Incorporating Genetic Biomarkers into Predictive Models of Normal Tissue Toxicity

Abstract

There is considerable variation in the level of toxicity patients experience for a given dose of radiotherapy, which is associated with differences in underlying individual normal tissue radiosensitivity. A number of syndromes have a large effect on clinical radiosensitivity, but these are rare. Among non-syndromic patients, variation is less extreme, but equivalent to a ±20% variation in dose. Thus, if individual normal tissue radiosensitivity could be measured, it should be possible to optimise schedules for individual patients. Early investigations of in vitro cellular radiosensitivity supported a link with tissue response, but individual studies were equivocal. A lymphocyte apoptosis assay has potential, and is currently under prospective validation. The investigation of underlying genetic variation also has potential. Although early candidate gene studies were inconclusive, more recent genome-wide association studies are revealing definite associations between genotype and toxicity and highlighting the potential for future genetic testing. Genetic testing and individualised dose prescriptions could reduce toxicity in radiosensitive patients, and permit isotoxic dose escalation to increase local control in radioresistant individuals. The approach could improve outcomes for half the patients requiring radical radiotherapy. As a number of patient- and treatment-related factors also affect the risk of toxicity for a given dose, genetic testing data will need to be incorporated into models that combine patient, treatment and genetic data.

Differences in DNA Repair Capacity, Cell Death and Transcriptional Response after Irradiation between a Radiosensitive and a Radioresistant Cell Line

“…It is well known that, even when patients are treated with the same curative dose, normal tissue toxicity shows variability between patients, indicating inter-individual differences in the intrinsic radiosensitivity1345. The mechanisms influencing intrinsic radiosensitivity still remain unclear and many factors may contribute to it, but it has been suggested that up to 80% of this variability could have a genetic basis3678.…”

TNFSF10/TRAIL regulates human T4 effector memory lymphocyte radiosensitivity and predicts radiation-induced acute and subacute dermatitis

“…Measurements of radiosensitivity using only cell based assays have faced uncontrolled experimental variability [23]. Here we show an association between T4EM lymphocytes radiosensitivity and three SNPs within the TRAIL/TNFSF10- gene.…”

Optimal design and patient selection for interventional trials using radiogenomic biomarkers: A REQUITE and Radiogenomics consortium statement

“…With the availability of stereotactic radiotherapy and increasingly proton therapy, defined patient groups at risk for toxicity based on their genetic profile and not only on dosimetric parameters (11,12) may be considered for these modalities.…”