Chemoresistance and Involvement of the NOTCH Pathway in Patients With Lung Adenocarcinoma (NOTCH)

CHEMO RESISTANCE TO PLATINUM COMPOUNDS AND NOTCH PATHWAYS IN PATIENTS RECEIVING NEOADJUVANT CHEMOTHRERAPY FOR LOCALLY ADVANCED ADENOCARCINOMA OF THE LUNG.

Every year in France, 30.000 deaths are due to lung cancer and 39.500 new cases of this disease are diagnosed (INCa 2014). Patients suffering from locally advanced non-small-cell lung cancer (NSCLC), stage IIIa, usually undergo a multimodality treatment including chemotherapy with platinum compounds before surgery (called neoadjuvant chemotherapy or induction chemotherapy). The reason of this combined modality treatment is the really poor prognosis of patients presenting a disease already spread to lymph nodes (classified N2 when the lymph node under the carina is affected). Up till now, the five-year survival of patients who underwent surgical resection of N2 NSCLC does not exceed 15%

Study Overview

• Status: Unknown
• Conditions: Lung Adenocarcinoma
• Intervention / Treatment: Other: biopsies

Detailed Description

Every year in France, 30.000 deaths are due to lung cancer and 39.500 new cases of this disease are diagnosed (INCa 2014). Patients suffering from locally advanced non-small-cell lung cancer (NSCLC), stage IIIa, usually undergo a multimodality treatment including chemotherapy with platinum compounds before surgery (called neoadjuvant chemotherapy or induction chemotherapy). The reason of this combined modality treatment is the really poor prognosis of patients presenting a disease already spread to lymph nodes (classified N2 when the lymph node under the carina is affected). Up till now, the five-year survival of patients who underwent surgical resection of N2 NSCLC does not exceed 15%.

NOTCH pathway seems to be implicated in the resistance of tumor to chemotherapy. It is known that NOTCH plays a role in the homeostasis of adult stem cells and of cancer stem cells, including intestine cancer and NSCLC. In breast cancer, it has been demonstrated that NOTCH 1 plays a role in the relapse and adding a treatment by an inhibitor of NOTCH decreases the recurrence rate. An activation of the NOTCH pathway was proven in human lung cancer cell lines (A549 and H460) treated with cisplatin. Furthermore, HES1 (Hairy enhance of split), a downstream gene resulting from NOTCH transcription, was upregulated in patient with relapse comparing resistant versus non-resistant adenocarcinoma NSCLC patients. It was proved, NOTCH pathway is associated with overall survival in NSCLC. Recently, it was showed that an inhibitor of NOTCH combined with chemotherapy strongly potentiates the anti-tumor effects of the systemic therapy. Therefore, one can hypothesize that platinum compound-induced NOTCH activation contributes to the resistance of NSCLC and beyond this point, to tumor progression.

• Study Type: Observational
• Enrollment (Anticipated): 18

Contacts and Locations

• Study Contact: Name: Jean Louis PUJOL, MD, PhD; Phone Number: 33 4 67 33 61 35; Email: jl-pujol@chu-montpellier.fr
• Study Contact Backup: Name: Camille TRAVERT; Phone Number: 33 4 67 33 61 35; Email: jl-pujol@chu-montpellier.fr

Study Locations

• France
  • Montpellier, France, 34290
    • Recruiting
    • PUJOL

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

• Six with demonstrated down-staging of a KRAS mutant adenocarcinoma
• Six with demonstrated no down-staging (persistent tumour cell involving lymph nodes in surgically resected specimens) of a KRAS mutant adenocarcinoma
• Six with or without non-staging and triple negative adenocarcinoma

Description

Inclusion Criteria:

patients of both sex, aged 75 years or younger, diagnostic specimen demonstrating an adenocarcinoma, KRAS mutation on exon 2 and codon 12 or codon 13 or triple negative, clinical pathological N2, having received a platinum-based regimen as first line therapy, at less three courses of chemotherapy must have been delivered, with only these molecules : cisplatin-vinorelbine, cisplatin-gemcitabine, cisplatin-docetaxel, cisplatin-paclitaxel, having been operated upon and having been surgically resected R0 or R1.

Exclusion Criteria:

patients having received more than one line of preoperative chemotherapy, having received concurrent chemo-radiotherapy as preoperative treatment, no available diagnostic specimen, patients who underwent R2 resection or no resection, patients affected by adenocarcinoma harbouring either EGFR mutation or EML4-ALK translocation, patients with pathological complete response (yT0yN0).

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
down-staging of a KRAS; Six with demonstrated down-staging of a KRAS mutant adenocarcinoma who underwent biopsie The biopsies of lung tumour samples will be analysed by immunochemistry (IHC), western blotting and qPolymerase Chain Reaction (PCR) approaches	Other: biopsies; The biopsies of lung tumour samples will be analysed by immunochemistry (IHC), western blotting and qPolymerase Chain Reaction (PCR) approaches in Six with demonstrated down-staging of a KRAS mutant adenocarcinoma, Six with demonstrated no down-staging (persistent tumour cell involving lymph nodes in surgically resected specimens) of a KRAS mutant adenocarcinoma and Six with or without non-staging and triple negative adenocarcinoma
no down-staging of a KRAS; Six with demonstrated no down-staging (persistent tumour cell involving lymph nodes in surgically resected specimens) of a KRAS mutant adenocarcinoma who underwent biopsie The biopsies of lung tumour samples will be analysed by immunochemistry (IHC), western blotting and qPolymerase Chain Reaction (PCR) approaches	Other: biopsies; The biopsies of lung tumour samples will be analysed by immunochemistry (IHC), western blotting and qPolymerase Chain Reaction (PCR) approaches in Six with demonstrated down-staging of a KRAS mutant adenocarcinoma, Six with demonstrated no down-staging (persistent tumour cell involving lymph nodes in surgically resected specimens) of a KRAS mutant adenocarcinoma and Six with or without non-staging and triple negative adenocarcinoma
non-staging and triple negative adenocarcinoma; Six with or without non-staging and triple negative adenocarcinoma who underwent biopsie The biopsies of lung tumour samples will be analysed by immunochemistry (IHC), western blotting and qPolymerase Chain Reaction (PCR) approaches	Other: biopsies; The biopsies of lung tumour samples will be analysed by immunochemistry (IHC), western blotting and qPolymerase Chain Reaction (PCR) approaches in Six with demonstrated down-staging of a KRAS mutant adenocarcinoma, Six with demonstrated no down-staging (persistent tumour cell involving lymph nodes in surgically resected specimens) of a KRAS mutant adenocarcinoma and Six with or without non-staging and triple negative adenocarcinoma

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
analysed by immunochemistry (IHC)	The biopsies of lung tumour samples will be analysed by immunochemistry (IHC)	1 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
western blotting (WB)	The biopsies of lung tumour samples will be analysed by western blotting (WB)	1 day
qPolymerase Chain Reaction (PCR)	The biopsies of lung tumour samples will be analysed by qPolymerase Chain Reaction (PCR)	1 day

Collaborators and Investigators

• Sponsor: University Hospital, Montpellier
• Collaborators: Institut de Recherche en Cancérologie de Montpellier (IRCM)
• Investigators: Study Director: Jean Louis PUJOL, MD, PhD, University Hospital, Montpellier

Study record dates

Study Major Dates

• Study Start: September 1, 2016
• Primary Completion (Anticipated): September 1, 2017
• Study Completion (Anticipated): December 1, 2017

Study Registration Dates

• First Submitted: September 8, 2016
• First Submitted That Met QC Criteria: September 8, 2016
• First Posted (Estimate): September 13, 2016

Study Record Updates

• Last Update Posted (Estimate): September 13, 2016
• Last Update Submitted That Met QC Criteria: September 8, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Adenocarcinoma; Adenocarcinoma of Lung
• Other Study ID Numbers: 9758

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED