Abstract Background: The 21-gene recurrence score (RS) is widely used to guide adjuvant chemotherapy decisions in hormone receptor-positive (HR+) HER2-negative (HER2-) early breast cancer (BC). However, in premenopausal women with node-positive disease, RS has limited utility in identifying low-risk individuals who may forgo chemotherapy. One understudied subgroup is postpartum BC (PPBC). PPBC is associated with higher rates of lymph node metastases, increased risk of distant recurrence, and worse overall prognosis, even after adjusting for traditional clinicopathologic factors. As such, PPBC, particularly in women with nodal involvement, may confound RS interpretation. We aimed to evaluate whether PPBC is associated with higher RS in premenopausal women with node-positive HR+HER2- BC compared to non-PPBC and nulliparous women, and if this impacted outcomes. Methods: We identified women aged ≤45 years with HR+ HER2- BC with node positive disease who underwent RS testing at a single academic institution between 2011 and 2024. Reproductive and clinicopathologic data were collected through medical record review. Patients were stratified into three groups: nulliparous, PPBC (diagnosis 5 years postpartum), and non-PPBC (≥5 years postpartum). Patients diagnosed with BC during pregnancy and patients with incomplete reproductive data were excluded. Multivariable linear regression was used to evaluate for differences in mean RS. Multivariable ordinal logistic regression was used to evaluate for differences in odds of increasing RS categories (0-15, 16-25, 25) between the groups. Time-to-event outcomes were analyzed using Kaplan-Meier survival estimates, and invasive disease-free survival (IDFS) was compared across groups using Cox proportional hazards regression models. Results: A cohort of 78 patients were included: nulliparous (n=27), PPBC (n=20), and non-PPBC (n=31). Compared to nulliparous women, patients with PPBC had a higher mean RS, with an average increase of 8.78 points (p=0.002). No difference in RS was observed between the non-PPBC group and nulliparous women (p = 0.63). Women in the PPBC group had 4.78 times the odds of being classified in a higher RS category compared to nulliparous women (p = 0.007), and 4.71 times the odds compared to nulliparous and non-PPBC groups combined (p = 0.003). No significant difference in odds of higher RS category was observed in the non-PPBC group compared to nulliparous women. Among all 78 patients, 46 (59.0%) received chemotherapy and this increased with RS category: 38.0% (RS 16), 57.1% (16-25), and 95.2% (25) (p=0.00022). Median follow-up time was 2.75 years (range: 0.115, 8.977, IQR=3.02), and there were 6 recurrences (7.7%). Five-year IDFS was 81.7% (0.608-1.00) in PPBC patients and 78.6% (0.544-1.00) in all others, with a non-significant trend toward lower recurrence risk in non-PPBC and nulliparous patients compared to PPBC (HR 0.47; 95% CI: 0.07-2.61; p=0.36). Among the subgroup of patients who did not receive chemotherapy (n=24), five-year IDFS was 66.7% (0.300-1.00) in the PPBC group versus 46.9% (0.117-1.00) in all other patients. Conclusions: In this cohort of young women with HR+HER2- node-positive BC, PPBC was associated with higher RS and RS category than BC in nulliparous women. Larger studies with longer follow-up will be needed to evaluate whether distinguishing PPBC from nulliparous and non-PPBC patients can refine RS interpretation in the node-positive setting and enhance its utility in identifying premenopausal patients with biologically low-risk disease who may safely forgo chemotherapy. Citation Format: S. Zhang, K. J. Queen, M. Lipsyc-Sharf, N. Duggirala, P. Spellman, A. Bardia, N. S. Kapoor. Postpartum breast cancer as a potential driver of increased 21-gene recurrence score (RS) and RS category for node-positive HR+/HER2- breast cancer 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 PS3-08-09.
Zhang et al. (Tue,) studied this question.