“Liquid biopsies” for early detection of therapy resistance

Custom-tailored therapies targeting specific structures such as HER2, EGFR or BRAF have substantially prolonged the survival of cancer patients with metastatic disease. Unfortunately, an initially successful therapy is often followed by a relapse of the disease after a few months only, which can be explained by the following two underlying mechanisms: on the one hand, due to the genetic heterogeneity found in many types of cancer, it is assumed that resistant tumor cells are already present in many patients at the time of therapeutic intervention; on the other hand, the administered drugs result in a selection of tumor cell clones that have developed de novo mutations favorable for tumor cell survival. Monitoring of genetic alterations in the course of systemic cancer disease at close intervals could thus help in recognizing the development of resistance at an early stage and in selecting the most appropriate therapy for each patient. Blood-based analytical methods would seem an appropriate tool for such genetic treatment monitoring, given that blood samples, in contrast to tissue biopsies, can be collected repeatedly without much effort and without exposing the patient to unnecessary risks. Together with our partners, we are planning to make use of this principle in a European research project on lung cancer to detect resistance to therapy at an early stage by molecular analysis of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA).

Publications

1. Polzer B, Klein CA. Metastasis awakening: the challenges of targeting minimal residual cancer. Nat Med. 2013 Mar; 19 (3): 274-5. doi: 10.1038/nm.3121.
2. Fischer JC, Niederacher D, Topp SA, Honisch E, Schumacher S, Schmitz N, Zacarias Föhrding L, Vay C, Hoffmann I, Kasprowicz NS, Hepp PG, Mohrmann S, Nitz U, Stresemann A, Krahn T, Henze T, Griebsch E, Raba K, Rox JM, Wenzel F, Sproll C, Janni W, Fehm T, Klein CA, Knoefel WT, Stoecklein NH. Diagnostic leukapheresis enables reliable detection of circulating tumor cells of nonmetastatic cancer patients. Proc Natl Acad Sci U S A. 2013 Oct 8; 110 (41): 16580-5. doi: 10.1073/pnas.1313594110. Epub 2013 Sep 24.
3. Klein CA. Selection and adaptation during metastatic cancer progression. Nature. 2013 Sep 19; 501 (7467): 365-72. doi: 10.1038/nature12628.