Abstract PS4-08-10: Clinical characteristics and survival outcomes of Pleomorphic Lobular Carcinoma: a comparative analysis with classical ILC and IDC

Abstract Introduction: Pleomorphic lobular carcinoma (PLC) is an understudied, rare and aggressive form of invasive lobular carcinoma (ILC), distinct from both invasive ductal carcinoma (IDC) and classical ILC. Though histologically related to ILC, PLC clinically resembles high-grade IDC. We evaluated overall survival (OS) and disease-specific survival (DSS) in PLC relative to IDC and ILC, using robust causal inference methods to adjust for clinicopathologic and treatment differences. Methods: The SEER (Surveillance, Epidemiology, and End Results) 17 database was used to identify all adult female patients with primary invasive breast cancer between 2000 and 2022. Inverse probability of treatment weighting (IPTW) based on a multinomial propensity score was used to adjust for baseline differences in demographics (age, race, income, rurality), tumor characteristics (grade, AJCC stage, receptor subtype) and treatment variables (surgery, radiation, chemotherapy). Covariate balance was assessed using standardized mean differences (SMDs) via Love plots. Residual imbalances (SMDs >0.15) were addressed using multivariable Cox models for doubly robust estimation. Proportional hazards (PH) assumption was assessed via Schoenfeld residuals. If satisfied, IPTW-weighted Cox models were used; if violated, time-varying Cox models with log(time) interactions estimated dynamic hazard ratios. Analyses were conducted at all-time, 5- and 10-year follow-ups. Kaplan-Meier curves were used to visualize survival by subtype. LASSO-regularized logistic regression identified 5- and 10-year OS and DSS predictors among PLC patients. Statistical analysis was conducted in R using p < 0.05. Results: Of the 721,127 patients identified, those with PLC (n = 181) when compared with IDC (n = 631,198) and ILC (n = 75,653) presented with larger (PLC: 3.49 ± 2.57 cm, IDC: 2.06 ± 1.53 cm, ILC: 2.73 ± 1.94 cm), higher-grade (grade 3+; PLC: 51.4%, IDC: 35.3%, ILC: 8.1%) and more advanced-stage tumors (stage III; PLC: 23.2%, IDC: 9.8%, ILC: 14.2%). PLC tumors were less likely to be HR+ (ER+ PLC: 70.7%, IDC: 77.6%, ILC: 94.3%; PR+ PLC: 58.6%, IDC: 67.4%, ILC: 80.0%), less likely to be HER2- (PLC: 43.6%, IDC: 50%, ILC: 60%) and more frequently triple negative (PLC: 8.8%, IDC: 6.9%, ILC: 0.8%). PLC patients received more mastectomies (PLC: 55.2%, IDC: 37.9%, ILC: 48.7%) and chemotherapy (PLC: 56.9%, IDC: 43.4%, ILC: 31.9%) yet had comparatively worse unadjusted OS (PLC: 64.1%, IDC 75.9%, ILC: 74.2%) and DSS (PLC: 86.7%,IDC: 91.4%, ILC: 91.1%). PH assumptions were violated in PLC vs ILC comparisons at all-time and 10-year follow-ups. Time-varying models demonstrated a significant early survival advantage in ILC over PLC in both OS (HR = 0.12, 95% CI: 0.05-0.28, p < 0.0001) and DSS (HR = 0.05, 95% CI: 0.02-0.14, p < 0.0001), though this benefit diminished over time (OS HR(tt) = 1.58, 95% CI: 1.29-1.93, p < 0.0001; DSS HR(tt) = 1.88, 95% CI: 1.46-2.43, p < 0.0001). For IDC, a survival advantage was present against PLC in OS at all-time (HR: 0.72, 95% CI: 0.56-0.93, p < 0.05), 5-year (HR = 0.68, 95% CI: 0.49-0.95, p < 0.05) and 10-year follow-up (HR = 0.74, 95% CI: 0.55-0.98, p < 0.05). In the PLC-specific LASSO analysis, poorer outcomes were associated with larger tumors, more advanced stage tumors and identifying as Black, while improved outcomes were associated with lower grade, HR+/HER2+ status and receiving chemotherapy. Conclusion: PLC is associated with significantly worse survival outcomes compared to both IDC and ILC. While ILC confers an early survival benefit that diminishes over time, IDC maintains a consistent OS advantage. Our findings support PLC as an aggressive subtype of ILC warranting dedicated research to improve earlier detection and treatment. Citation Format: D. Walji, V. Giannakeas, D. W. Lim. Clinical characteristics and survival outcomes of Pleomorphic Lobular Carcinoma: a comparative analysis with classical ILC and IDC [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 PS4-08-10.