A Retrospective Study Project of Clinico-molecular Characterization in Patients With Metastatic Colorectal Cancer

A Proof-of-concept Study Investigating the Comparison of the RAS Mutational Status Between Primary Tumor and Metastasis in Patients Affected by Metastatic Colorectal Cancer on the Basis of Different Chemotherapeutic Regimens

This is a retrospective, translational, proof-of-concept study on tumor biopsies done on patients affected by mCRC and exhibiting RAS mutation.

For each patient it will be selected the tissue biopsies of primary tumour and of paired resected metastasis.

Study Overview

• Status: Completed
• Conditions: Mestastatic ColoRectal Cancer
• Intervention / Treatment: Genetic: Tumor biobsies analysis

Detailed Description

the study implies the subdivision into three groups with a 1:1:1 ratio.

• The first group includes patients treated with surgery of the primary tumor, neoadjuvant chemotherapy plus bevacizumab and, finally, the surgical resection of liver metastasis.
• The second group is similar to group one, with the exception that patients were not treated with a bevacizumab-based regimen.
• The third group, the control group, includes patients presenting with synchronous primary tumour and metastasis resected without any preoperative systemic therapy

Genomic DNA from formalin-fixed paraffin-embedded (FFPE) tissues from the primary tumor and metastatic lesions will be extracted. The genomic DNA will be assessed for the RAS mutational status in a quantitative and qualitative manner using two different approaches: a real-time PCR approach using the SensiScreen® kit (PentaBase Aps) and a next-generation sequencing approach using the Ion Torrent platform by applying the Ion AmpliSeq™ Cancer Hotspot Panel v2 (ThermoFisher Scientific). The real-time PCR is able to provide the relative quantification of the RAS mutant allele by comparing the Ct value of the mutation with respect to the Ct of the reference gene. This ratio will be calculated for both the primary tumor and for the metastasis and then compared. Ion Torrent gives directly the percentage of the mutant allele in each sample. Furthermore, the Cancer Hotspot Panel v2 provides data (both quantitative and qualitative) about the mutational status of additional 49 genes, including the most relevant and frequently mutated genes in CRC (i.e.: APC, TP53, PIK3CA, BRAF and PTEN) and the relative mutational pattern of the primary tumor and the one of the distant metastasis will be compared.

• Study Type: Observational
• Enrollment (Actual): 45

Contacts and Locations

Study Locations

• Switzerland
  • Bellinzona, Switzerland, 6500
    • Istituto Oncologico della Svizzera Italiana

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

metastatic ColoRectal Cancer patients exhibiting RAS mutation and who received a treatment

Description

General inclusion criteria (valid for all the three cohorts):

• patients with biopsy-proven, stage IV CRC;
• RAS mutation at diagnosis;
• availability of tissue biopsy/resection of both primary tumour and paired liver metastasis for the molecular characterization;

General exclusion criteria (valid for all the three cohorts):

• inadequate material for the molecular characterization of the primary tumour and/or of the related metastasis;
• insufficient amount (%) of tumour cells;

Specific inclusion criteria for each group:

1. st group:

   • first-line bevacizumab plus chemotherapy before resection of liver metastases;
   • metastases must be resected metachronously with respect to the primary tumor.

2. nd group:

   • first-line chemotherapy without bevacizumab before resection of liver metastases;
   • metastases must be resected metachronously with respect to the primary tumor.

3. rd group:

   • no systemic therapy (immediate surgical resection of primary tumor and paired liver metastases);
   • primary tumour and metastasis can be synchronous or metachronous.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
neoadjuvant chemotherapy plus bevacizumab; Patients treated with surgery of the primary tumor, neoadjuvant chemotherapy plus bevacizumab and, finally, the surgical resection of liver metastasis.	Genetic: Tumor biobsies analysis; Analysis on archived tumor biopsies
neoadjuvant chemotherapy; Patients treated with surgery of the primary tumor, neoadjuvant chemotherapy and, finally, the surgical resection of liver metastasis.	Genetic: Tumor biobsies analysis; Analysis on archived tumor biopsies
control group; Patients presenting with synchronous primary tumour and metastasis resected without any preoperative systemic therapy.	Genetic: Tumor biobsies analysis; Analysis on archived tumor biopsies

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of RAS mutant clones in the metastatic lesion	To confirm that the administration of an antiangiogenic treatment in mCRC RAS mutant patients before liver metastasis resection leads to a significant reduction of RAS mutant clones in the metastatic lesion	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Molecular patterns other than RAS	Compare molecular patterns other than RAS in the primary tumor and paired liver metastasis	6 months

Collaborators and Investigators

• Sponsor: Sara De Dosso
• Collaborators: Clinical Trial Unit Ente Ospedaliero Cantonale; Istituto Cantonale di Patologia
• Investigators: Study Chair: Sara De Dosso, MD, Ente Ospedaliero Cantonale, Bellinzona; Principal Investigator: Milo Frattini, MD, Istituto Cantonale Patologia

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2020
• Primary Completion (Actual): July 2, 2020
• Study Completion (Actual): July 2, 2020

Study Registration Dates

• First Submitted: April 5, 2020
• First Submitted That Met QC Criteria: April 5, 2020
• First Posted (Actual): April 8, 2020

Study Record Updates

• Last Update Posted (Actual): August 11, 2020
• Last Update Submitted That Met QC Criteria: August 7, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms
• Other Study ID Numbers: IOSI-ICP-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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