Currently, breast cancer related clinical decisions rely heavily on the presence of three receptors on the cell surface: HER2, ER and PR. This is very limited compared to other types of cancer where specific gene mutations have been identified that can predict the sensitivity to certain treatments. Investigating breast cancer biology by sequencing tumor DNA or cells that are circulating in the bloodstream can lead to new discoveries. This method is being adopted by a number of recent clinical trials, with the potential of unlocking new personalized breast cancer treatments.
The context
Personalized treatment relies on the availability of biomarkers that can be easily and frequently determined. This ensures up-to-date information on tumor biology and allows physicians to predict which treatments could be successful, monitor the progress when treatment has started, investigate why treatments stop working, and screen for relapse. So-called “liquid biopsies”, using a simple blood draw, could provide such data as individual tumor cells and DNA of destroyed cells are circulating in the bloodstream. Current technologies are capable of isolating and characterizing these individually, making it possible to study the tumor genetically.
The nuts and bolts
Circulating tumor cells (CTC) are rare cells that break away from a tumor and move into the blood stream. These cells are most likely responsible for cancer metastasis. Their existence was already reported in 1869, but we are just starting to harness their clinical value. Because they are so rare and quickly broken down, isolating them is challenging. Furthermore they are outnumbered by “normal” blood cells approximately a million to one. Novel techniques succeed in sorting out CTC using affinity for specific cell-surface molecules, or based on physicochemical properties that distinguish them such as size, density or surface charges.
The number of CTC has been found to predict progression free survival and overall survival of breast cancer patients. In the DETECT trial, it was found that counting CTC before and after chemotherapy can be used to monitor treatment benefit. However, other research showed that a simple cell count was not enough to be able to predict the benefit of switching to a different chemotherapy. Detailed molecular profiling of CTC, for example by next-generation sequencing, can reveal the mutations that are present in the tumor. These can lead to the discovery of new targets and have been shown to allow the prediction of treatment success.
In the turnover of tumor cells, their DNA is also released into the bloodstream. Similar to CTC, a higher quantity of circulating tumor DNA (ctDNA) is associated with a poorer prognosis. The detection of DNA in the blood isn’t based on physicochemical separation from the rest of the blood, but relies on the direct determination of its sequence. ctDNA has also been found to be a sensitive biomarker in breast cancer patients. Different trials are underway to investigate the effect of mutations in ctDNA on treatment success. For example, in the BOLERO-2 trial, patients with the mutation D538G in the ESR1 gene of ctDNA were found to get a 3.1-month progression free survival benefit from the addition of everolimus to their regimen. In the BELLE-2 trial, the PIK3CA gene in ctDNA predicted the efficacy of a combination treatment in postmenopausal women with endocrine resistant advanced breast cancer.
How will this help me?
Determining gene mutations in tumors already enables personalized treatment in different cancers and has therefore become standard clinical practice. In breast cancer, the first steps are being taken towards this kind of tailored treatment. Different trials are now working towards this goal, by including sequencing data from tumor cells and DNA present in the bloodstream in their results, coupled to clinical endpoints. Making use of such circulating biomarkers would allow physicians to diagnose and follow-up breast cancer patients frequently using a simple blood draw, thereby avoiding invasive procedures.
Source
The potential for liquid biopsies in the precision medical treatment of breast cancer – Cancer Biology & Medicine (2016).