HER2-Positive Circulating Tumor Cells in Breast Cancer

Abstract

PurposeCirculating Tumor Cells (CTCs) detection and phenotyping are currently evaluated in Breast Cancer (BC). Tumor cell dissemination has been suggested to occur early in BC progression. To interrogate dissemination in BC, we studied CTCs and HER2 expression on CTCs across the spectrum of BC staging.MethodsSpiking experiments with 6 BC cell lines were performed and blood samples from healthy women and women with BC were analyzed for HER2-positive CTCs using the CellSearch®.ResultsBased on BC cell lines experiments, HER2-positive CTCs were defined as CTCs with HER2 immunofluoresence intensity that was at least 2.5 times higher than the background. No HER2-positive CTC was detected in 42 women without BC (95% confidence interval (CI) 0–8.4%) whereas 4.1% (95%CI 1.4–11.4%) of 73 patients with ductal/lobular carcinoma in situ (DCIS/LCIS) had 1 HER2-positive CTC/22.5 mL, 7.9%, (95%CI 4.1–14.9%) of 101 women with non metastatic (M0) BC had ≥1 HER2-positive CTC/22.5 mL (median 1 cell, range 1–3 cells) and 35.9% (95%CI 22.7–51.9%) of 39 patients with metastatic BC had ≥1 HER2-positive CTC/7.5 mL (median 1.5 cells, range 1–42 cells). In CTC-positive women with DCIS/LCIS or M0 BC, HER2-positive CTCs were more commonly detected in HER2-positive (5 of 5 women) than HER2-negative BC (5 of 12 women) (p = 0.03).ConclusionHER2-positive CTCs were detected in DCIS/LCIS or M0 BC irrespective of the primary tumor HER2 status. Nevertheless, their presence was more common in women with HER2-positive disease. Monitoring of HER2 expression on CTCs might be useful in trials with anti-HER2 therapies.

Minimal Residual Disease and Circulating Tumor Cells in Breast Cancer

“…In this study, pretreatment detection of CTCs was confi rmed as an indepen dent predictor for both disease-free survival and overall survival [56]. Several other investigators have detected CTCs by CellSearch® in 9% to 38% of patients with early BC without reporting survival data [57][58][59].…”

“…Because of the availability of anti-HER2 agents, HER2 expression was studied on DTCs [71][72][73] and CTCs [33,42,55,59,66,[74][75][76][77][78] (Table 2) and was correlated with HER2 expression on the primary tumor. In most studies, HER2 expression on DTCs/CTCs is more prevalent in women with HER2-positive BC than in women with HER2-negative BC in both non-metastatic and metastatic settings.…”

Circulating Tumour Cells: Implications and Methods of Detection

“…Metastatic breast cancer patients have been reported to have a range of 0 to a few thousand CTCs per 1-10 mL of blood (Flores et al, 2010;Talasaz et al, 2009) , compared to early stage breast cancers which from the limited publications to date as well as results from our own laboratory, report a range of 0 to less than 10 CTCs per 7-20 mL of blood (Ignatiadis et al, 2011;Lang et al, 2009;Shaw et al, 2011). A major obstacle is obtaining a sufficient number of CTCs, void of contaminating white blood cells, for downstream purposes such as genome, transcriptome or proteome analysis.…”

“…cases, apoptotic Aktas et al, 2009;Fehm et al, 2010;Ignatiadis et al, 2011;Wikman et al, 2008). These are not exclusive characteristics however, and a great degree of phenotypic heterogeneity exists within this population of cells.…”

The Promise of Circulating Tumor Cells for Precision Cancer Therapy

“…This has led to multicenter trials investigating whether these discordant patients still benefit from HER2-specific therapies [136,137]. For example, the ongoing DETECT III study is enrolling patients with metastatic breast cancer treated with up to three chemotherapy lines for metastatic disease who are found to have HER2 + CTCs (HER2 status of primary tumor and metastatic lesions must be negative) and randomizing them to standard therapy (chemotherapy or endocrine therapy) versus standard therapy plus lapatinib, a dual TKI that interrupts the HER2/neu and EGFR pathways [138].…”