Almost 150 years ago, T.R. Ashworth first described the presence of epithelial cells in the blood of a woman with metastatic breast cancer, which were very similar in appearance to her primary tumour cells. As was to be discovered decades later, these so-called circulating tumour cells would help to improve diagnosis and increase the efficacy of cancer treatments.
The arrival of liquid biopsy, a fast and effective new technique to identify tumour mutations, represents a significant step forward in the fight against cancer. In an interview in the New York Times Dr Josep Baselga of the Memorial Sloan Kettering Cancer Center said that “liquid biopsy could change forever the way we follow up not only response to treatments but also the emergence of resistance, and down the line could even be used for really early diagnosis”.
In this regard, a study published in The Lancet Oncology suggested that liquid biopsy was capable of detecting tumours such as diffuse large B-cell lymphoma between three and five months before the onset of the first clinical symptoms of the recurrence of this cancer type. The trial, which was conducted on 126 patients, showed a positive predictive value of 88.2% (95% CI; 63.6-98.5) in detecting tumour recurrence.
Susan Arnold (Wikimedia)
As Giuseppe Curigliano from the European Society for Medical Oncology (ESMO) points out, cancer genome sequencing is already key to deciding which treatment to administer to each patient. According to Ivo Gut, CNAG [Spanish Genomic Analysis Centre] director, this technology “has evolved more than computers over the last ten years”. A better understanding of how tumour cell DNA changes is helping to promote precision medicine, but what happens with circulating tumour cells?
As Curigliano observes, liquid biopsy may overcome some of the drawbacks of traditional biopsy of the primary tumour, which, according to the researcher of the European Institute of Oncology in Milan, involves certain risks for patients. Tumour biopsy is a painful, time-consuming and costly procedure, whereas liquid biopsy could “capture” the entire heterogeneity of the tumour in a single sample and monitor genetic changes in real time.
This is an extremely important aspect, as genomic research has led to a significant shift of focus in medicine. Just a few days ago, scientists from the University of Oviedo and Hospital Clínic of Barcelona discovered that one in five cases of chronic lymphatic leukaemia is caused by mutations in the noncoding DNA of patients. This is the second time that tumour-causing mutations have been identified in these genomic regions, following research conducted in 2013 which found that changes to noncoding DNA led to the onset of melanoma in certain cases. This research into cancer-related recurrent genetic mutations in noncoding DNA once again revealed their heterogeneity. The group led by Dr Elías Campo and Dr Carlos López Otín further supported this finding, concluding that there were, on average, 3000 genetic mutations per patient that differentiated cancer cells from healthy cells.
This broad “genetic catalogue” underlines the need for clinical practice to rapidly progress towards personalised treatment based on the patient's unique DNA profile, rather than the tumour site. By assessing mutations in circulating tumour cells, liquid biopsy may speed up the identification of this vast heterogeneity. But in the words of Curigliano himself, this technique will not only help us to understand what happens in the primary tumour, but it will also increase our knowledge of the causes of metastasis.
The first centre in the world to trial liquid biopsy was the Vall d’Hebron Institute of Oncology (VHIO), which incorporated the pioneering BEAMing platform for the study of colorectal cancer. According to Dr Josep Tabernero, “a single blood sample could produce results in two or three days”, making it possible to determine RAS (KRAS and NAS) mutation status and thereby offer specific and personalised treatment.
The CORRECT study was conducted to assess the incorporation of this technology. Published by the VHIO in The Lancet Oncology, it further supported the usefulness of liquid biopsy in patients with metastatic colorectal cancer. The phase III clinical trial, which was conducted in more than 500 patients, found that liquid biopsy played a vital role in the choice of cancer treatment based on the genetic mutations of the individual patient. Using the BEAMing platform, Dr Josep Tabernero’s group demonstrated that many of these DNA mutations were not found in the primary tumour, but rather in the course of metastatic disease. In this regard, liquid biopsy may offer more information than traditional biopsy of the primary tumour, thereby facilitating personalised and more effective cancer therapies. The VHIO study is the first to use such a large cohort of patients, thus offering even more evidence of the clinical benefits of liquid biopsy than other trials.
Because of the good results obtained to date in various studies, this technology is already being used in many leading medical centres. One such centre is Hospital Universitario Fundación Jiménez Díaz in Madrid, which has been using ultrasensitive liquid biopsy in clinical practice since June. Thanks to the partnership between Merck Serono and Sysmex Inostics, this technique has been integrated to analyse RAS mutation status, thereby enabling treatments adapted to each individual metastatic colorectal cancer patient to be administered. In so doing, the hospital became the first medical centre in Madrid, and the second in the world, to apply liquid biopsy to personalise detection and cancer treatments based on the genetic profile of the patient's circulating tumour cells: cells discovered more than 150 years ago, which will act as a “decoy” in the battle against cancer.