Postpartum diagnosis demonstrates a high risk for metastasis and merits an expanded definition of pregnancy-associated breast cancer

Our results demonstrate that a breast cancer diagnosed within five-years postpartum has a significant 2.8 times higher risk for metastasis and a 2.7 times higher mortality risk compared to nulliparous cases. Our data further shows that a postpartum breast cancer diagnosis is an independent risk factor for recurrence and death. In our cohort, the increased risk of death imparted by a postpartum diagnosis was higher when compared with previous published studies [22‐24, 26, 31]. A strength of our study is the ability to include clinical and pathologic characteristics known to affect prognosis into our adjusted outcomes analysis for the effect of pregnancy on recurrence and death. As such, one potential reason for our higher risk differences may be the absence of clinical characteristics in prior PABC studies and thus the inability to report adjusted risk estimates [23, 26, 31].

In our cohort, parous women diagnosed ≥5 years following last childbirth trended toward a prognosis intermediate to PABC <5 and nulliparous women. We propose that the period of postpartum risk may persist to at least five-years postpartum as demonstrated by these data, which are likewise supported by previously published studies highlighting the postpartum window of risk [22‐26, 31]. In two of these population-based studies, poor outcomes were observed in women diagnosed up to eight years after childbirth [23], as well as a recent study demonstrated peak mortality in women diagnosed postpartum and persisting up to 10-years post-diagnosis [26]. We intentionally looked at our data by individual number of years postpartum to identify if an early “cutoff” of increased risk existed and found that the postpartum risk of recurrence and death is not limited to the first or second-year postpartum, as some studies previously suggested [1, 15, 16, 18]. At present, we cannot delineate the exact outer limit of this postpartum timeframe which may influence poor maternal prognosis. However, further study in larger cohorts with complete clinical data is necessary to better define the true extent and clinical implications of this interaction between postpartum diagnosis and increased risk of breast cancer recurrence and death.

Another aim of our study was to identify a methodological reason for the disparate results in prior PABC studies. An important distinction of our study is the utilization of rigorously defined parity status. Prior studies have combined pregnant and early postpartum cases as PABC and utilized various referent populations. Six published studies reporting outcomes included parous women diagnosed within seven to 24 months of last childbirth in the non-PABC “control” group—four studies identify an increased risk for PABC cases [1, 15, 16, 18] and two report no increase in risk [11, 12]. Of the four studies identifying an increased risk for PABC cases, three used a PABC cohort comprised of predominately early postpartum cases [1, 15, 18]. One study used a PABC cohort comprised of 40 % early postpartum and 60 % pregnant cases [16].When we applied similar definitions of PABC [pregnant and up to 1 year postpartum] and non-PABC [nulliparous and beyond 1 year postpartum] to our cohort, we also did not observed a significant increased risk associated with PABC (Table 4). We believe the inclusion of high-risk postpartum cases in the non-PABC control population blurs the true risk associated with a postpartum and nulliparous diagnosis. While our numbers of combined pregnant and <1 year postpartum are small, we provide evidence for the first time that the definition of the PABC and the nulliparous groups may obscure the risk of metastasis and death in postpartum breast cancer.

Currently, it is challenging to explain the conflicting data provided by these numerous studies to clarify the potential individual contributions of the pregnant and postpartum settings on breast cancer outcomes. Studies with pregnancy-specific data often include cases definitively treated during pregnancy, cases with early trimester terminations, and cases diagnosed during pregnancy, but treated postpartum [12, 18, 32] within the pregnant cohort. The impact of these clinical factors on breast cancer outcomes for women diagnosed during pregnancy is unknown. Furthermore, studies examining pregnant cases treated with definitive intent during pregnancy and concomitant maintenance of the pregnancy demonstrate equivalent outcomes to age-matched, stage-matched, non-pregnant controls [33, 34]. Our pregnancy cohort all completed delivery and received surgery and/or chemotherapy during pregnancy. We report a higher percentage of Her2 neu and triple negative cases over other subtypes which are unique to cases diagnosed during pregnancy (Table 5). A similar increase of triple negative associated with diagnosis during pregnancy was recently reported [17]. However, the size of our pregnant cohort does not permit further characterization, conclusions, or outcomes investigation at this time. Currently, others are making important efforts to build a large pregnant breast cancer registry to provide the resources necessary to help address these questions [2].

Our observation of equal presentation of biologic subtypes between nulliparous, PABC <5, and later parous cases contrasts prior reports [1, 12, 13, 16, 17] and may reflect underlying differences in sociodemographic and lifestyle factors in this dominantly Caucasian, single-state cohort. Importantly, it may also reflect a difference in outcomes depending on the definition of PABC. Previous studies that reported on combined pregnant and early postpartum cancers found an “aggressive phenotype,” characterized by advanced clinical stage, larger tumor size, increased nodal involvement, and higher histologic grade [1, 11, 12, 16]. Moreover, compared to non-PABC cases, various studies reported these combined pregnant and early postpartum tumors are marked by reduced estrogen and progesterone receptor positivity [1, 12, 13, 16], as well as higher frequency of Her2 neu positivity but not specifically the triple negative subtype [13, 17]. When early postpartum and pregnant cases were evaluated independently, there was contradictory data reported on the clinicopathologic features of these pregnant and postpartum subsets [12, 13, 17‐20]. Moreover, a recent PABC publication concluded triple negative tumors were more likely to be diagnosed within two-years postpartum [17]. However, in that study, when the pregnant (n = 8) cases were separated from the exclusively postpartum cases (n = 30), there was no association of triple negative tumors with a postpartum diagnosis [17]. In summary, we believe it is important to recognize that the characteristics of breast cancers diagnosed during pregnancy or postpartum may differ based on PABC definition, as well as due to potential confounders such as race or size of the cohort. The causal relationships between concurrent or prior pregnancy and tumor characteristics at diagnosis are not fully understood and beyond the scope of this report. However, as our data demonstrate, tumor characteristics alone do not account for the poorer prognosis of postpartum breast cancer and identification of the drivers for this increased risk of postpartum breast cancers are necessary to improve clinical outcomes.

To our knowledge, our study is unique in providing a contemporary comparison of outcomes between exclusively nulliparous and postpartum young women’s breast cancer cohorts. The favorable outcomes of our nulliparous group, compared to prior studies with similar cohorts, may reflect a period effect as breast cancer treatment has improved significantly over time [24, 31, 32]. Our data demonstrate a striking 2.7 higher risk of death for women diagnosed within five-years postpartum compared to nulliparous, after adjusting for biologic subtype, clinical stage, and year of diagnosis. Our research program has identified postpartum breast involution as being promotional to tumor growth, invasion, and metastasis in preclinical models [30]. Similar tumor promotional attributes have been identified in human breast involution [30, 35], as recently reviewed [36]. Therefore, we hypothesized that human postpartum breast cancer has poorer prognosis that is not solely explained by an enrichment of traditional poor prognostic factors that are tumor cell centric [8, 10, 30, 35]. While our results do not definitively prove the role of involution as etiologic for poorer postpartum outcomes, it does support the potential that breast involution imparts a unique tumor microenvironment as a mechanism for this increased risk [8, 36]. Further research in human cohorts on the interaction of pregnancy and subsequent breast cancer will need to include additional potential confounders, such as diversification of race, number of prior pregnancies with age at first pregnancy and intervals between, lactation data, gene mutation status, and detailed family history.

The under recognition of PABC and its impact on maternal outcomes is likely an unintended consequence of the variable definitions of the disease and the conflicting outcomes data. We demonstrate that limiting the definition of PABC as cases diagnosed during or within one year of a completed pregnancy translate into a low PABC incidence (10 %) in our Colorado cohort. Expanding the definition of PABC to within five-years postpartum increases this incidence to 29 % for women diagnosed ≤45 years. This higher PABC incidence is substantiated in a recently published study of young women’s breast cancer where 35 % of cases were diagnosed within five-years postpartum [17]. In addition, PABC incidence could be as high as 53.0 % or more of young women’s breast cancer if the trend in later parous groups (≥5 and <10 years postpartum) becomes significant in analyses of larger cohorts with longer followup (Fig. 3). If the distribution of postpartum PABC in our cohort is nationally representative, over a five-year period we would expect approximately 34,000 incident invasive breast cancer cases attributable to high risk postpartum PABC (PABC <5), and 6,900 incident diagnoses annually [37, 38].

Pregnancy ubiquitously proceeds involution and has its own significant biologic programs that influence breast cancers diagnosed both ante- and postpartum [8, 36]. Postpartum breast involution is a biologically unique event that is also emerging as a potential risk factor for premenopausal breast cancer [8, 30, 36]. Understanding the differences between breast cancers diagnosed during pregnancy and postpartum would better permit the translation of informative data from basic science and epidemiologic studies into the clinical care of young women’s breast cancer. Therefore, we propose defining PABC as two distinct subsets—cases diagnosed during pregnancy and cases diagnosed postpartum—to facilitate clarity in the PABC field.