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Burgeoning Radiogenomics Efforts Aim to Improve Cancer Therapy, Reduce Toxicities


NEW ORLEANS (GenomeWeb) – At the annual meeting of the American Association for Cancer Research in New Orleans on Tuesday, Icahn School of Medicine Professor Barry Rosenstein and University of Manchester Professor Catharine West presented work they've done in the relatively young field of radiogenomics: using cancer patients' genomic information to improve radiotherapy outcomes.

There is a large amount of clinical variability observed in response to radiotherapy, Rosenstein said, and the theory some researchers have is that the variance in phenotype can be explained in some part by the variation in genotype. Rosenstein and his colleagues focus on the complications of radiotherapy rather than its efficacy because the therapy produces high cure rates, but can also cause severe complications that can have an adverse impact on quality of life.

One goal of the radiogenomics field is to perform genome-wide association studies to identify SNPs that could affect the outcome of radiotherapy and then develop assays capable of predicting radiation injuries, Rosenstein said. Researchers are aiming to learn which molecular pathways are responsible for these toxicities.

"Once we have this sort of information, we may be able to develop agents to mitigate those effects," Rosenstein said, adding that for years, "we thought people who developed adverse effects did so randomly, sort of bad luck." If there was a test that could help predict adverse effects, he said, "it's actionable information" that could "improve the therapy index." Clinicians could seek to do a different treatment or modify the dose of radiation.

SNP genotyping could allow patients to be stratified by genetic risk. And whole-genome analysis avoids the need for a priori assumptions of which genes are conferring susceptibility for adverse effects from radiotherapy. As part of the Radiogenomics Consortium (RGC) — established in 2009 by Rosenstein, West, and their colleagues — nearly 200 researchers at 114 institutions in 26 countries are now performing GWAS studies and pooling their data to perform meta-analyses to identify SNPs that could be responsible for adverse response.

The studies the consortium has already done have filtered through millions of SNPs and have identified eight so far that may have some bearing on toxic response to radiotherapy — these have been confirmed in multiple cohorts and have genome-wide significance. Rosenstein added that as additional studies are performed, he believes they will identify further SNPs.

The most surprising thing they found, he said, was that the SNPs they identified had no obvious connection to radiation response, but rather all play a role in the function of the organ in which damage has occurred.

And there are other questions the consortium would like to answer, according to Manchester's West. For example, does a risk SNP that's applicable to the pelvis also affect toxicity in risk in the head and neck? And, importantly, does an increased genetic predisposition to developing cancer increase a patient's sensitivity to radiotherapy, and therefore potentially to adverse effects?

On this last question, West believes the answer is no. This may be counterintuitive — after all, exposure to radiation increases the risk of breast and prostate cancer, she said, and both prostate and breast cancer patients are more radiosensitive because of the effects of DNA damage on cellular response. So, it would be reasonable to think that high genetic predisposition to cancer might cause a patient to have more radiotherapy toxicity.

As part of their efforts, West and her colleagues genotyped 1,160 breast cancer patients using Illumina CytoSNP12 genotyping and imputed the results using a 1000 Genomes Project panel. In all, they found 90 breast cancer risk SNPs, but when they compared this data to actual toxic events from radiotherapy, they found no association between high polygenic predisposition to breast cancer and increased risk of toxicity. An identical study for prostate cancer yielded 75 predisposition risk SNPs, and again, no association between polygenic risk and toxicity.

Rosenstein noted there are several RGC analyses in the works, possibly adding another 6,000 cases or more to the cases already studied. And some researchers, including West, are also participating in an EU consortium called REQUITE: Validating Predictive Models and Biomarkers of Radiotherapy Toxicity to Reduce Side-Effects and Improve Quality of Life in Cancer Survivors, which is three years into a multi-center observational cohort study of breast, prostate, and lung cancer. The researchers involved are validating toxicity SNPs discovered in other studies and are searching for more. They're about to genotype another 4,000 to 5,000 patients, Rosenstein said.

Another important study is the DOD Prostate Cancer Research Program, which has enrolled up to about 7,000 subjects. That analysis will be particularly powerful as the researchers already have GWAS genotyping information and detailed clinical information for all the subjects. That team plans to develop predictive models for toxicity, he added.

The research may also soon find its way into the clinic. Through a Small Business Innovation Research grant, the NCI has helped the RGC team up with a biotech company called L2 Diagnostics — the partners hope to create a kit or low-cost assay to be used by clinicians and labs to predict a patient's response to radiotherapy toxicity, Rosenstein said. He added that they're also working with the US Food and Drug Administration to make such a diagnostic available in the clinic within five years.