They have developed a clinical genomic-adjusted radiation dose (GARD) model for individualizing radiotherapy based on their previously developed gene-expression radiosensitivity index.1,3 The clinically validated radiosensitivity index score is based on expression of 10 tumor genes: AR, c-Jun, STAT1, PKCβ, RelA, cABL, SUMO1, PAK2, HDAC1, and IRF1.1,3 The radiosensitivity index was validated for patients with breast, esophageal, head and neck, and rectal tumors.1,3,5

Using 8271 tumor samples, the researchers calculated GARD using radiosensitivity index scores and a statistical-extrapolation model to predict radiotherapeutic effect on tumors at 20 disease sites.3


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They then tested GARD associations with 538 radiotherapy patients’ outcomes using 5 clinical cohorts (the Erasmus Breast Cancer Cohort, The Cancer Genome Atlas Glioblastoma Patient Cohort, the Karolinska Breast Cancer Cohort, Moffitt Lung Cancer Cohort, Moffitt Pancreas Cancer Cohort).3

“GARD independently predicted clinical outcome in breast cancer, lung cancer, glioblastoma, and pancreatic cancer,” the Torres-Roca team reported.3

For example, for the Erasmus Breast Cancer Cohort, high GARD scores were associated with significantly longer 5-year distant-metastasis–free survival times (hazard ratio [HR] 2.11; 95% CI, 1.13-3.94; P =.018).3

Among patients with head and neck cancer, median GARD scores were higher in those with oropharyngeal tumors than other tumors (GARD 39.71 vs. 32.56; P =.042).3 That was consistent with better radiation therapy outcomes for patients with oropharyngeal cancer.3

“Precision medicine encompasses all therapeutic applications for patient care,” they noted.3 “With multidisciplinary care becoming standard for most patients with cancer, it is crucial that precision medicine is expanded beyond medical oncology. GARD potentially provides a clinically actionable framework that could allow the integration of biological differences into radiotherapy dose.”

GARD is the first tool that could allow radiation therapy planning to “depart from the uniform application of radiotherapy.”3

The authors called for genomically guided clinical trials of radiation therapy.

“Their results show that GARD is superior to radiosensitivity index alone in predicting the radiotherapy effect of a given dose,” noted Philip Poortmans, MD, of the Radboud University Medical Center, Nijmegen, the Netherlands, and coauthors, in a companion essay published alongside the paper from Torres-Roca’s team.1

But GARD is not yet ready for broad clinical use, and intratumor genetic heterogeneity might pose a challenge, Poortmans’ team warned.1 “We should be cautious not to generalize the current findings, especially in cases of unconventional radiotherapy (ie, hypofractionation, ablative radiotherapy, intraoperative radiotherapy, and particle therapy),” they wrote.1

Even if GARD does see adoption in clinical radiation therapy, real individualization of radiation oncology will still require consideration of clinical and pathological variables.1

References

1. Poortmans P, Kaidar-Person O, Span P. Radiation oncology enters the era of individualised medicine. Lancet Oncol. 2017;18(2):159-160. doi: 10.1016/S1470-2045(16)30660-X

2. Andreassen CN. Searching for genetic determinants of normal tissue radiosensitivity — are we on the right track? Radiother Oncol. 2010;97(1):1-8.

3. Scott JG, Berglund A, Schell MJ, et al. A genome-based model for adjusting radiotherapy dose (GARD): a retrospective, cohort-based study. Lancet Oncol. 2017;18(2):202-211. doi: 10.1016/S1470-2045(16)30648-9

4. Eschrich S, Zhang H, Zhao H, et al. Systems biology modeling of the radiation sensitivity network: a biomarker discovery platform. Int J Radiat Oncol Biol Phys. 2009;75(2):597-505.