Publications

Abstract

Purpose

Young premenopausal women develop breast cancer (BC) within 5–10 years of the last childbirth, known as post-partum breast cancers (PPBC), often present with aggressive disease. The exact mechanisms that lead to poor prognosis in these patients are largely unknown.

Methods

We have evaluated the association of clinical and reproductive factors with BC in a cohort of women ≤ 45 years (N = 155) with long-term follow-up. Based on duration since last childbirth (LCB), grouped patients into PPBC1 (LCB ≤ 5 years), PPBC2 (LCB between 6 and 10 years), PPBC3 (LCB > 10 years), and NPBC (age-matched nulliparous BC patients). We compared disease-free survival and hazard associated with recurrence/metastasis between the groups. RNA sequencing of tumor samples was performed from three parous groups (n = 10), and transcriptomic data were analyzed for differentially expressed genes and altered pathways.

Results

Women in the PPBC1 group had an early menarche and late age at first and last childbirth compared to other groups. Survival analysis within lymph node-positive tumors showed that PPBC1 tumors had a worse prognosis than PPBC2 and NPBC tumors (p = 0.015 and p = 0.026, respectively). Clustering of the differentially expressed genes between the groups showed distinct expression in early PPBC (E-PPBC) tumors. Pathway analysis revealed upregulation of invasive-related pathways along with T cell exhaustion, extracellular matrix remodeling, angiogenesis, and epithelial-to-mesenchymal transition in E-PPBC tumors.

Conclusion

Early PPBC is a unique subtype with aggressive clinical features and distinct biology. Further research is needed to accurately project the risk of recurrence and optimal treatment strategies in these young patients.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10549-023-06956-6.

Keywords: Post-partum breast cancer, Invasion, Prognosis, Time since last childbirth

Introduction

Breast cancer (BC) is the most prevalent cancer and the leading cause of cancer-related deaths and morbidity among women worldwide. The proportion of cancer in young premenopausal women with BC is higher in low–middle-income countries probably due to changes in lifestyle and reproductive factors [1, 2]. Delays in pregnancy and older age at childbirth are associated with the early onset of BC. Previous literature shows that BC in younger women is usually associated with aggressive clinical features compared to BC in the older population [3, 4]. Aggressive disease associated with higher morbidity and mortality in the younger population poses a substantial public health problem.

Some of the unique subtypes of BC confined only to young women in the premenopausal age group are pregnancy-associated BC which develops during pregnancy and post-partum breast cancer (PPBC), which extends up to 10 years after the recent childbirth. Studies have shown a transient increase in the BC risk during early post-partum period, compared to age-matched nulliparous BC patients [5, 6]. Previous studies have reported that BC diagnosed in early post-partum duration is more aggressive than diagnosed during pregnancy [7, 8]. PPBC is associated with a threefold increase in metastasis and death related to BC [8, 9], affecting approximately one-third or more of younger women with BC globally. Despite such a huge burden, PPBC is not yet considered a distinct class of BC. Tumor staging and biologic subtyping alone may be insufficient to accurately assess the risk of recurrence and optimal treatment strategies in young premenopausal patients with BC.

Post-partum mammary gland involution is mainly investigated in animal models. Apoptosis-induced cell death and extracellular matrix (ECM) remodeling, like wound healing, are known mechanisms of involution. Rodent model studies have demonstrated that during post-partum involution, the ECM is enriched in collagen, fibronectin fragments, and matrix metalloproteinases (MMPs), contributing to increased invasion and metastatic potential of tumor cells [10-13]. Distinct patterns of immune infiltration in PPBC patients compared to nulliparous BC patients suggest an immunosuppressive microenvironment that might contribute to early disease progression [14]. The exact mechanism that leads to poor prognosis in PPBC in humans is unknown.

In the current study, we assessed the tumor characteristics and risk associated with developing PPBC in women ≤ 45 years of age, grouped them based on post-partum duration compared to nulliparous BC patients. We further evaluated differential biological pathways between early (1–5 years) and late post-partum (> 6 years) within age-matched BC patients.

Materials and methods

Patient cohort

The study included a retrospective hospital-based cohort of 155 primary BC patients of age ≤ 45 years who did not receive any prior treatment were recruited for the study from two tertiary cancer care hospitals in Bangalore, India. The diagnosis of BC was confirmed histologically. The maximum follow-up duration was 102 months, with a total loss to follow-up of less than 4% and median follow-up duration of 55 months. The institutional ethical review board approved the study. Informed consent was obtained from all the patients. All the clinical and histopathological information was obtained from the patient’s clinical records. Age at menarche, first childbirth (FCB), and last childbirth (LCB) were collected from medical records or were documented based on specific interrogations with the patients. Patients associated with ambiguous data regarding childbirth were excluded from the study. Information regarding treatment and progression of the disease or disease-related events was obtained during follow-up.

The study cohort was subdivided into four subgroups: PPBC1 (PPBC with LCB ≤ 5 years), PPBC2 (PPBC with LCB between 6 and 10 years), PPBC3 (PPBC with LCB > 10 years), and NPBC (age-matched nulliparous BC patients).

Details of the methods used for RNA sequencing, data processing, functional enrichment analysis, and statistical analysis are mentioned in Additional file 1.

Results

We accessed women with BC aged ≤ 45 years from a retrospective series of 777 tumors. Among these, 155 (20%) were ≤ 45 years with a mean age ± SD of 38.9 ± 5 years. 48% had tumors size > 3 cm and nearly half (45%) were grade 3. Most tumors were lymph node positive (60%) and had a higher proportion of triple-negative BC (29%).

Categorization based on the time since LCB showed 15% (23/155) were within the first 5 years (PPBC1), 25% (38/155) were between 6 and 10 years (PPBC2), 46% (72/155) had tumors 10 years after most recent childbirth (PPBC3), and 14% (22/155) were NPBC.

Association of reproductive and clinicopathological features among different groups

Examination of the association of reproductive features between the 3 PPBC groups showed PPBC1 patients had a significantly older age at FCB and LCB compared to PPBC2 and PPBC3 (FCB, p = 0.007 and p < 0.0001; LCB, p = 0.020 and p < 0.0001, respectively). We also noticed that PPBC2 patients had significantly higher age at FCB and LCB than PPBC3 patients (FCB, p = 0.003; LCB, p < 0.001). In addition, within the PPBC1 group, 91% of patients were comparatively younger at menarche (Fisher exact test, p = 0.047). No association with the number of live births (calculated as parity) was observed among the parous groups. Results are represented in Table 1. There was no association with the family history of BC.