No abstract

An MRI-based prediction model of (near-)complete pathological response following CRT in rectal cancer patients, shows a high predictive performance in an external validation cohort. The clinically relevant features in the model make it an interesting tool for implementation of organ-preserving strategies in rectal cancer.

Overview and main research question of studies in radiation treatment planning of oesophageal cancer (Table 1), pancreas cancer (Table 2), liver cancer (Table 3), rectal cancer (Table 4), anal cancer (Table 5)

Moderate dose escalation with VMAT resulted in superior dose-volume parameters compared to 3D-CRT, translating into lower acute toxicity. Additionally, improved tumor response after VMAT up to 50 Gy might contribute to a higher percentage of patients achieving a complete response.

algorithms with false discovery rate (FDR) correction. These genomic findings were correlated with clinical data. Results: Of 341 pts in the MMC arm, 64 had tumor DNA available and 62 underwent successful WES. WES of the cisplatin arm is ongoing. Baseline characteristics and clinical outcomes did not differ significantly between MMC cases that did vs. did not undergo WES. Known cancer genes significantly mutated in the MMC arm included the PI3 kinase (PI3K) pathway members PIK3CA (29%, FDR qZ0.001) and PTEN (6.5%, qZ0.038); EP400 (18%, qZ0.020), a chromatin remodeling protein previously implicated in modulation of HPV oncogenicity; and FBXW7 (15%, qZ0.026), a ubiquitin ligase tumor suppressor also mutated in other squamous cell carcinomas. Median tumor mutational burden was 5.8 nonsynonymous mutations per megabase (min-max: 2.9-22.9). Chromosome 3q29 (harboring PIK3CA) was amplified in 50% of samples (q<0.001). EP400 mutations were associated with younger age at diagnosis (mean 45.5 y AE 4.8 vs. 58.6 y AE 10.6, pZ0.002); no recurrently mutated cancer genes were associated with T stage, N stage, or sex. On Cox multivariable analysis with T stage, N stage, and sex, FBXW7 mutations were associated with significantly inferior DFS (HR 2.47 [1.02-5.96], pZ0.045) and a trend towards inferior OS (HR 2.61 [0.97-7.04], pZ0.058). Conclusion: These results represent the most comprehensive genomic characterization of AC to date and, uniquely, are contextualized with clinical data from a phase III trial. Clinical-genomic analysis of the MMC arm of NRG/RTOG 98-11 revealed frequent alterations in the PI3K pathway and an association between EP400 mutations and younger age; moreover, FBXW7 mutations were associated with inferior outcomes. WES of the cisplatin arm is ongoing and will provide additional power to detect genomic events and clinical associations. These hypothesis-generating results suggest that profiling clinical trial specimens with modern sequencing-based approaches may help advance genomically-informed, precision oncology approaches for pts treated with CRT.