with unique clinicopathological, molecular and immunological features?

Background Postpartum breast cancer (PP-BC) represents an under-recognized, yet high-risk subset of breast cancer diagnosed in young women. Breast cancers that occur 1 to 2 years postpartum are characterized with a 2-fold increased risk for metastasis and higher death rates in comparison to breast cancers diagnosed in age-matched women outside but also during pregnancy. The poorer prognosis and increased risk for metastasis and death of PP-BC cannot solely be explained by altered clinical risk factors, like delayed diagnosis and deregulation of gestational hormones during or shortly after pregnancy. Although the exact molecular mechanisms remain unclear, it has been hypothesized that alterations in the breast, uniquely occurring in the postpartum window, are underlying the poor prognosis of PP-BC. During pregnancy, remarkable proliferation and differentiation occur to prepare the mammary gland epithelium for lactation. After delivery, or in case breastfeeding is given, after lactation, a regression occurs of the fully differentiated gland back to its pre-pregnant state, a process also referred to as involution. In rodents, the process of mammary gland involution shares striking similarities with the tissue-remodeling programs that are activated during wound healing and inflammation. Rodent mammary gland involution results in an altered organization of the extracellular matrix (ECM), which in turn stimulate the influx and activation of immunosuppressive immune cells that can promote tumor cell escape from the mammary gland. In breast cancer patients, the correlation of poor outcomes and changes in immune cell infiltration has been well studied and has been driving investigations into immunotherapy as a means of breast cancer treatment. However, the (immune)biology of the postpartum mammary gland in women remains an understudied field. In this research project we Aimed to elucidate whether PP-BC, specifically diagnosed during postpartum mammary gland involution (PP-BCPW), has different clinicopathological characteristics with worse metastatic and survival rates and exhibits unique molecular and immunological features when compared to breast cancers diagnosed during lactation (PP-BCDL), during pregnancy (Pr-BC) or outside the context of a pregnancy (NP-BC, nulliparous women).

Methodology A large-scale retrospective study was set up in premenopausal women aged 25 to 40 years and diagnosed with invasive primary breast cancer. Through the collection of detailed lactation data, we were able to stratify our patient population in the following 4 subgroups: postpartum breast cancer patients that had their diagnosis in the first 2 years after delivery, in case no breastfeeding was given, or post-weaning (as a surrogate for involution, PP-BCPW); postpartum breast cancer patients that are diagnosed while still lactating (PP-BCDL); pregnant breast cancer patients (Pr-BC); and patients that never have been pregnant (NP-BC).

Firstly, using clinicopathological and epidemiological data of 1180 young women that were diagnosed with invasive primary breast cancer, the clinicopathological profile of our PP-BCPW cohort was assessed relative to that of the PP-BCDL, Pr-BC and NP-BC cohorts. Differences in prognostic parameters, first site of distant metastasis, and risks for metastasis and death were determined between patient groups (Chapter 3 and Chapter 4). We identified a twofold increased the risk of metastasis and death in PP-BCPW patients when compared to our control groups. Prognosis was found to be worst for PP-BCPW patients who breastfeed £ 3 months prior to a breast cancer diagnosis. Although differences were observed in standard prognostic characteristics between patient groups, these would not fully underlie these differences.

Subsequently, an extensive molecular and immunological characterization of the mammary tumor and its (immune)microenvironment was performed using whole transcriptome sequencing as well as immunohistochemical (IHC) analyses on FFPE tumor tissue of a subset of these patient groups, well-controlled for surrogate molecular subtype and stage (Chapter 5). We found that subpopulation of PP-BCPW patients with a high infiltration of plasma B-cells, but low expression levels of an immunoglobulin (Ig) gene signature, shifted towards high IgG and low IgA gene expression levels, have a particularly increased risk for metastasis and death. Overall, these data demonstrate that PP-BCPW is a heterogeneous disease in which the B-cell compartment of the post-weaning mammary tumor microenvironment plays an important role and underlie patient prognosis.

In Conclusion, the depicted analyses in these unique cohorts of PP-BCPW, PP-BCDL, Pr-BC and NP-BC patients have provided novel clinicopathological data on PP-BC diagnosed during the post-weaning period, as a surrogate for mammary gland involution, and provided a primary indication that, at the molecular and cellular level, PP-BCPW should be seen as a distinct entity. This may point to differences in tumor or host biology in breast cancers diagnosed during involution versus breast cancers diagnosed outside this process. Further dissections of the tumor-infiltrating B-cell populations together with the exact Ig spectrum within the intratumoral context of PP-BC may open new perspectives for (personalized) immunotherapy or patient management in this specific group of young breast cancer patients.

Date:22 Sep 2015 →  9 Jan 2023
Keywords:breast cancer
Disciplines:Endocrinology and metabolic diseases, Gynaecology and obstetrics, Nursing
Project type:PhD project