ASCO 2016
Liquid biopsy may help guide treatment decisions for advanced solid tumours
Prof Philip Mack - University of California Davis, Davis, USA
On behalf of my co-investigators I am pleased to report a comprehensive analysis of next generation sequencing conducted in circulating tumour DNA from over 15,000 patients with advanced disease. To our knowledge this is the largest ever liquid biopsy study conducted to date. There has been growing interest and, indeed, a real need for improved comprehensive tumour genetic profiling that will allow us to guide patients towards appropriate targeted therapies based on the unique molecular make-up of their tumours. It’s been known for decades that advanced cancers shed tumour DNA into the bloodstream and this circulating tumour DNA or ctDNA harbours all of the same cancer-associated mutations of potential use in diagnostics, what we commonly term nowadays as precision therapeutics.
So the purpose of this study was to assess the accuracy and clinical utility of a highly sensitive next generation sequencing technique for cancer mutation testing conducted exclusively in blood draws. The study included 17,628 blood specimens from 15,191 patients with advanced cancer. A comprehensive, commercially available liquid biopsy assay known as Guardant360 was used to profile four of the major classes of gene alterations that can be detected in plasma in seventy different genes. Cases comprised fifty different cancer types in this study. The clinical utility and accuracy of this test was assessed for tumour alterations, particularly those detected at very low frequencies in the blood. The results were compared to publically available population scale sequencing projects, most notably the Cancer Genome Atlas.
So a major finding in this study was that ctDNA here, circulating tumour DNA mutation patterns, were highly concordant between tissue analysis, as reported by the TGCA, and plasma analysis as reported in this study. As an example, in this graphic we see the distribution and frequency of mutations in the EGFR gene. This gene is critically important to lung cancer patients because if they harbour one of the activating mutations that you see on this graphic then they are likely to have an exquisite response to one of the FDA approved EGFR tyrosine kinase inhibitors. So the upper part, the top part, of this graphic shows the distribution of these mutations as they are reported in the Cancer Genome Atlas. Marrying that, below the line is what is reported in our current study in plasma circulating tumour DNA. You can see the exact same activating mutations are present at very similar frequencies to what is observed in the tissue. The key difference, though, is that circulating tumour DNA additionally detected the presence of resistance alterations such as the T790M, shown [?? 3:10] here in the box, which are not present at the time of initial biopsy typically but are emergent in patients as they progress on therapy.
Other findings are shown here. Circulating tumour DNA analysis identified cancer mutations that were useful as biomarkers in 85% of the cases. In 49% of these these biomarkers were associated with FDA approved targeted drugs. For patients with tumours that have acquired resistance to an effective treatment ctDNA analysis detected the presence of resistance mutations that can be used to guide the choice of subsequent lines of therapy. The detection of key cancer mutations in plasma circulating tumour DNA occurred at the frequencies and distributions expected from large databases such as the cancer genome atlas. This remained true even for mutations detected at very low levels. In fact, 50% of all alterations were detected at ctDNA fractions of less than 0.4%. Anecdotally, alterations observed in circulating tumour DNA fractions were seen at frequencies as low as 0.6% responded to treatment, highlighting the importance of assay sensitivity.
The advantages of plasma testing are numerous when compared to tumour biopsies when tumour biopsies are not practical, available or feasible. For one thing it’s easy to do in any clinic, it’s a simple blood draw, and it avoids all the complications related to biopsies. It allows physicians to monitor changes in the genetics of the disease over time as it evolves. It can potentially identify mutations in metastatic lesions not observed in the original tumour biopsy and it provides an opportunity to identify treatment induced resistance mechanisms that are important for continuing therapy for patients who are progressing and allowing them to maintain control of their tumour. With that I thank you very much for your attention.
