Patterns of central nervous system and leptomeningeal involvement in advanced breast cancer with invasive lobular histology: a large multicenter study with a focus on estrogen receptor-positive/HER2-negative disease.

Background

Invasive lobular carcinoma (ILC) is known to exhibit distinct metastatic patterns compared with carcinoma of no special type (NST); however, little is known about its specific propensity for central nervous system (CNS) and leptomeningeal (LM) involvement, particularly in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative subtype. PATIENTS AND

Methods

We leveraged a multicenter study of 1710 patients with advanced breast cancer (BC). We recorded site of first metastatic recurrence and occurrence/type of the first CNS event. The study endpoints were CNS-free survival, LM-free survival, and post-LM survival. The risk of LM as the first CNS event across histological types was evaluated using a competing-risk framework.

Results

Among 1587 patients with known tumor histology, 15.5% had ILC. Within the ER-positive/HER2-negative BC cohort (n = 669), 31.5% of patients developed a CNS event. ILC and NST were associated with similar metastatic CNS-free survival [hazard ratio (HR) 1.30, 95% confidence interval (CI) 0.95-1.77, P = 0.095]. In contrast, metastatic LM-free survival was significantly and independently shorter in ILC versus NST (multivariate analysis of LM events without concurrent brain metastases, adjusted HR 4.94, 95% CI 1.57-15.83, P = 0.006). Consistently, Fine-Gray competing-risk analysis confirmed a significantly higher risk of LM involvement as the first CNS event for ILC versus NST (adjusted subdistribution hazard ratio 5.07, 95% CI 1.57-16.41, P = 0.007). Among patients with ER-positive/HER2-negative BC and LM disease, ILC was associated with worse post-LM survival compared with NST (HR 2.79, 95% CI 1.03-4.17, P = 0.040). In patients with ILC presenting with extracranial metastatic disease, we observed similar LM-free survival between those treated with cyclin-dependent kinase 4 and 6 inhibitors and those who were not (P = 0.286).

Conclusions

In patients with ER-positive/HER2-negative advanced BC, ILC was independently associated with a higher cumulative incidence of LM as the first CNS event than NST. Patients with ILC who developed LM also experienced poorer post-LM survival. These findings highlight the need for heightened clinical awareness and support prospective studies evaluating earlier LM detection in this population.