Radiation Oncology Gets a Dose of Precision Medicine

For the first time in this era of precision medicine, physicians can optimize radiation therapy dosage based a patient’s tumor genomics.

The new genomic-adjusted radiation dose (GARD) technology, co-invented by Jacob Scott, MD, of Cleveland Clinic and Javier Torres-Roca, MD, of Moffitt Cancer Center, offers treatment teams a simple and reliable tool to match radiation dosage with a tumor’s molecular profile. It is currently being commercialized through a company founded by Torres-Roca called CvergenX.

“Radiation therapy has been one-size-fits-all when it comes to the dose of the radiation given,” says Scott, a physician-scientist in Cleveland Clinic’s Department of Translational Hematology and Oncology Research. “Radiation oncologists have made a lot of progress in shaping dosage—minimizing side effects and sparing healthy tissue—but the field has largely been left out of the genomics revolution sweeping through cancer care.”

GARD combines LQ and RSI

GARD represents the world’s first validated and scalable answer to this problem and offers radiation therapists an easy-to-interpret recommendation for radiation dosing, based on an individual patient’s genomic likelihood of response to treatment.

GARD’s scoring combines two well-validated algorithms—the linear-quadratic (LQ) model and the gene-expression based radiosensitivity index (RSI), developed by Dr. Torres-Roca and colleagues—when calculating the recommended dosage.

While the LQ model offers well-known clinical efficacy in identifying equivalent dosing strategies, it cannot account for an individual tumor’s genomic predisposition to respond to radiation. The RSI, however, evaluates expression levels of 10 different genes that have been found to affect a tumor’s response to radiation.

Combining information gleaned from a patient’s gene-expression and the LQ model results in a spectrum of GARD scoring, in which higher values correlate with higher likelihood of clinically relevant response to radiation therapy.

A framework for genomic-adjusted radiation dose (GARD)
(A) The left plot shows the proportion of patients in each radiotherapy dose group. On the right plot, GARD values for each individual patient are presented ranked from the highest to lowest value; each line represents an individual patient; colour relates to dose assigned. Nine patients in the cohort had a GARD higher than 100; these patients were assigned a GARD of 100. Pie charts show dose assignments for patients in GARD score groups: (B) high (89·41–100 percentile); (C) middle (30·41–89·4 percentile); and (D) low (0–30·4 percentile). GARD=genomic-adjusted radiation dose.
[Figure and legend republished with permission from Elsevier.]

The Lancet Oncology publication provides a detailed overview of testing GARD, which includes more than 8,200 primary tumor tissue samples from 20 disease sites in the Total Cancer Care Protocol. Additional testing included in The Lancet Oncology paper includes 263 samples from the Erasmus Breast Cancer Cohort, 77 from the Karolinska Breast Cancer Cohort, 60 from the Moffitt Lung Cancer Cohort, 40 from the Moffitt Pancreas Cancer Cohort and 98 from The Cancer Genome Atlas Glioblastoma Patient Cohort.

In these tests, GARD independently predicted clinical outcomes in breast cancer, lung cancer, glioblastoma and pancreatic cancer. Additionally, 5-year distant-metastasis-free survival was longer in patients of the Erasmus Breast Cancer Cohort whose GARD scores were higher than in those with low GARD values.

In short, test results offer a strong correlation between GARD scoring, which can be affected through changes in radiation dose, and clinical outcomes.

Long overdue

Targeted chemotherapies and immunotherapies are sweeping through cancer care, as researchers, drug developers and physicians seek new ways to treat the individual tumor, rather than the disease site.

As optimistic as many are about the future of this burgeoning field of precision (or personalized) medicine, about half of all cancer cures in the United States come from radiation therapy; only $1 is spent on radiation oncology research for every $20 spent on cancer drug studies.

Scott hopes GARD and other initiatives like it will pave the way for more funding and support to work on customizing radiation therapy using the same genomics tools available in the rest of the oncology landscape.

“As we bring radiation therapy into the era of precision medicine, we have an opportunity to make significant gains in this field that will help millions of patients,” says Scott.

Photo Credit: ©Russell Lee