A Prospective Study Utilizing Circulating Cell Free DNA (cfDNA) Use in the Detection of RAS Mutations in Patients With Advanced Colorectal Cancer.

Summary

Colorectal cancer remains the commonest cancer among men, and third commonest among women in Saudi Arabia . Presentation with metastatic disease occurs in almost one third of patients , with 5-year survival decreasing significantly from 90% in stage 1 to 14% once the disease is metastatic . There is enthusiasm in the potential for liquid biopsies to provide easily accessible genetic biomarkers for mutational cancer characterization . Epidermal growth factor receptor (EGFR) monoclonal antibodies are widely used in the treatment of advanced colorectal cancer that do not harbor RAS mutations (RAS wild type). Hence genotyping of oncogenic RAS mutations is essential prior to the initiation of systemic therapy for such patients as the presence of these mutations predict resistance to EGFR targeted antibodies such as Cetuximab and Panitumumab . Detection of such mutations has been done on tissue biopsies with the disadvantage of this being an invasive procedure, and data suggesting that such testing may not be reflective of the true mutational burden of the disease since a single fragment of tissue may be inadequate to reflect the intratumoral heterogeneity. There is increasing evidence suggesting that liquid biopsies or blood based mutational profiling can provide a more comprehensive molecular profile of the disease, and carries the advantage of being minimally invasive. Serial liquid biopsies can act as a tool to identify spatial and temporal heterogeneity predicting response or resistance to targeted agents, and can shed light into the emergence (or disappearance) of specific mutations that may potentially be targeted with newer anti cancer agents .

Circulating cell free DNA (cfDNA) consists of small nucleic acid fragments liberated from cells by rupture, necrosis or apoptosis, and is now increasingly being used to detect RAS (and other) mutations in patients with advanced colorectal cancers. KRAS has remained an "undruggable" target for decades until the most recent evidence that showed a new anticancer drug that targets KRAS G12C mutation.

The investigators aim to perform cfDNA testing on patients with advanced colorectal cancers who have no RAS mutations (and hence start on EGFR inhibitors) as baseline, compare the results with mutational analysis on fresh tumor tissue, and perform cfDNA at first progression to determine what mutations have emerged, and specifically look for KRAS G12C mutation, which can be targeted with a new novel anti cancer drug . These patients will be collected over a 12 month period (with the aim of performing this on at least 100 patients), and followed from diagnosis (with baseline cfDNA) and until progression on EGFR inhibitors (where another cfDNA sample will be taken). A detailed proposal delineating this process will follow once accepted.

This project is unique as it examines mechanisms of resistance to anti-EGFR inhibitors in our patients with advanced colorectal cancers, determines the prevalence of a specific mutation using liquid biopsies and examining cfDNA use, and may have therapeutic implications in facilitating obtaining KRAS G12C inhibitors for such patients.

Conditions

• Colon Cancer

Interventions

DRUG

investigator choice re-challenge with anti EGFR Rx

Upon second progression, patients will be enrolled into the study as per inclusion criteria and consent, and a cfDNA blood test will be drawn, and RAS status will be examined. If RAS is wildtype, then the investigator will decide whether to re-challenge with an anti EGFR antibody , or give SOC third line chemotherapy (Regorafenib or TAS-102).

Sponsors & Collaborators

• National Guard Health Affairs

  lead OTHER_GOV

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2021-02-21

Primary Completion

2024-02-29

Completion

2024-02-29

Countries

• Saudi Arabia

Study Locations