Prognostic significance and predictive value of circulating tumor cells in invasive lobular breast carcinoma - an exploratory analysis of the STIC CTC trial

In patients with metastatic breast cancer (MBC), ≥5 circulating tumor cells (CTC)/7.5mL of blood is a validated adverse prognostic marker. The STIC CTC phase III trial (N=778, HR+ HER2- MBC) showed that ≥5 CTC/7.5mL before treatment predicted greater benefit from first-line chemotherapy over endocrine therapy for progression-free (PFS) and overall survival (OS). This exploratory analysis examines these results by histological subtype, comparing invasive lobular carcinoma (ILC) and carcinoma of no special type (NST). Baseline CTC count (CellSearch®) and its impact on PFS and OS were compared between ILC (N=159) and NST (N=571). The survival benefit of chemotherapy in patients with high CTC counts was then re-evaluated separately for each subtype. Before treatment, ILC had significantly higher CTC counts than NST (median: 10 [Q1=2, Q3=40] vs. 1 [Q1=0, Q3=7]). ≥5 CTC/7.5mL was found in 64% (95%CI [56-71]) of ILC and 31% (95%CI [28-35]) of NST patients, correlating with shorter PFS and OS in both. However, ILC patients with ≥5 CTC/7.5mL saw no significant benefit from CTC-informed chemotherapy (PFS: HR=0.91 [0.55-1.52]; OS: HR=0.83 [0.46-1.52]). In contrast, NST patients with ≥5 CTC/7.5mL had markedly improved outcomes with chemotherapy (PFS: HR=0.54 [0.37-0.81]; OS: HR=0.37 [0.21-0.66]). ILC shed more CTCs than NST, likely due to biological differences. While the ≥5 CTC/7.5mL threshold remained a valid prognostic marker for both, it was predictive of chemotherapy benefit in NST, but not ILC. These findings highlight differences in biomarker utility between ILC and NST, affecting both threshold relevance and treatment response.