Table 2.

Future of predictive tumor biomarkers in curative radiation oncology^*

Biological parameter	Examples of candidate biomarkers	Association with radioresistance or radiosensitivity	Potential intervention(s)	Current clinical status
Number of clonogenic tumor cells or CSCs	Cell surface markers such as CD44	Higher baseline number of clonogenic cells or CSCs correlates with radioresistance	Higher radiation dose or radiosensitizer for high CSC content	Tumor volume is a surrogate for CSC number and influences RT dosing in clinical practice
Accelerated tumor cell repopulation	EGFR expression	Accelerated repopulation of clonogenic tumor cells during RT causes radioresistance	Shortening of overall treatment time limits number of clonogenic cells that need to be sterilized by RT	HNSCC histology used as surrogate in clinical practice to guide accelerated fractionation schemes
Tumor sensitivity to RT fraction size	No candidate markers currently exist to predict α/β of individual tumors	Some tumor types are associated with high sensitivity to RT fraction size (low α/β of < 10 Gy)	Hypofractionation (>2 Gy daily fraction size)	Breast or prostate histology used as surrogate in clinical practice to guide hypo-fractionation schedules
Tumor hypoxia	PET/MRI-based imaging markers Gene expression signatures	Tumor hypoxia reduces radiation damage to DNA, thereby increasing radioresistance	Combination of RT with hypoxic radio-sensitizer or dose increase to hypoxic tumor regions	Not yet used in clinical practice
HPV status	HPV16 DNA or p16 expression	HPV infection causes radiosensitivity, likely through interfering with DNA repair	Treatment de-intensification	De-intensified treatment to reduce toxicity in HPV+ HNSCC in clinical trials
Intrinsic radiosensitivity	DSB repair gene mutations, gene expression signatures, repair foci (eg, γ-H2AX), ctDNA response	Variation in ability of tumor cells to cope with radiation damage may cause radiosensitivity or radioresistance	Treatment de-intensification or intensification, respectively	Not yet used in clinical practice
Tumor genotype	Mutations in oncogenes such as KRAS, BRAF, EGFR, etc.	Tumor mutation status may correlate with radiosensitivity or radioresistance	Treatment de-intensification or intensification, respectively	Not yet used in clinical practice

^*CSC = cancer stem cells; ctDNA = circulating tumor DNA; DSB = double-strand break; HNSCC = head and neck squamous cell carcinoma; HPV = human papilloma virus; RT = radiation therapy.