The influence of removal of primary tumor on incidence and phenotype of circulating tumor cells in primary breast cancer

Abstract

Recent studies have shown that the detection of circulating tumor cells (CTC) pre and postoperatively in the peripheral blood of primary breast cancer patients may be an indicator for poor survival. This study aimed to investigate the influence of removal of the primary tumor on incidence and phenotype of circulating tumor cells in primary breast cancer. 209 primary breast cancer patients could be included into this analysis. Blood sampling was performed both pre and postoperatively. The blood specimens were immunomagnetically enriched using AdnaTest BreastCancerSelect within 4 h after blood withdrawal, followed by RNA isolation and subsequent gene expression analysis by reverse transcription and multiplex PCR using AdnaTest BreastCancerDetect. Three breast cancer-associated tumor markers and two hormone receptor genes were amplified: GA733-2, Muc-1, Her-2, ER, PR. In addition, bone marrow (BM) status was intraoperatively determined. Forty-three of 209 patients (21%) had pre and/or postoperatively circulating tumor cells. The positivity rates after surgery were higher but did not differ significantly (12% pre and 16% postoperatively, P = 0.264). Disseminated tumor cells in BM were seen in 32 of 209 cases (15%). Patients with positive BM status had significantly higher CTC positivity rates both pre and postoperatively compared to those with negative BM status. The most common CTC phenotype was triple negative (24 patients) followed by HER2+/ER-/PR- subtype (10) and ER and/or PR positive (9). Interestingly, 41 of 43 primary tumors (95%) were ER and PR positive. Removal of the primary tumor did not alter the phenotype of CTC. Surgery does not significantly influence the tumor cell load in the blood stream. CTC phenotype before and after the surgery generally remains identical but may differ from that of the primary tumor.

Dormancy in breast cancer

“…We and others previously reported a discrepancy between cancer cells from the primary tumor and those in secondary sites, such as blood and bone marrow, especially with regard to HER2 and ER status. 15,[62][63][64][65] HER2 gene amplification can be acquired during disease progression, even if the primary tumor was HER2-negative at the beginning of treatment. 66 However, patients with HER2-negative tumors but HER2-positive MRD are not eligible for HER2-based treatment.…”

“…67 Inversely, MRD cells are generally ER-negative and progesterone receptornegative, despite originating from a hormone receptorpositive tumor. 15,68 This might be relevant to clinicians when selecting patients for targeted or endocrine therapy. In a cohort of 88 patients with ER-positive primary tumors who presented with DTC in their bone marrow, only 14% had ER-positive DTC.…”

“…13,14 Nonetheless, approximately one-third of patients fail to clear tumor cells from the blood following removal of primary tumor. 15,16 Only a small fraction of CTC may be viable and able to enter secondary sites by mechanical entrapment or active migration through the endothelial cell layer. [17][18][19][20] Factors supporting extravasation are highly heterogeneous, including platelets; leucocytes; macrophages and factors secreted by them; selectins and their ligands expressed on endothelial cells and tumor cells, respectively; integrins; and fibrin deposition.…”

Prognostic value of circulating tumor cells in metastatic breast cancer: a systemic review and meta-analysis

“…In a retrospective study of 203 MBC patients, Munzone et al [36] found that CTCs in MBC patients most commonly had the luminal-A/luminal-B HER2(-) phenotype. In contrast, Banys et al [37] found that the most common CTC phenotype was triple negative and that the primary tumors of all CTCpositive patients were luminal [32]. Other studies did not indicate a significant correlation between the presence of CTCs and various breast cancer molecular subtypes [15].…”

Klinische Relevanz zirkulierender Mammakarzinomzellen

“…Dies erklärt möglicherweise die mangelnde Eliminierung von ZTZ durch neoadjuvante und/oder adjuvante Systemtherapien. In vielen Untersuchungen konnte gezeigt werden, dass trotz positiven Hormonrezeptorstatus des Primärtu-mors ZTZ meistens hormonrezeptornegativ sind [1,3]. Im Gegensatz dazu kann der Nachweis von HER2 im Verlauf der MRD positiv sein, obwohl der Primärtu-mor HER2-negativ war.…”