Abstract Background: Postpartum breast cancer (PPBC), which arises during breast involution after childbirth and lactation, is linked to worse outcomes in young women with breast cancer (YWBC). Definitions of PPBC are not standardized, with some sources defining PPBC as 0-5 years postpartum and others defining it as up to 10 years postpartum. Prior studies suggest PPBC is associated with higher 21-gene recurrence scores (RS) and other high-risk molecular features, but detailed molecular profiles of breast cancer risk based on different PPBC definitions are limited. We aimed to identify a subset of PPBC that may be biologically distinct by comparing RS, individual gene expression levels, and pathologic tumor grade in different groups of PPBC stratified by timing of postpartum breast cancer diagnosis. Methods: We identified women aged ≤45 years with hormone receptor (HR)-positive, HER2-negative breast cancer who underwent RS testing at a single academic cancer center between 2011 and 2024. Reproductive and clinicopathologic data, including parity and timing of most recent childbirth relative to tumor testing were collected through electronic medical record review. Patients were stratified into four groups: nulliparous, PPBC1 (diagnosis 5 years postpartum), PPBC2 (diagnosis 5-10 years postpartum), and diagnosis 10-years postpartum. Patients who were diagnosed with breast cancer during pregnancy and patients with incomplete reproductive data were excluded. Linear regression was used to evaluate for differences in mean RS and gene expression scores for estrogen receptor (ER), progesterone receptor (PR), and HER2. Ordinal logistic regression was used to evaluate for differences in odds of increased RS categories (0-15, 16-25, 25) and increased pathologic tumor grade. All models were adjusted for age at diagnosis and nodal status. Results: A cohort of 381 HR+HER2- breast cancer patients were identified and classified as: nulliparous (n=149), PPBC1 (n=71), PPBC2 (n=92), and 10-years postpartum (n=69). In our study, the average RS for women in the PPBC1 group was 5.13 points higher than for nulliparous women (95% CI: (2.38, 7.88), p 0.001). In contrast, there was no statistically significant difference in the average RS when comparing between the nulliparous and PPBC2 group (p = 0.39) or the 10-years postpartum group (p = 0.065). Similarly, after adjusting for age and nodal status, the odds of having a higher RS category for the PPBC1 group were 2.44 times that of nulliparous women (95% CI: (1.41, 4.22), p 0.001), but there was no statistically significant difference in the odds of moving up one RS category between nulliparous women and the PPBC2 group (p = 0.60) or the 10-years postpartum group (p = 0.055). Regarding PR gene expression, the average score decreased by approximately half a point for all postpartum women compared to nulliparous women (p = 0.002 for PPBC1, 0.047 for PPBC2, 0.006 for 10-years postpartum). There was no statistically significant difference in ER or HER2 gene score between nulliparous and postpartum women. In terms of histological grade, the odds of increasing by one pathology grade unit for women with PPBC1 were 2.00 times that of women who are nulliparous (95% CI: (1.14, 3.52), p = 0.015). The odds were no different for women who are PPBC2 or 10-years postpartum compared to nulliparous women (p = 0.90, 0.76, respectively). Conclusions: In this cohort of patients, breast cancer diagnosed within five years postpartum is associated with significantly higher RS and histological grade compared to nulliparous young women, independent of nodal involvement. On the other hand, breast cancer diagnosed 5-10 years postpartum does not show this association. These findings support refining the definition of PPBC in ER+HER2- breast cancer as disease diagnosed within five years postpartum, based on its distinct molecular risk profile. Citation Format: S. Zhang, K. J. Queen, N. Duggirala, M. Lipsyc-Sharf, K. Hong, Y. Suresh, C. Hamilton, M. Pitta, N. Chien, E. La, P. Spellman, A. Bardia, N. S. Kapoor. Defining postpartum breast cancer based on 21-gene recurrence score abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-07-11.
Zhang et al. (Tue,) studied this question.