Liquid Biopsy and Gene Signature to Guide Non-Operative Management of Rectal Cancer (NO-CUT Trial) (6° anno)

Rectal cancer (RC) constitutes approximately 30% of all colorectal cancers (CRC), thus contributing to the third cause of oncologic mortality in Western Countries. Surgical resection of the rectum following chemo-radiation therapy (CT-RT) is the mainstay of treatment for locally advanced tumors. For patients achieving clinical complete response after CT-RT, application of a non-operative management (NOM) with avoidance of mutilating surgery is emerging as a treatment option. However, in the absence of randomized controlled trials that are unlikely to be performed in this setting, NOM is not recommended as standard of care. Single-arm clinical trials accompanied by robust translational studies are expected to support this approach toward clinical practice. The project is based on the hypothesis that multidimensional genetic, epigenetic, and transcriptomic assessment in tumor tissue and plasma of locally advanced RC patients may discriminate those patients who can benefit from NOM. This can be accomplished by excluding those patients with residual disease by circulating tumor DNA or methylated epigenetic markers and/or those with tumor stromal signature associated with resistance to CT-RT. Project aims: to test as primary endpoint the performance of transcriptomic gene signature and dynamic of circulating genetic and epigenetic markers in predicting 2.5 year distant relapse-free survival in patients with locally advanced RC treated with CT-RT and NOM; secondary endpoints will include evaluation of patient-reported quality of life and association of the biomarkers with local tumor regrowth. In a prospective clinical study (NO-CUT Trial), 180 patients with locally advanced RC will receive XELOX induction polychemotherapy followed by pelvic radiation therapy and capecitabine and then will be re-staged by standard clinical and imaging procedures. Those patients achieving clinical complete or near complete response will be managed with NOM (NOM Cohort), while other patients will undergo standard surgery and follow-up (Surgery Cohort). In both cohorts, transcriptomic gene signature will be performed on a baseline tumor biopsy and longitudinal assessment of ctDNA and 6-MGP will be performed at baseline, after CT-RT, and during follow-up for 2.5 years or until relapse. Within this multidimensional biomarker assessment, we expect to identify patients best suited for NOM throug: a) validating or disprove the transcriptomic stromal gene signature for predicting objective response to CT-RT, and b) exploring the performance of ctDNA and 6-MGP for identifying patients at higher risk of relapse through survival analysis in both cohorts. We will innovatively adopt a multidimensional circulating and tissue biomarkers approach for identifying patients who can best safely be managed without surgery. This would lead to a step forward integration of personalized medicine into multimodal treatment of cancer.