Evaluation of cfDNA as a Marker of Response in Rectal Cancer

Evaluation of cfDNA as a Marker of Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

A pathological complete response (pCR) after surgery occurs in approximately 20% of rectal cancer patients submitted to neoadjuvant chemotherapy, with apparent survival benefit. This group could, potentially, be spared the morbidity of surgery.

The diversified response to neoadjuvant chemotherapy (nCRT) amongst tumors suggests a complex relationship between tumor biology and response possibly due to a number of genetic or molecular pathways that might regulate chemoradiosensitivity.

Accumulating evidence indicated that circulating cell-free nucleic acids can be a promising biomarker of response, in liquid biopsy, for rectal cancer. The concentration of baseline plasma cell-free DNA (cfDNA) appears significantly higher in responders compared to non-responders.

The objective of this study is to investigate the potential role of cfDNA as a marker of pCR (or partial response) to nCRT as well as a marker of outcomes (overall survival and disease-free survival).

The investigators are conducting a prospective, observational, cohort, non-randomized study of consecutive patients with locally advanced rectal cancer submitted to nCRT, followed by surgical excision 6-12 weeks later. Patients are assigned to groups according to their pathological response to nCRT. A total of 20 patients with complete pathological response, 50 partial response and 50 non-responders will be selected over a year and followed for another year. Participants will be observed and examined during the entire course of treatment and the follow-up period.

Serial analysis of cfDNA through liquid biopsies will be performed in consecutive patients at specific time points (pre-nCRT, post-nCRT and postoperative week 1), incorporating analysis of concentration, dimension of DNA fragments, % of mutation frequency (CIN, APC, p53, MSI, KRAS, BRAF, EGFR, cKIT) and next-generation sequencing of tumour biopsy and surgical specimens.

This study will serve as the feasibility of a larger, comparative study.

Study Overview

• Status: Completed
• Conditions: Cancer of Rectum
• Intervention / Treatment: Diagnostic test: Analysis of cfDNA

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Marina Morais, MD; Phone Number: +351910918588; Email: morais1000@gmail.com

Study Locations

• Portugal
  • Porto
    • Matosinhos, Porto, Portugal, 4464-513
      • Hospital Pedro Hispano

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients aged over 18 years old, ECOG 0-2
2. High-risk patients with biopsy proven rectal adenocarcinoma who will undergo long-course chemoradiotherapy and who are potentially eligible for curative surgery
3. Patients who can fully understand the content of the informed consent form and sign it upon their own opinion
4. Patients who can coordinate with the researchers to undergo the long-term post-treatment rechecks and follow-up

Exclusion Criteria:

1. Patient has any underlying or current medical condition, which would interfere with the evaluation of the patient (e.g., end-stage liver disease, pulmonary hypertension, systemic lupus erythematosus etc.).
2. Patient has severe mental illness.
3. Patient has any other conditions, which would interfere with the evaluation of the subject.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: pCR	Diagnostic test: Analysis of cfDNA; Analysis of cfDNA through liquid biopsy
Experimental: Partial responders	Diagnostic test: Analysis of cfDNA; Analysis of cfDNA through liquid biopsy
Active Comparator: Non-responders	Diagnostic test: Analysis of cfDNA; Analysis of cfDNA through liquid biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ryan tumor regression grade system (number of patients with complete/partial/no response)	Tumour pathological response, on surgical specimen, to neoadjuvant chemoradiotherapy	Through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of participants with 1 and 2-year disease free recurrence	1 and 2 years

Collaborators and Investigators

• Sponsor: Hospital Pedro Hispano
• Collaborators: Diogo Melo Pinto, MD, Hospital Pedro Hispano; Telma Fonseca, MD, Centro Hospitalar de São João; Silvestre Carneiro, PhD, Centro Hospitalar de São João; Isabel Prieto, PhD, Hospital La Paz, Madrid

Study record dates

Study Major Dates

• Study Start (Actual): November 18, 2019
• Primary Completion (Actual): April 30, 2021
• Study Completion (Actual): December 30, 2021

Study Registration Dates

• First Submitted: March 9, 2020
• First Submitted That Met QC Criteria: March 20, 2020
• First Posted (Actual): March 24, 2020

Study Record Updates

• Last Update Posted (Actual): May 19, 2023
• Last Update Submitted That Met QC Criteria: May 17, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: rectal cancer; neoadjuvant therapy; cfDNA
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms
• Other Study ID Numbers: 85/19/56C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: since the beginning, for 2 years
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No