Tracking Drug Resistance in Metastatic Breast Cancer

Cancer is a global issue, affecting more than one in three of us over the course of our lifetimes. More than this, it is a deeply personal disease for the families and individuals involved. The recent debate surrounding Angelina Jolie’s decision to undergo a double mastectomy (after finding she was a carrier of a mutant BRCA1 gene) highlights the passion evoked by this issue. 

The BRCA1 gene itself, and its role in inheritable breast cancer, was discovered in part by the Wellcome Trust Sanger Institute at the University of Cambridge. Cambridge continues to be at the forefront of breast cancer research, and now scientists at the University are uncovering the personal nature of cancer at the genetic level. Recent research even shows how non-invasive “liquid biopsies” can be used to track the development of drug resistance in cancers.

Advances in DNA sequencing technology are beginning to reveal a number of individual mutations within a tumour that make the disease as unique as the patient. Whats more, scientists are beginning to grasp that a tumour, far from being a lump of identical cells, is in fact a heterogenous mixture of different cancer phenotypes. This intratumour heterogeneity is true to the principals laid down by Charles Darwin more than 150 years ago – cancer evolves within the body in response to survival pressures.

As cancer grows and spreads in the body, it acquires new mutations conferring disease resistance, a more aggressive phenotype or even a small proliferative advantage over neighboring cells. Because cancer cells grow and multiply so rapidly, even when a chemotherapy kills 99% of a tumour, the 1% of chemo-resistant cells left will still be able to give rise to a new tumour mass. The kick is that this time, the whole tumour could be resistant to the original therapy.

The phenomenon of intratumour heterogeneity, and the ability of cancer cells to develop resistance to chemotherapy, led many to predict a long and hard battle to fully understand and treat the disease. Indeed, the potential benefits of personalised medicine are outstripped only by the challenges of realising them.

But recent discoveries have renewed optimism in personalised therapy. Previously, critics rightfully pointed out that in order to track tumours and offer targeted therapies, doctors would have to periodically take small samples of tumour for sequencing. These biopsies are costly and risky procedures, especially if tumours are deep in the body, or have spread to distant sites of metastasis. Furthermore, the intratumour heterogeneity means there is no guarantee of capturing the entirety of genetic diversity in a single biopsy.

New research has shown, however, that tumours release DNA into the bloodstream. Consequently, there’s been growing hope that analysis could provide a quick and simple ‘liquid biopsy’ to track the mutational state of a tumour. Researches at Cambridge have recently published compelling evidence (Murtaza et al. 2013) that circulating tumour DNA could take a snapshot of mutations in a patients breast cancer.

This is a potential game changer. For the first time, doctors could have a non-invasive means of not only tracking the progress of cancer treatment, but to specifically target it to the individual patient and to change tactics if resistance develops.

 

Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. 

Murtaza et al. 2013, Nature 

 

What they looked for. 

Researchers followed six patients with advanced metastatic forms of cancer. These patients donated regular blood samples during the course of their chemotherapy, the researchers extracted circulating DNA (ctDNA) from the liquid, non-cellular, portion of the blood. Samples were analysed using exome sequencing, a form of next generation genome sequencing which analysis a small fraction of the entirety of the human genome.

Researchers looked at 20,000 genes and compared how them in tumour and normal DNA. Crucially, because patients also donated blood before starting therapy, researchers could also compare tumour DNA from before, during and after treatment.

 

What they found. 

Each of the patients followed had a large number of mutations present in their DNA, associated with a cells transition into cancer. Other mutations, however, subtly changed in response to therapy, and this is what interested the researchers. They cross referenced mutations in response to therapy, with databases of known mutations involved in drug resistance and were able to make quite a few conclusions.

For example, one patient with breast cancer was treated with tamoxifen and herceptin, but after researchers found higher levels of mutant MED1 (a gene linked to tamoxifen resistance), they were then switched to a combination of lepatinib and capecitabine. Although this could have the potential to drastically increase a patients response to therapy, unfortunately this particular patient then developed a mutation in the GAS6 gene, linked to resistance to drugs similar to lepatinib.

 

The Future. 

This new research opens the door to using DNA as a reliable biomarker, this has long been talked about, but never shown to be useful in a clinical setting quite as succinctly as it has here. It is hoped that in the future, doctors will be able to tailor cancer treatment to an individuals unique set of genetic mutations. This treatment will then be able to evolve, as the patients tumour does, switching drugs as resistance evolves to ensure complete clearance of a patients tumour burden.

 

 

Written by John

John

I’m a recent Pharmacology Graduate from Glasgow, currently working toward a PhD in Cancer Research from the University of Cambridge. My main research aims are to understand the clonal dynamics in breast cancer, and how they are altered by therapy.

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