TORONTO, November 3, 2022 – In recent years, the ‘Wait and Watch’ (W&W) approach has been an alternative to surgery for locally advanced rectal cancer (LARC) patients after neoadjuvant chemoradiotherapy (nCRT). The W&W approach aims to prevent unessential surgery and to improve patient’s quality of life. A point of consideration for the W&W approach is that the recurrence risk of patients who are non-pathologic complete response (non-pCR) might increase. The existence of residual tumor cells in non-pCR patients may lead to local recurrence or even distant metastasis without surgical intervention under a W&W care approach. A recent prospective study published in the Journal of Clinical Chemistry, led by the Shanghai Fudan University Cancer Center and Geneseeq Technology Inc., demonstrated the clinical utility of cell-free DNA 5’-end motif profile in the prediction of pCR in LARC patients undergoing nCRT treatment.

This study recruited 103 LARC patients who received nCRT at the Fudan University Shanghai Cancer Center from February 2016, to October 2017. The treatment response of the patients was evaluated using pCR status and pathological or MRI tumor regression grade (mrTRG). Plasma samples were collected at baseline (T1), before the 15th (T2), before the 25th (T3) fractions of nCRT and after nCRT (T4). The extracted cell-free DNAs (cfDNAs) were subjected to targeted deep sequencing of 422 cancer-related genes at an average depth of 4000X, and cfDNA 5’-end motif profiles were extracted to construct an elastic-net logistic regression model to predict non-pCR status before surgery.

Using cross-validation, the constructed model based on the 5’-end motif profile alone showed a high AUC of 0.90 (95%CI: 0.89-0.91). The combination of the 5’-end motif and mrTRG further improves the model’s prediction power, achieving an AUC of 0.92 (95%CI: 0.90-1.00). cfDNA detection and mrTRG detection are two investigated methods that have been used for distinguishing pCR from non-pCR patients. cfDNA detection alone had a high specificity and a low sensitivity while mrTRG1 detection had a high sensitivity with low specificity. Here the combination model based on the combination of the 5’-end motif and mrTRG showed greatly improved sensitivity and specificity compared to cfDNA detection or mrTRG detection alone. Furthermore, the models based on the 5′-end motif profile alone or in combination with mrTRG consistently demonstrated good predictive ability for patients without detectable cfDNA mutations (AUC 0.94, 95% CI, 0.93–0.95; AUC 0.95, 95% CI, 0.94–0.96).

“The combination model using 5’-end motif and mrTRG showed promising performance for predicting pCR in different cohorts, which can be of great value to improve disease outcomes and quality of life for LARC patients.”, says Dr. Hua Bao, author, and director of Geneseeq Research Institute.