Background: Circulating tumor cells (CTCs) have repeatedly been shown to carry independent prognostic information in metastatic breast cancer (MBC). A CTC count of 5 cells per 7.5 mL blood is a generally accepted cut-off, where MBCs with <5 CTCs are classified as MBCindolent and ≥5 CTCs as MBCaggressive. Furthermore, several studies have shown that the presence of CTC clusters add prognostic information to CTC count alone. Invasive lobular carcinoma (ILC) is the second most common histological breast cancer (BC) type (~10%). The vast majority of all BCs (~80%) are classified as invasive ductal carcinoma (IDC). Many distinguishing clinicopathological and genomic features have been identified between these two types, but in spite of this, current clinical management strategies and treatments are similar and mainly based on studies dominated by IDCs.

The aim of this study was to explore potential differences in the distribution and prognostic significance of CTC count and CTC clusters in metastatic ILC vs. IDC, in a prospective observational study.

Patients and methods: Between April 2011 and June 2016, 139 women with newly diagnosed metastatic ILC (N=28) and IDC (N=111) were included. CTCs and CTC clusters were detected, using CellSearch technology (Menarini Silicon Biosystems), at baseline (BL) before first-line systemic therapy, and during the first 6 months of follow-up (FU). The primary endpoint was progression-free survival (PFS) and the secondary endpoint overall survival (OS). Median FU time was 49 (27-93) months.

Results: There was a highly significant (P<0.001) difference in the median CTC count between ILC (70, range 0-2598) and IDC (2, range 0-668) at BL, and presence of CTC clusters was also higher (36% vs. 18%, P=0.07). These differences between ILC and IDC persisted in the luminal A-like subgroup. The CTC count and CTC clusters declined in both ILC (median count 4, range 0-85; clusters: 4%) and IDC (median count 0, range 0-263; clusters: 12%) after 1 month of systemic treatment, but the decline was most pronounced in ILC. Seventy-nine percent of the ILCs and 46% of the IDCs were classified as MBCaggressive (CTC ≥5) at BL (P=0.003). The prognostic value of CTC ≥5 on PFS (HR 1.5, 95% CI 0.55-4.0, P=0.44) and OS (HR 2.4, 95% CI 0.71-8.3, P=0.16) in ILC was weak, whereas significant prognostic effects were seen in IDC (PFS: HR 1.7, 95% CI 1.2-2.6, P=0.007; OS: HR 2.1, 95% CI 1.3-3.3, P=0.002). With higher cut-offs the prognostic impact of CTC count on PFS/OS was significant also in ILC (CTC ≥20: HR 3.0, 95% CI 1.3-6.8, P=0.01 / HR 3.1, 95% CI 1.2-8.3, P=0.02) (CTC ≥80: HR 3.6, 95% CI 1.5-8.8, P=0.004 / HR 5.9, 95% CI 2.0-17.8, P=0.002) and the prognostic effect in IDC remained. The presence of ≥1 CTC cluster was a negative prognostic factor significantly associated with impaired survival in ILC (PFS: HR 4.6, 95% CI 1.7-12.4, P=0.003; OS: HR 4.9, 95% CI 1.7-13.8, P=0.003), whereas the effect was weaker in IDC (PFS: HR 1.2, 95% CI 0.69-2.0, P=0.55; OS: HR 1.9, 95% CI 1.1-3.3, P=0.02). First-line systemic treatment was similar in ILC vs. IDC (endocrine 46% vs. 39% and chemotherapy 54% vs. 61%) and the overall prognosis did not differ (PFS: HR 0.89, 95% CI 0.57-1.4, P=0.59; OS: HR 0.99, 95% CI 0.60-1.6, P=0.96).

Conclusions: In this study of metastatic ILC and IDC, the CTC count at BL was remarkably higher in ILCs and the presence of CTC clusters was also more common, in spite of the fact that no difference in prognosis was seen. The prognostic value of the generally accepted CTC cut-off (≥5) was clearly weaker and the presence of CTC clusters stronger in ILC vs. IDC. A higher cut-off might be more suitable in ILCs in order to better discriminate between MBCindolent and MBCaggressive forms, and CTC clusters could potentially add prognostic information.

Citation Format: Ulrik Christoffer Narbe, Pär-Ola Bendahl, Kristina Aaltonen, Mårten Fernö, Carina Forsare, Charlotte Levin Tykjær Jørgensen, Anna-Maria Larsson, Lisa Rydén. The distribution and prognostic significance of circulating tumor cells are different in invasive lobular carcinoma compared to invasive ductal carcinoma of the breast [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-01-04.