Long-term outcomes of patients with HER2-positive invasive lobular carcinoma in the ALTTO trial (BIG 2-06/NCCTG N063D [Alliance]).

542 Background: Invasive lobular carcinoma (ILC) is the second most common histologic subtype of breast cancer (BC), representing 10–15% of cases. HER2 overexpression is rare in ILC, and there is limited data on the clinical characteristics and outcomes of patients (pts) with HER2-positive (HER2+) ILC treated with adjuvant trastuzumab. This study aims to investigate the prognostic value of ILC histology in this setting. Methods: ALTTO was a multicenter, randomized phase III trial evaluating the efficacy of trastuzumab, lapatinib, their sequence, or combination as adjuvant therapy in pts with HER2+ early BC. Pts with pure ILC or invasive BC of no special type (NST) who were enrolled in trastuzumab-containing arms of the ALTTO trial were included in this analysis. Central pathology review confirmed histologic subtype and was used for classification, while local pathology was used when centralized review was unavailable (USA and China). Survival outcomes, including disease-free survival (DFS), and overall survival (OS) were evaluated using Kaplan-Meier method and multivariate Cox regression adjusted for prognostic factors. Patterns of relapse were analyzed and compared across histological subtypes. Time to distant recurrence (TTDR) and time to CNS recurrence were summarized using cumulative incidence functions. Results: Among pts in the trastuzumab-containing arms (N = 6281), 84.4% underwent central pathology review, with a concordance rate of 67.4% for ILC diagnosis. A total of 61 pts with pure ILC (1.0% of the cohort) and 5981 pts with NST were included in the analysis. Pts with ILC were older (mean 54.8 vs. 50.9 years; p=0.002), more likely White (95.1% vs. 68.8%; p<0.001), and postmenopausal (72.1% vs. 56.3%; p=0.01). The proportion of pts with ILC (vs NST) was higher in Europe (67.2% vs 53.7%) and lower in Asia-Pacific (8.2% vs 30.6%) (p<0.001). A significantly higher proportion of ILC (vs NST) were hormone receptor-positive (80.3% vs. 57.4%; p<0.001), Grade 1-2 (51.7% vs. 39.3%; p=0.05). At a median follow-up of 9.8 years (IQR 6.9-10.0), no significant differences in DFS (hazard ratio [HR] 1.14, 95% CI 0.66-1.97; adjusted HR [aHR] 1.33,0.77–2.31), OS (HR 0.96, 0.43-2.15; aHR 1.09, 0.48–2.44), or TTDR (HR 1.67, 0.91–3.05) were observed between ILC and NST. Central nervous system (CNS) relapses were more frequent in ILC (13.6% at 10y, 95% CI 7.1–26.1%) than in NST (5.0%, 4.5–5.7%), with an HR of 3.14 (1.52–6.48) for CNS recurrences in ILC when compared to NST. Conclusions: Long-term outcomes were comparable between ILC and NST in HER2+ early BC treated with trastuzumab-containing regimens. The higher incidence of CNS metastases in ILC highlights its unique relapse pattern, necessitating further investigation to optimize treatment. High discordance between central and local pathology emphasizes the need for standardized histological review in trials and treatment decisions. Clinical trial information: NCT00490139 .