The Invisible Revolution

Andre Goy, MD

Editor-in-Chief of

Oncology & Biotech News

Chairman and Director Lymphoma Division Chief John Theurer Cancer Center at HackensackUMC Chief Science Officer and Director of Research and Innovation Regional Cancer Care Associates Professor of Medicine, Georgetown University

In hematology, including in lymphoma, circulating clonal cells are part of the disease, including in Hodgkin lymphoma, as we showed recently.¹ Circulating tumor cells (CTCs) in hematology help us for diagnostic purposes, but also to evaluate response as a tracer of depth of remission either by flow negative complete remission (CR) in chronic lymphocytic leukemia or molecular CR in lymphomas or leukemia, which likely will become the next endpoint in most lymphoproliferative disorders.

There is now also clear evidence of shed naked clonal DNA representative of the tumor that can be used for the same purpose and predict early recurrence. A liquid biopsy, or blood sample, can also provide the genetic landscape of all cancerous lesions (primary and metastases), as well as offering the opportunity to systematically track genomic evolution.

The first description of CTCs was made in 1869, but more recent significant technical steps forward have dramatically helped our ability to detect and isolate those cells. CTCs have now been documented in epithelial tumors, particularly in breast,² colon,³ prostate,⁴ and lung cancers, among others.

CTCs in peripheral blood originate from solid tumors and are involved in the process of hematogenous metastatic spread to distant sites for the establishment of secondary foci of disease. They have been associated with outcome reflecting tumor burden and invasiveness of the disease. More recently, studies are going beyond detection and enumeration, exploring the CTCs as a means to better understand the mechanisms of tumorigenesis, invasion, metastasis, and the value of CTC characterization for prognosis and tailoring of treatment.⁵

CTCs can allow for early detection of recurrence but could obviously be a precious tool for cancer screening far beyond standard screening technology that is now routinely used. CTCs, which are relatively rare and require sensitive collection and enrichment technology^,6 provide information at both the genetic and cellular level. However, cell-free tumor DNA is emerging as an effective alternative to CTCs, with the benefits of easier collection and analysis.

An example of clinical implementation of CTCs in breast cancer from a large multicenter study was recently reported in Lancet Oncology.⁷ Interestingly, a detection of at least one CTC (65% of the patient population) impacted progression-free survival (PFS). However, when they increased the threshold to a CTC count of 5 per 7.5 mL or higher at baseline, this became a significant predictor for both PFS and overall survival. In addition, the changes on treatment after 6 to 8 weeks had significant impact on outcome. Finally, there were strong correlations between the burden of CTCs and performance status, tumor burden, and bone and liver metastases. CTCs were much better than conventional tumors markers (CEA and CA-15.3) at baseline and during therapy to predict outcome.

One of the most promising aspects of CTCs and the emergence of modern CTC technologies is enabling serial assessments to be undertaken at multiple time points along a patient’s cancer journey, offering new capabilities for pharmacodynamic, prognostic, predictive, and intermediate endpoint biomarker studies. Additional validation is needed, but CTCs seem to reflect the original tumor heterogeneity. Technology looking at ex vivo growth for potential drug screening is being developed,⁸ though I believe the ability to look at dynamic changes in vivo while a patient receives a novel therapy, for example, might be more relevant and useful to detect response or resistance. Given the difficulties encountered from a regulatory standpoint, as well as practical and logistical issues when one tries to add correlative studies in clinical trials, the impact CTCs could have and will have is truly amazing. I regularly write in this column about the need to push forward and embrace precision medicine in oncology. There is no doubt that CTCs as liquid biopsies will help fill a big piece of the puzzle to help in this endeavor!

References

1. Gharbaran R, Park J, Kim C, Goy A, Suh KS. Circulating tumor cells in Hodgkin’s lymphoma - a review of the spread of HL tumor cells or their putative precursors by lymphatic and hematogenous means, and their prognostic significance. Crit Rev Oncol Hematol. 2014;89(3):404-417.
2. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351(8):781-791.
3. Sastre J, Maestro ML, Puente J, et al. Circulating tumor cells in colorectal cancer: correlation with clinical and pathological variables. Ann Oncol. 2008;19(5):935-938.
4. Schilling D, Todenhöfer T, Hennenlotter J, et al. Isolated, disseminated and circulating tumour cells in prostate cancer [published online July 10, 2012]. Nat Rev Urol. doi:10.1038/nrurol.2012.136.
5. Krebs MG, Metcalf RL, Carter L, et al. Molecular analysis of circulating tumour cells-biology and biomarkers. Nat Rev Clin Oncol. 2014;11(3):129-144.
6. Alix-Panabières C, Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer. 2014;14(9):623-631.
7. Bidard FC, Peeters DJ, Fehm T, et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol. 2014;15(4):406-414.
8. Alderton GK. Therapy: using CTCs to test drug sensitivity. Nat Rev Cancer. 2014;14(9):576.