Molecular Signature From Tumor to Lymph Nodes

Официальное название

Molecular Signature From Tumor to Lymph Nodes: How to Identify the Right Candidate for IIIA-N2 Lung Cancer Surgery?

Обзор

Mediastinal lymph node (LN) involvement (N2) in non-small cell lung cancer (NSCLC) concerns 15% of resectable tumors and is associated with a poor prognosis and an overall survival reaching 9 to 49%. Literature fails to provide any definitive consensus regarding the management of these patients, except for the platinum-based doublet chemotherapy. The N2 involvement remains a matter of debate because of its not yet well-classified heterogeneity. Regarding anatomy, the Mountain and Dresler's regional LN classification for lung cancer staging remains the reference. Different studies classified IIIA-N2 disease into 4 groups, in addition to the skip-N2 phenomenon: minimal-N2, N2 single station, N2 multiple stations, and bulky-N2. Other subgroups were recently proposed for the 8th edition of the TNM: N2a1 - single station skip, N2a2 - single station non-skip, N2b - multiple stations. The French National Cancer Institute (INCa) proposed guidelines, but in case of cN2 staging without mediastinal infiltration, guidelines remained imprecise ("resectability should be discussed for each case") and suggested surgery first, or induction chemotherapy, or concomitant chemoradiation. Thus, optimal management of cIIIA-N2 remains controversial but complete tumor resection can be related to long-term survival in some patients, including 10 years after surgery \[1\]. In this situation, the identification of markers that will help select IIIA-N2 patients who will benefit from surgical resection is mandatory.

Подробное описание

We planned a comprehensive molecular characterization of tumors and lymph nodes to evaluate the impact of molecular signatures and molecular heterogeneity on disease-free survival after surgery in IIIA-N2 NSCLC patients. Identification of specific molecular profiles in primary tumors and evolution profiles in nodes might provide clues to the potential risk of metastatic evolution and trigger specific management.

For patients included prospectively, we planned to analyze cell free circulating tumor DNA (ctDNA) as prognostic marker. Because multiple biopsies are not always available in care settings, ctDNA could also be analyzed as a surrogate marker of molecular heterogeneity. Next generation sequencing (NGS) that was validated in our lab to screen ctDNA using a specific bio-informatics workflow allows accurate and cost effective ctDNA screening

Первичные конечные точки

• 3-year disease-free survival [Срок оценки: 3 years]

Вторичные конечные точки (4)

• 5-year disease-free survival [Срок оценки: 5 years]
• pathological architectural patterns WHO 2015 classification [Срок оценки: 5 years]
• anatomical lymphatic spread [Срок оценки: at the end of molecular analyses]
• ctDNA [Срок оценки: 3 years]

Критерии участия

Критерии включения

• Adult patient, men and women age >18 years
• Patients operated with a curative intent for an IIIA-cN2 NSCLC
• Social security affiliation
• Written informed consent for patient included in part 2 (prospective) or not opposing the use of this data for patient included in part 1 (retrospective)

Критерии исключения

• Patient with T4, R1 or R2 surgical resection, sublobar resection, no radical lymphadenectomy
• Patient under protectives measures
• Pregnancy or breast-feeding

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Франция · 12 центров

• Hôpital du Haut-Lévêque, CHU de Bordeaux — Bordeaux
• Hôpital Militaire Percy — Clamart
• Hôpital Nord — Marseille
• Hôpital Pasteur, CHU de Nice — Nice
• Hegp-Aphp — Paris
• Hôpital Européen Georges-Pompidou — Paris
• Hôpital Bichat — Paris
• Hôpital Cochin — Paris
• … и ещё 4 центра

Публикации

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• Legras A, Mordant P, Arame A, Foucault C, Dujon A, Le Pimpec Barthes F, Riquet M. Long-term survival of patients with pN2 lung cancer according to the pattern of lymphatic spread. Ann Thorac Surg. 2014 Apr;97(4):1156-62. doi: 10.1016/j.athoracsur.2013.12.047. Epub 2014 Feb 26. PMID 24582052
• Lin IF, Chang WP, Liao YN. Shrinkage methods enhanced the accuracy of parameter estimation using Cox models with small number of events. J Clin Epidemiol. 2013 Jul;66(7):743-51. doi: 10.1016/j.jclinepi.2013.02.002. Epub 2013 Apr 6. PMID 23566374
• Pecuchet N, Rozenholc Y, Zonta E, Pietrasz D, Didelot A, Combe P, Gibault L, Bachet JB, Taly V, Fabre E, Blons H, Laurent-Puig P. Analysis of Base-Position Error Rate of Next-Generation Sequencing to Detect Tumor Mutations in Circulating DNA. Clin Chem. 2016 Nov;62(11):1492-1503. doi: 10.1373/clinchem.2016.258236. Epub 2016 Sep 13. PMID 27624137
• Peduzzi P, Concato J, Feinstein AR, Holford TR. Importance of events per independent variable in proportional hazards regression analysis. II. Accuracy and precision of regression estimates. J Clin Epidemiol. 1995 Dec;48(12):1503-10. doi: 10.1016/0895-4356(95)00048-8. PMID 8543964
• Tapak L, Saidijam M, Sadeghifar M, Poorolajal J, Mahjub H. Competing risks data analysis with high-dimensional covariates: an application in bladder cancer. Genomics Proteomics Bioinformatics. 2015 Jun;13(3):169-76. doi: 10.1016/j.gpb.2015.04.001. Epub 2015 Apr 20. PMID 25907251
• Um SW, Joung JG, Lee H, Kim H, Kim KT, Park J, Hayes DN, Park WY. Molecular Evolution Patterns in Metastatic Lymph Nodes Reflect the Differential Treatment Response of Advanced Primary Lung Cancer. Cancer Res. 2016 Nov 15;76(22):6568-6576. doi: 10.1158/0008-5472.CAN-16-0873. Epub 2016 Sep 13. PMID 27634761
• Vittinghoff E, McCulloch CE. Relaxing the rule of ten events per variable in logistic and Cox regression. Am J Epidemiol. 2007 Mar 15;165(6):710-8. doi: 10.1093/aje/kwk052. Epub 2006 Dec 20. PMID 17182981

Идентификаторы

NCT: NCT04677205 · D20180155 · D20180155 · 2019-A02635-52

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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