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Abstract
Although luminal-type primary breast cancer can be efficiently treated, development of metastatic disease remains a significant clinical problem. We have previously shown that luminal-type circulating tumor cells (CTCs) co-expressing the tyrosine-kinase MET and CD47, a ligand involved in cancer cell evasion from macrophage scavenging, are able to initiate metastasis in xenografts. Here, we investigated the clinical relevance of MET-CD47 co-expression in 255 hormone receptor positive breast tumors by immunohistochemistry and found a 10.3- year mean overall-survival difference between MET-CD47 double-positive and double-negative patients (p<0.001) MET-CD47 co-expression defined a novel independent prognosticator for overall-survival by multivariate analysis (Cox proportional hazards model: HR: 4.1, p<0.002) and CD47 expression alone or in combination with MET was strongly associated with lymph node metastasis. Furthermore, flow cytometric analysis of metastatic patient blood revealed consistent presence of MET+CD47+ CTCs (range 0.8 - 33.3% of CTCs) and their frequency was associated with increased metastatic spread. Finally, primary uncultured CTCs with high MET+CD47+ content showed an enhanced capacity to initiate metastasis in mice. Detection and targeting of MET and CD47 may thus provide a rational basis for risk stratification and treatment of patients with luminal-type breast cancer.
Highlights
Breast cancer is the most frequent type of cancer in women and the second leading cause of women cancer mortality [1]
We have previously shown that luminal-type circulating tumor cells (CTCs) co-expressing the tyrosine-kinase MET and CD47, a ligand involved in cancer cell evasion from macrophage scavenging, are able to initiate metastasis in xenografts
MET positivity was associated with a decreased mean overallsurvival of 5.6 years, (p=0.001 by log-rank test, Cox proportional hazards model: hazard ratio (HR)=2.2, 95% confidence interval (CI)=1.3–3.6, p=0.002, Figure 1B and D, Table 2 and Supplementary Table 1) when compared to MET negative tumors
Summary
Breast cancer is the most frequent type of cancer in women and the second leading cause of women cancer mortality [1]. Comparison of large patient cohorts at the genomic level reveals increasing numbers of breast cancer molecular subtypes [2,3,4]. Luminal subtypes, which express the estrogen receptor (ER) and/or the progesterone receptor (PR) but not HER2, are the most frequent subtypes of breast cancer, representing more than 70% of patients [10]. Patients with luminal-type breast cancer generally have a good prognosis (between 75% and 86% overall 5-year relative survival, [11]), many patients still succumb to the disease due to its capacity to disseminate to distant organs even decades after the removal of the primary tumor [12]. Biomarkers able to detect patients at risk to undergo metastatic spread are urgently needed in order to develop early detection methods and to initiate preventive treatments for these patients, before the onset of deadly metastasis
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