Tumor sequencing before and after neoadjuvant chemoradiotherapy in locally advanced rectal cancer: Genetic tumor characterization and clinical outcome.

Background And Purpose: Neoadjuvant chemoradiotherapy (NCRT) is a standard treatment option for locally advanced rectal cancer. However, there is still conflicting data about the genetic landscape and potential dynamics during and after NCRT. This study evaluated oncogenic driver mutations before NCRT and investigated corresponding resection samples after treatment.

Materials And Methods: In 17 patients the pre-therapeutic biopsy and in ten cases the related resection specimen were investigated by next-generation sequencing using a dedicated cancer panel (708 genes). Oncogenic driver mutations and tumor mutational burden (TMB) were compared pre- and post NCRT to evaluate stability of the genomic landscape. TMB and frequently detected driver mutations were correlated with outcome parameters.

Results: In our corresponding tumor samples before and after NCRT 95.2 % of the oncogenic driver mutations could be found in both specimens whereas one and one mutation were not detectable after NCRT. TMB decreased in all patients after neoadjuvant treatment.  ±  mutations and TMB ≥ 5 were associated with impaired outcome.

Conclusion: Most oncogenic driver mutations investigated persisted after neoadjuvant treatment. At the same time, we did not observe ascending TMB after treatment but decline. Thus, NCRT does not seem to induce a relevant number of new driver mutations or mutational burden. Genetic profiling implies the potential to support tumor-informed approaches and outcome estimation in future.