Abstract SY23-01: Blood-borne tumor cell dissemination in cancer patients
Authors: Klaus Pantel, Stefan Werner
Journal: Cancer Research (2019)

Abstract Disseminated tumor cells (DTCs) can be found in the bone marrow (BM) of patients with various types of solid tumors including breast, colon and lung cancer. Because BM is a mesenchymal organ and carcinomas are derived from epithelial tissues, detection of epithelial intermediate filaments - keratins - is widely applied for specific detection of DTCs in BM or circulating tumor cells (CTCs) in blood of patients with carcinomas as the most frequent cancer types (1). The presence of DTCs in BM predicts the development of overt metastases both in the bone and other organs. For instance in breast cancer patients with localized disease, the presence of DTCs increased the risk of relapse and cancer-associated death, indicating that BM is an important distant site for detecting early hematogenous spread of carcinoma cells (2). Furthermore, the detection of DTCs in BM is a significant prognostic factor with respect to poor overall survival, breast cancer-specific survival, disease-free survival and distant-disease-free survival during a 10-year observation period (3). Besides breast cancer, the presence of DTCs in BM is also of prognostic relevance for patients with other epithelial malignancies such as prostate and lung cancer (4, 5). Likewise DTCs can be found in BM of colon cancer patients, although the formation of overt bone metastases in this cancer entity is a rare event (6). Thus, one can postulate that the BM is a hideout where DTCs may survive adjuvant therapy in a dormant state, and DTCs might be able to re-circulate to other distant sites where these cells find a better suited environment for metastatic outgrowth (e.g., liver or lungs in colon cancer (7). The detection of DTCs in BM is furthermore correlated to local relapse at the primary tumor site, a surprising finding that has been validated in experimental studies. This supports the provocative hypothesis that DTCs in the BM can re-circulate back to the primary tumor site to contribute to local relapse (8). In addition to improving patient diagnosis, DTC detection and characterization has provided important new information that helped to better understand the cascade of metastatic events. As such in a bone metastasis dormancy model it was shown that aberrant expression of vascular cell adhesion molecule 1 (VCAM-1) promotes the transition from indolent micro-metastasis to overt metastasis as regulators of progression from DTCs to bone metastases (9). Also clinical analysis of human invasive breast cancers revealed a strong correlation between PGC-1α expression in invasive cancer cells and the formation of distant metastases, supporting the finding that metabolic adaptation of DTCs is important for survival at the distant site (10). Importantly, a gene expression signature of early dissemination have been defined. By using the presence of DTC in BM to define breast cancer patients with early disseminated breast cancer, we identified in particular RAI2 as a novel metastasis-associated gene especially related to early occurring bone metastasis and chromosomal instability in ERα-positive breast tumors (11). More recently, single-cell sequencing have been applied to identify and trace the origin of DTCs in breast cancer. This study revealed a heterogeneous population of DTCs with specific DNA copy number aberrations (CNA) which is present in the BM of non-metastatic breast cancer patients. Evolutionary reconstruction analysis of bulk tumor and DTC genomes enabled the ordering of CNA events in molecular pseudo-time and traced the origin of the DTCs to either the main tumor clone, primary tumor subclones, or subclones in an axillary lymph node metastasis (12). Collectively, the detection and characterization of DTC in patients with cancer provides important information about the malignant progression of tumors. Moreover, DTC technologies significantly contributed to the understanding of minimal residual disease (MRD) in cancer patients that are otherwise free of clinically manifest metastases. Most cancer patients are treated with (neo)adjuvant therapy that is directed against MRD and this critical stage of cancer progression can be followed by DTC technology. In 2010, DTC detection in BM was approved along with the detection of tumor cells in blood (CTC) or distant non-regional lymph nodes by introducing a cM0(i+) class in the TNM staging system of breast cancer for patients with otherwise no clinical or radiographic evidence of distant metastases (13). Nevertheless, BM sampling represents an invasive procedure with residual risks for the patient and thus it is not integrated into the routine management of patients with solid tumors. For this reason, exploiting blood rather than BM as a source of, Liquid Biopsy“ has received enormous attentions over the past 10 years (14). Large-scale clinical studies in early breast cancer have shown that the detection of CTCs at primary diagnosis is significantly linked to subsequent metastatic relapse (15-17), and the persistence of CTCs detected years after adjuvant therapy represent MRD relevant to the patient's outcome (18). Thus, in future clinical trials CTC analysis may help to select and monitor efficient “post-adjuvant” therapies against MRD (19). CTC analyses have also helped to analyze the tumor biology behind the metastatic cascade and revealed the complex heterogeneity and plasticity of CTCs in cancer patients (20, 21). Besides the analysis of CTCs, liquid biopsies analytes include products released from tumors like DNA, RNA or extracellular vesicles which can provide interesting information on the evolution from MRD to overt metastasis (22, 23). However, viable total CTCs enables us to perform functional in vitro and in vivo studies (22). Although blood analyses can be easily integrated into routine clinical practice one should be aware that detection and molecular characterization of DTCs in metastasis-prone environment provides complementary information. BM has been introduced as Liquid Biopsy source approx. 30 years ago and documented already MHC downregulation on DTCs (24) as important immune escapes mechanisms that is now of utmost clinical importance in the exciting era of immune therapies in oncology. 1. K. Pantel, R. H. Brakenhoff, B. Brandt, Nat Rev Cancer 8, 329 (May, 2008).2. S. Braun et al., N Engl J Med 342, 525 (Feb 24, 2000). 3. S. Braun et al., N Engl J Med 353, 793 (Aug 25, 2005). 4. J. Kollermann et al., J Clin Oncol 26, 4928 (Oct 20, 2008). 5. K. Pantel et al., Lancet 347, 649 (Mar 9, 1996). 6. K. Flatmark et al., Clin Cancer Res 8, 444 (Feb, 2002). 7. K. Pantel, R. H. Brakenhoff, Nat Rev Cancer 4, 448 (Jun, 2004). 8. M. Y. Kim et al., Cell 139, 1315 (Dec 24, 2009). 9. X. Lu et al., Cancer Cell 20, 701 (Dec 13, 2011). 10. V. S. LeBleu et al., Nat Cell Biol 16, 992 (Oct, 2014). 11. S. Werner et al., Cancer Discov 5, 506 (May, 2015). 12. J. Demeulemeester et al., Genome Biol 17, 250 (Dec 9, 2016). 13. S. B. Edge, C. C. Compton, Ann Surg Oncol 17, 1471 (Jun, 2010). 14. K. Pantel, C. Alix-Panabieres, Trends Mol Med 16, 398 (Sep, 2010). 15. F. C. Bidard et al., J Natl Cancer Inst 110, 560 (Jun 1, 2018). 16. W. J. Janni et al., Clin Cancer Res 22, 2583 (May 15, 2016). 17. S. Riethdorf et al., Clin Cancer Res 23, 5384 (Sep 15, 2017). 18. E. Trapp et al., J Natl Cancer Inst (Oct 11, 2018). 19. K. Pantel, D. F. Hayes, Nat Rev Clin Oncol 15, 129 (Mar, 2018). 20. S. A. Joosse et al., Clin Chem 64, 1505 (Oct, 2018). 21. M. Yu et al., Science 345, 216 (Jul 11, 2014). 22. C. Alix-Panabieres, K. Pantel, Cancer Discov 6, 479 (May, 2016). 23. A. Bardelli, K. Pantel, Cancer Cell 31, 172 (Feb 13, 2017). 24. K. Pantel et al., Cancer Res 51, 4712 (Sep 1, 1991). Citation Format: Klaus Pantel, Stefan Werner. Blood-borne tumor cell dissemination in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY23-01.