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Tryptophan Catabolism and Response to Therapy in Locally Advanced Rectal Cancer (LARC) Patients.

ABSTRACT: In locally advanced rectal cancer patients (LARC), preoperative chemoradiation improves local control and sphincter preservation. The response rate to treatment varies substantially between 20 and 30%, and it is an important prognostic factor. Indeed, nonresponsive patients are subjected to higher rates of local and distant metastases, and worse survival compared to patients with complete response. In the search of predictive biomarkers for response prediction to therapy in LARC patients, we found increased plasma tryptophan levels in nonresponsive patients. On the basis of plasma levels of 5-hydroxy-tryptophan and kynurenine, the activities of tryptophan 5-hydroxylase 1 (TPH1) and indoleamine-2,3-dioxygenases 1 (IDO1)/tryptophan-2,3-dioxygenase (TDO2) have been obtained and data have been correlated with gene expression profiles. We demonstrated that TDO2 overexpression in nonresponsive patients correlates with kynurenine plasma levels. Finally, through the gene expression and targeted metabolomic analysis in paired healthy mucosa-rectal cancer tumor samples, we evaluated the impact of tryptophan catabolism at tissue level in responsive and nonresponsive patients.

SUBMITTER: Crotti S

PROVIDER: S-EPMC7593679 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Tryptophan Catabolism and Response to Therapy in Locally Advanced Rectal Cancer (LARC) Patients.

Crotti Sara S Fraccaro Alessandra A Bedin Chiara C Bertazzo Antonella A Di Marco Valerio V Pucciarelli Salvatore S Agostini Marco M

Frontiers in oncology 20201015

In locally advanced rectal cancer patients (LARC), preoperative chemoradiation improves local control and sphincter preservation. The response rate to treatment varies substantially between 20 and 30%, and it is an important prognostic factor. Indeed, nonresponsive patients are subjected to higher rates of local and distant metastases, and worse survival compared to patients with complete response. In the search of predictive biomarkers for response prediction to therapy in LARC patients, we fou ...[more]

PMID: 33178611

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Project description:ImportanceTreatment of locally advanced rectal (LARC) cancer involves chemoradiation, surgery, and chemotherapy. The concept of total neoadjuvant therapy (TNT), in which chemoradiation and chemotherapy are administered prior to surgery, has been developed to optimize delivery of effective systemic therapy aimed at micrometastases.ObjectiveTo compare the traditional approach of preoperative chemoradiation (chemoRT) followed by postoperative adjuvant chemotherapy with the more recent TNT approach for LARC.Design, setting, and participantsA retrospective cohort analysis using Memorial Sloan Kettering Cancer Center (MSK) records from 2009 to 2015 was carried out. A total of 811 patients who presented with LARC (T3/4 or node-positive) were identified.ExposuresOf the 811 patients, 320 received chemoRT with planned adjuvant chemotherapy and 308 received TNT (induction fluorouracil- and oxaliplatin-based chemotherapy followed by chemoRT).Main outcomes and measuresTreatment and outcome data for the 2 cohorts were compared. Dosing and completion of prescribed chemotherapy were assessed on the subset of patients who received all therapy at MSK.ResultsOf the 628 patients overall, 373 (59%) were men and 255 (41%) were women, with a mean (SD) age of 56.7 (12.9) years. Of the 308 patients in the TNT cohort, 181 (49%) were men and 127 (49%) were women. Of the 320 patients in the chemoRT with planned adjuvant chemotherapy cohort, 192 (60%) were men and 128 (40%) were women. Patients in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with planned adjuvant chemotherapy cohort. The complete response (CR) rate, including both pathologic CR (pCR) in those who underwent surgery and sustained clinical CR (cCR) for at least 12 months posttreatment in those who did not undergo surgery, was 36% in the TNT cohort compared with 21% in the chemoRT with planned adjuvant chemotherapy cohort.Conclusions and relevanceOur findings provide additional support for the National Comprehensive Cancer Network (NCCN) guidelines that categorize TNT as a viable treatment strategy for rectal cancer. Our data suggest that TNT facilitates delivery of planned systemic therapy. Long-term follow-up will determine if this finding translates into improved survival. In addition, given its high CR rate, TNT may facilitate nonoperative treatment strategies aimed at organ preservation.

Dataset Information

Tryptophan Catabolism and Response to Therapy in Locally Advanced Rectal Cancer (LARC) Patients.

Publications

Tryptophan Catabolism and Response to Therapy in Locally Advanced Rectal Cancer (LARC) Patients.

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