SEPTIN9 Gene Methylation Ratio as Follow-Up Biomarker in Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer

There are not reliable biomarkers for the assessment of tumor response to total neoadjuvant therapy (TNT) and the early detection of local regrowth or systemic relapse in patients with locally advanced rectal cancer (LARC). Our aim is to evaluate the utility of SEPTIN9 methylation ratio (SEPT9mr) for prediction and assessment of tumor response to TNT and for early diagnosis of local regrowth and systemic metastases in patients with LARC.

Patients with LARC undergoing TNT were prospectively included. SEPTIN9 methylation status gene in plasmatic cfDNA was determined by ddPCR and expressed as SEPT9mr at 3 times: pre-treatment, evaluation of tumor response and follow-up. Association between pre-treatment SEPT9mr, tumor response to TNT and metastatic risk was explored. Association between SEPT9mr variation between samples and tumor response to TNT, local regrowth and systemic metastases was also explored.

Sixty patients were included. Pre-treatment SEPT9mr (p = 0.004) significantly associated with tumor response to TNT, but not with metastatic risk during follow-up (p = 0.289). Variation of SEPT9mr during TNT did not significantly associate with tumor response to TNT (p = 0.130). Variation of SEPT9mr during follow-up did not associate with the development of local regrowth (p = 0.533) but significantly associated with the development of systemic metastases (p = 0.026).

Pre-treatment SEPT9mr can predict tumor response to TNT, but not the metastatic risk during follow-up. Variation of SEPT9mr between samples seems to be useful for early detection of systemic metastases during follow-up but not for evaluation of tumor response to TNT or detection of local regrowth.