A genome-based model for adjusting radiotherapy dose (GARD): a retrospective, cohort-based study

Abstract

Background: Despite its common use in cancer treatment, radiotherapy has not yet entered the era of precision medicine, and there have been no approaches to adjust dose based on biological differences between or within tumours. We aimed to assess whether a patient-specific molecular signature of radiation sensitivity could be used to identify the optimum radiotherapy dose.

Methods: We used the gene-expression-based radiation-sensitivity index and the linear quadratic model to derive the genomic-adjusted radiation dose (GARD). A high GARD value predicts for high therapeutic effect for radiotherapy; which we postulate would relate to clinical outcome. Using data from the prospective, observational Total Cancer Care (TCC) protocol, we calculated GARD for primary tumours from 20 disease sites treated using standard radiotherapy doses for each disease type. We also used multivariable Cox modelling to assess whether GARD was independently associated with clinical outcome in five clinical cohorts: Erasmus Breast Cancer Cohort (n=263); Karolinska Breast Cancer Cohort (n=77); Moffitt Lung Cancer Cohort (n=60); Moffitt Pancreas Cancer Cohort (n=40); and The Cancer Genome Atlas Glioblastoma Patient Cohort (n=98).

Findings: We calculated GARD for 8271 tissue samples from the TCC cohort. There was a wide range of GARD values (range 1·66-172·4) across the TCC cohort despite assignment of uniform radiotherapy doses within disease types. Median GARD values were lowest for gliomas and sarcomas and highest for cervical cancer and oropharyngeal head and neck cancer. There was a wide range of GARD values within tumour type groups. GARD independently predicted clinical outcome in breast cancer, lung cancer, glioblastoma, and pancreatic cancer. In the Erasmus Breast Cancer Cohort, 5-year distant-metastasis-free survival was longer in patients with high GARD values than in those with low GARD values (hazard ratio 2·11, 95% 1·13-3·94, p=0·018).

Interpretation: A GARD-based clinical model could allow the individualisation of radiotherapy dose to tumour radiosensitivity and could provide a framework to design genomically-guided clinical trials in radiation oncology.

Funding: None.

Conflict of interest statement

Declaration of interests

JGS and JFT-R are named inventors in a patent pending for systems for providing personalised radiation therapy. SAE and JFT-R are named inventors in patent number 8,660,801, patent number 8,665,598 and patent number 7,879,545 are related to radiosensitivity index. PJ reports receipt of personal fees from Novocure. SAE is a cofounder of Cvergenx and serves on the board and as an officer for the company. He holds stock and stock options in the Cvergenx. HLM serves on the board of directors for Cancer Genetics and on an advisory board for Kew Corporation. JFT-R reports stock in Cvergenx and has a patent issued for radiation sensitivity index with royalties paid to Cvergenx, and a patent pending for GARD.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. 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 2:. GARD score distribution and density within 70 Gy (A), 60 Gy (B), and 45 Gy (C) dose levels, by disease site

The red dot represents the median GARD value for each disease site at assigned dose levels. Colours in the plot correlate with the sample density. GARD=genomic-adjusted radiation dose. SCC=squamous cell carcinoma. OPX=oropharyngeal. IDC=invasive ductal carcinoma. TCC=transitional cell carcinoma. NMSC=non-melanoma skin cancer. RCC=renal cell carcinoma.

Figure 3:. GARD and distant-metastasis-free survival in the Erasmus Breast Cancer Cohort

(A) GARD values for each individual patient are presented ranked from the highest to lowest value; each line represents an individual patient and colour relates to radiotherapy dose received. The number of patients in each group and the GARD ranges are online (appendix p 4). (B) Kaplan-Meier plot for distant-metastasis-free survival comparing patients with high GARD (≥38·9; the 75th percentile) with patients with low GARD (

Figure 4:. A model for genomic-informed radiation dose in breast cancer

(A) The red line shows the physical radiotherapy dose required to meet the GARD threshold (GARD≥38·9) with increasing RSI. This curve is based on the radiotherapy effect calculated for distant metastasis (not local control) using the Erasmus Breast Cancer Cohort. (B) The probability of patients reaching the GARD threshold (GARD>38·9) in an unselected population as a function of radiotherapy dose. (C) Estimates of the potential therapeutic effect (HR for high versus low GARD subpopulations) of increased radiotherapy dose (the reference dose is 50 Gy). GARD=genomic-adjusted radiation dose. RSI=radiosensitivity index. HR=hazard ratio.