Genomic-adjusted radiation dose and outcomes in radiotherapy-treated locally advanced rectal cancer: a pooled multicohort analysis including the TIMING, OPRA, and CAO/ARO/AIO-94 prospective trials

Background. Treatment of locally advanced rectal cancer (LARC) increasingly varies in radiotherapy use, sequence, and intensity. Pretreatment biomarkers for the mismatch-repair-proficient majority remain limited: the biopsy-adapted Immunoscore predicts neoadjuvant response and recurrence risk, but no available biomarker estimates intrinsic tumor radiosensitivity or guides radiotherapy dose, use, or sequence. Genomic Adjusted Radiation Dose (GARD) combines the biopsy-derived Radiosensitivity Index (RSI) with the prescribed dose-fractionation schedule through the linear-quadratic model to estimate tumor-specific modeled radiation effect. We sought to evaluate whether pretreatment GARD is prognostic for outcomes in radiotherapy-treated LARC. Patients and methods. We performed a retrospective pooled analysis of 497 patients with LARC drawn from four prospective clinical trial and institutional cohorts; 335 patients (67%) were prospectively enrolled in clinical trials. The cohort spanned induction chemotherapy followed by chemoradiotherapy (CRT) (n=142), CRT followed by consolidation chemotherapy (n=120), and CRT without sequential chemotherapy (n=235). Pretreatment gene expression was measured by microarray or RNA sequencing and harmonized across platforms before GARD calculation. The primary endpoint was disease-free survival (DFS). GARD was evaluated continuously using cohort-stratified Cox regression and dichotomized at the outcome-blind pooled-cohort median of 19.3. Multivariable models adjusted for age, sex, and clinical stage. Results. Median follow-up was 5.3 years. Among 456 patients evaluable for DFS, 99 experienced an event. Higher GARD was associated with longer DFS as a continuous variable (hazard ratio [HR] per 1-unit increase, 0.92; 95% CI, 0.86-0.99; p=0.027) and at the median threshold (GARD >19.3 versus <19.3: HR, 0.62; 95% CI, 0.41-0.92; p=0.021). Five-year DFS was 81% versus 73%, and 10-year DFS was 80% versus 66%, respectively. GARD remained independently associated with DFS after adjustment for age, sex, and clinical stage (HR, 0.92; p=0.023). Overall survival (OS) was directionally consistent but not statistically significant (HR per 1-unit increase, 0.94; p=0.18). Among 445 patients with evaluable Neoadjuvant Rectal (NAR) scores, higher-GARD patients had lower median NAR scores (8.4 versus 15.0; p=0.004), were more frequently classified as low risk (34% versus 21%), and were less frequently classified as high risk (23% versus 31%). Among 460 patients evaluable for pathologic complete response (pCR), the pCR rate was numerically higher with higher GARD (22% versus 15%; odds ratio per 1-unit increase, 1.07; p=0.09). Conclusions. Pretreatment GARD, a biology-based model of tumor-specific radiation effect, stratified DFS independently of clinical stage and was associated with NAR-defined pathologic response across contemporary treatment sequences. These findings provide multicohort evidence of prognostic validity but do not establish prediction of radiotherapy benefit. Prospective GARD-stratified trials should test whether incorporating tumor radiosensitivity into decisions about radiotherapy use, dose, and sequence improves tumor control and organ preservation while reducing treatment-related morbidity.