Detection and clinical relevance of hematogenous tumor cell dissemination in patients with ductal carcinoma in situ

Abstract

Hematogenous tumor cell dissemination is a crucial step in systemic disease progression and predicts reduced clinical outcome in breast cancer patients. Only invasive cancers are assumed to shed tumor cells into the bloodstream and infiltrate lymph nodes. However, recent studies revealed that disseminated tumor cells (DTCs) may be detected in bone marrow (BM) of patients with preinvasive lesions, i.e., ductal carcinoma in situ (DCIS). The purpose of this analysis was to examine the incidence and clinical value of DTC detection in a large series of patients with pure DCIS. 404 patients treated for DCIS at the University Hospital Tuebingen, Germany were included into this analysis. BM was analyzed by immunocytochemistry (pancytokeratin antibody A45-B/B3) using ACIS system (Chromavision) according to the ISHAGE evaluation criteria. Sentinel nodes were analyzed in 316 patients by step sectioning and hematoxylin-eosin staining. DTCs were detected in 63 of 404 patients (16 %). No correlation was observed between BM status and tumor size, grading, histology or Van Nuys prognostic index. In two cases, metastatic spread into lymph nodes was observed; isolated tumor cells were found in one patient. After a median follow-up of 45 months (range 3-131 months), 3 % of BM positive patients died compared to 1 % of BM negative patients (p = 0.254). Relapse of any kind was observed in 7 % of patients with DTCs vs. 5 % of patients without DTCs (p = 0.644). The differences in overall (p = 0.088) and disease-free survival (p = 0.982) calculated by log-rank test were not statistically significant. Tumor cell dissemination may be detected in patients diagnosed with DCIS. Whether these cells disseminate from real preinvasive mammary lesions or represent the earliest step of microinvasion, remains unclear. A longer follow-up may be necessary to accurately assess clinical value of these cells in DCIS patients.

Molecular Markers as Prognostic Factors in DCIS and Small Invasive Breast Cancers

“…Interestingly, the frequency of DCIS with disseminated tumor cells (25.0%) did not significantly differ from that of invasive breast cancer (19.6 %; p = 0.57). Despite caution should be taken because of the very small sample size in our study, this observation supports previous results of early dissemination and systemic spread already in pre-invasive disease [18][19][20][21].…”

“…This result seems counterintuitive and sample size is again an issue here. But beside potential technical and statistical issues similar data have been obtained before [18][19][20][21]28] suggesting that profound but undetectable dissemination may occur very early. Our results also hint towards a better prognosis of luminal type tumors both in DCIS and invasive breast cancer.…”

Is invasion a necessary step for metastases in breast cancer?

“…Support for the notion that breast cancer dissemination can occur in pre-invasive stages of tumour progression comes from the consistent finding of circulating tumour cells in the peripheral blood (or in the bone marrow) of patients with DCIS. In six studies (range 19–404 patients), between 13 and 25% of DCIS patients were found to have circulating tumour cells [ 29 – 34 ]. It has been proposed that such cells derive from an occult (micro)-invasive lesion within DCIS.…”

Liquid Biopsy in Breast Cancer

“…Individual tumour cells reaching the blood vessels and their subsequent dissemination are important steps in the metastatic cascade. According to studies, pre-invasive lesions of the breast, such as ductal carcinoma in situ (DCIS), can be accompanied by tumour cell dissemination 2 , 18 , so that haematogenous tumour cell dissemination is considered an early event in the course of malignant disease. The CellSearch system can detect circulating tumour cells in 20 – 30% of patients with non-metastatic breast cancer 19 ( Table 2 ).…”

“…The so-called “Halsted Doctrine”, which viewed breast cancer as a local event with healing only possible by the most radical surgery, was replaced by the “Fischer Doctrine”, which regards even early stage breast cancer as a systemic disease 1 . Today we know that haematogenous dissemination already takes place in very early stages of breast cancer and that the circulating tumour cells (CTCs) will even be found in patients with pre-invasive breast lesions 2 . At the same time the hypothesis of metastatic inefficiency states that most of these cells are eliminated by the immune system or the mechanical shear forces in the blood 3 , 4 .…”