Genome-Adjusted Radiation Dosing Could Lead To Personalised Radiotherapy

Expression of radiosensitive genes may help to tailor radiotherapy for cancer patients

medwireNews: A genomic-adjusted radiation dose (GARD) could allow personalisation of radiotherapy, suggests research published in The Lancet Oncology.

“[A] central requirement for precision medicine in radiation oncology is the ability to inform radiation dose parameters to match individual tumour biology, thus delivering the right radiation dose for the right patient”, say Javier Torres-Roca, from Moffitt Cancer Center and Research Institute in Tampa, Florida, USA, and co-authors.

“GARD provides, to the best of our knowledge, the first opportunity to genomically inform radiation dose and our findings suggest it is a feasible approach to precision radiation oncology.”

The investigators used 8271 tissue samples collected from 20 tumour sites in radiotherapy-treated participants of the observational Total Cancer Care (TCC) protocol to test their hypothesis that GARD would relate to clinical outcome.

GARD was calculated using a previously validated radiosensitivity index score, based on 10 radiosensitive genes, and the linear quadratic model, which describes the biological response to radiation; a high GARD value suggests a strong therapeutic effect with radiotherapy, they explain.

Javier Torres-Roca et al report that patients showed a wide range of GARD values, from 1.66 to 172.4. In all, 30% of samples were assigned to the 45 Gy dose level, 59% to the 60 Gy dose level and 11% to the 70 Gy or more level.

But there was a “wide range” of GARD values within each uniform radiotherapy dose group, with the 45-Gy group showing GARD of 3.03 to 56.34 and the 60 Gy patients from 1.66 to 122.38, while those assigned to 70 Gy had a GARD range of 9.73 to 172.4.

Higher radiotherapy dose did not always translate to a better radiotherapy effect within a tumour population. “Thus highly radiosensitive patients (those with a low radiosensitivity index) assigned to 45 Gy had GARD values that were similar to some patients assigned to higher radiotherapy doses (60 or 70 Gy) but who were less radiosensitive”, the researchers explain.

Of note, patients with gliomas and sarcomas, who are frequently treated with 70 Gy, had the lowest median GARD values, whereas those with cervical cancer and oropharyngeal head and neck cancer, who usually receive 60 Gy, had the highest.

“GARD ranges are consistent with the clinical heterogeneity of radiotherapy therapeutic benefit”, the researchers write, with the scores for these individual tumour types reflecting radiotherapy outcomes previously found in clinical studies.

Modelling revealed that GARD significantly predicted longer distant metastasis-free survival in 263 patients in the Erasmus Breast Cancer Cohort, with a hazard ratio of 0.92 for the patients with a GARD value above the 75th centile versus those with a lower value. By contrast, other risk factors in the group, such as age, stage and tumour hormone receptor status, were not associated with this survival outcome.

Similarly, GARD was significantly linked to relapse-free survival in 77 patients included in the Karolinska Breast Cancer Cohort, to local disease control in 60 patients forming a Moffitt Lung Cancer Cohort, and to overall survival in both 98 patients in The Cancer Genome Atlas Glioblastoma Patient Cohort and 40 patients in the Moffitt Pancreas Cancer Cohort.

The authors of an accompanying comment congratulate the study investigators but say that while GARD has been shown to be superior to the radiosensitivity index for predicting the efficacy of a given radiotherapy dose, “[w]e should be cautious not to generalise the current findings, especially in cases of unconventional radiotherapy”, such as hypofractionation or intraoperative treatment.

“Before applying this model into daily clinical practice—by increasing the dose for more resistant tumours and lowering the dose for more sensitive tumours—further validation will definitely be required in independent subsets of patients for whom tumour material as well as clinical outcomes are available”, write Philip Poortmans, from Radbound University Medical Center in Nijmegen, the Netherlands, and team.

References

Scott JG, Berglund A, Schell MJ, et al. A genome-based model for adjusting radiotherapy dose (GARD): a retrospective, cohort-based study. Lancet Oncol; Advance online publication 16 December 2016. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30648-9

Poortmans P, Kaidar-Person O, Span P. Radiation oncology enters the era of individualised medicine. Lancet Oncol; Advance online publication 16 December 2016. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30660-X  

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