Tuesday, April 9, 2013

More On Circulating Tumor DNA

It seems that there is a significant amount of new work being done on evaluating cancers via circulating tumor cells and their DNA. Another paper in Nature states:

Cancers acquire resistance to systemic treatment as a result of clonal evolution and selection. Repeat biopsies to study genomic evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumour heterogeneity Recent studies have shown that genomic alterations in solid cancers can be characterized by massively parallel sequencing of circulating cell-free tumour DNA released from cancer cells into plasma, representing a non-invasive liquid biopsy. 

Here we report sequencing of cancer exomes in serial plasma samples to track genomic evolution of metastatic cancers in response to therapy. Six patients with advanced breast, ovarian and lung cancers were followed over 1–2 years. For each case, exome sequencing was performed on 2–5 plasma samples (19 in total) spanning multiple courses of treatment, at selected time points when the allele fraction of tumour mutations in plasma was high, allowing improved sensitivity. 

For two cases, synchronous biopsies were also analysed, confirming genome-wide representation of the tumour genome in plasma. Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance. ...treatment with gefitinib

These results establish proof of principle that exome-wide analysis of circulating tumour DNA could complement current invasive biopsy approaches to identify mutations associated with acquired drug resistance in advanced cancers. Serial analysis of cancer genomes in plasma constitutes a new paradigm for the study of clonal evolution in human cancers.

Cancer Research UK commented on the works as follows:

Scientists ... used traces of tumour DNA, known as circulating tumour DNA (ctDNA) found in cancer patients’ blood to follow the progress of the disease as it changed over time and developed resistance to chemotherapy treatments.  

They followed six patients with advanced breast, ovarian and lung cancers and took blood samples, which contained small amounts of tumour ctDNA, over one to two years.

By looking for changes in the tumour ctDNA before and after each course of treatment, they were able to identify which changes in the tumour’s DNA were linked to drug resistance following each treatment session.

Using this new method they were able to identify several changes linked to drug-resistance in response to chemotherapy drugs such as paclitaxel (taxol) which is used to treat ovarian, breast and lung cancers, tamoxifen which is used to treat oestrogen-positive breast cancers and transtuzumab (Herceptin) which is used to treat HER2 positive breast cancers.

And they hope this will help shed new light on how cancer tumours develop resistance to some of our most effective chemotherapy drugs as well as providing an alternative to current methods of collecting tumour DNA – by taking a sample direct from the tumour – a much more difficult and invasive procedure.

 As we noted in a previous note regarding the same set of procedures by others researchers this is a useful method to detect the progression of cancer.

However the following observations are of note:

1. Are these coming or going cells, namely are the cells on their way to a metastasis or the result of one.

2. Can we use these cells to determine the changes in DNA expression as the cells progress.

3. How effective a prognostic tool are these measurements.

4. What therapeutic methods can be applied now knowing this information.

Thus is this data of primary use or secondary. Notwithstanding its clinical use it does represent an excellent tool for genomic progression.


Murtaza M et al, Noninvasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA (2013) Nature.