Novel Treatment-Specific Genetic Marker on the Horizon

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One of the areas of personalized medicine that has signaled a new era is the development of genetic signatures that can be used to select therapy that is likely to be effective in separate disease sites: for example, Oncotype DX for breast and colon cancer and MammaPrint for breast cancer. These are considered disease-specific signatures.

By contrast, until now, no treatment-specific genetic signatures have been available, but that is about to change, according to the physician who spearheaded development of the first radiation-specific genetic signature.

At the recent 2014 Annual Meeting of ASTRO, Personalized Medicine in Oncology caught up with Javier F. Torres-Roca, MD, a radiation oncologist at the Moffitt Cancer Center in Tampa, FL. Torres-Roca said, “Fifty percent of all cancer patients receive radiation as part of their cancer therapy, and thus the development of a radiation-specific signature is critical. We are the only group that has developed a radiation-specific gene expression signature. This 10-gene signature is a radiation therapy–specific biomarker that predicts response and outcome. This marker is not predictive with other treatments.�

The signature is called the radiosensitivity index (RSI, commercial name InterveneXRT) and consists of the following genes:
Oncogenes: cABL, P65/RelA
Inflammatory response: STAT1, IRF1
Transport/ubiquitination: SUMO1, PKC
Cell cycle: PAK2, HDAC, c-JUN, AR

“RSI-good or -low� patients are deemed radiosensitive, and those found to be “RSI-poor or -high� are considered radiation resistant when correlating the signature with outcomes such as overall survival, disease-free survival, locoregional recurrence, and response.

Torres-Roca said that there have been 4 publications on the development and initial validation of the radiation-specific signature. At the 2014 ASTRO meeting, 10 presentations and 1 panel discussion focused on the second phase of validation in outcomes with breast, lung, pancreatic, prostate, and brain cancer, as well as metastatic colorectal cancer. These abstracts (2463, 2224, 2615, 1246, 2649, 2899, 3633, 3916, 1420, 1031, and 2873) can be found at www.astro.org.

“We show that if patients are not receiving radiation therapy, there is no difference between resistant and sensitive patients [to a specific treatment]. But if they are undergoing radiation therapy, sensitive patients [according to the genetic signature] do better, and those who are nonsensitive have a worse outcome. We have tested outcomes that include overall survival in glioblastoma, relapse-free survival in breast cancer, locoregional recurrence in breast cancer and head and neck cancer, disease-free survival in lung cancer, response in metastatic colorectal cancer, response in rectal and esophageal cancer, and distant metastases in prostate cancer.�

The signature took 11 years to develop, Torres-Roca said. First the researchers trained the signature to predict cell survival after radiation in cancer lines. The final signature was tested in more than 15,000 tumor samples and correlated with clinical outcomes in 2000 samples across disease sites that are treated with radiation, he explained.
He believes the signature will be clinically actionable – showing that higher doses of radiation may be needed in resistant patients [according to the signature] and lower radiation doses in sensitive patients.

“If the test is done before treatment, it will be clinically actionable. You may be able to avoid radiotherapy if a patient is unlikely to benefit. Treating patients inappropriately is very expensive. There is a lot of imprecision in the decisions we make in radiation oncology. We need better tools, and this is one tool we can use in radiation oncology. This signature gives us the opportunity to optimize radiation delivery and dosing,� he said.

Torres-Roca and his colleague Steven Eschrich, PhD, also from Moffitt, have founded a company called CvergenX that holds the exclusive commercial license to the genetic signature.
A commercial assay based on the signature is being developed in a joint venture with CvergenX, the National Cancer Institute, Moffitt Cancer Center, and the Asan Medical Center in Korea.

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