Callum Rakhit

2016 AFPGR Participant
Circulating DNA Predicts Patient Response to Treatment in Lung Cancer
About Callum

Callum Rakhit is a research student working towards completion of his doctoral degree in the MRC Toxicology Unit. Callum is supervised by Professor Catrin Pritchard and Dr. Miguel Martins.

About My Research

Cancer is responsible for approximately 8.2 million deaths worldwide per year, constituting around 15% of all human mortality. Lung cancer incidence doubled between 1975 and 2005, and this trend for increasing incidence over time is expected to continue into the future. There is, therefore, a pressing need to improve methods involved in the prevention, detection and treatment of cancer.

Cancer is a heterogeneous disease of the genome characterised by changes in the composition, expression and regulation of DNA and its downstream products that lead to uncontrolled cellular proliferation. Lung cancer is the most common form of the disease, arising primarily from mutations that occur throughout the ageing process and in response to environmental factors such as smoking or air pollution. Patients with lung cancer typically have a broad range of genetic alterations driving their disease, meaning treatments need to be carefully tailored to the context of an individual’s genetic background to be effective. Generally this is done by sampling a subsection of a patient’s tumour through biopsy, a technique that can be restrained by tumour accessibility and the inherent invasiveness of the method. The ability to accurately and sensitively detect cancer causing changes in key genomic regions non-invasively through circulating cell-free plasma DNA (cfDNA) is revolutionising the possibilities of both the early detection and personalised treatment of cancer.

Using a sensitive and high-throughput technique known as Next Generation Sequencing (NGS) we can elucidate the composition of numerous key genomic areas involved in driving lung cancer from patient cfDNA. By coupling NGS of cfDNA with a clinical trial we aimed to find factors that could predict how patients would respond to treatment based solely on their baseline, pre-treatment, cfDNA profile. The trial compared treatment with a single agent (docetaxel) versus a combination treatment (docetaxel plus the heat shock protein 90 inhibitor ganetespib) in 301 individuals.

Research Findings

Factors prognostic of survival as well as patient populations more responsive to combination therapy were identified, based solely on cfDNA samples taken prior to treatment.

Patients with “high” cfDNA concentrations had significantly lower overall survival rates than patients with “low” cfDNA levels. The difference in survival between high and low level cfDNA groups was maintained regardless of whether patients were treated with combination therapy or single agent.

The total number of mutations a patient possessed was predictive of their response to treatment. Patients with a “high” number of mutations had an improved overall survival with the combination treatment versus single agent.

Patients mutant for the TP53 gene had significantly shorter survival with single agent treatment but not with combination treatment, suggesting a role for this gene in predicting response to treatment.

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