Transformation Into Small Cell Lung Cancer : a Mode of Resistance to Treatment

Study Overview
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Brief Summary
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The discovery of oncogenic mutations and the use of targeted therapies have transformed the management of certain tumors. Thus 12 to 15% of bronchial adenocarcinomas (AD) carry mutations of EGFR and receive from the first line inhibitors of this kinase (ITK). Despite spectacular results, relapse and resistance are quasi-general phenomena. In most known cases, EGFR-TKI resistance mechanisms involve secondary mutations of EGFR or the activation of alternative oncogenic pathways. However, in 5 to 15% of patients, resistance is manifested by the emergence of a small cell carcinoma (CPC), a cancer of neuroendocrine origin very different from AD by its cellular, molecular and epidemiological characteristics. This phenotypic transformation is an almost unique phenomenon in oncology and its molecular bases are not understood. To study this phenomenon, a Franco-Italian network was established that documented and collected cases of this rare tumor. This series is the subject of detailed anatomopathological, clinical and therapeutic documentation. This project aims to investigate the exome of one or more matched lesion regions to evaluate the evolutionary processes leading from the initial AD to the relapsing CPC. These results will guide future research on predictive markers of relapse and their targeted treatment.

Detailed Description
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An international multicentric retrospective collection of cases was performed between 2005 and 2017. A global e-mailing to a network of thoracic oncology centers in France and Italy called for the selection of retrospective cases. Consecutive non small cell lung cancer (NSCLC) patients with stage III or IV EGFR NSCLC with or without initial EGFR mutation with a secondary transformation to small cell lung cancer (SCLC) in participating centers in France and Italy were included. Patients with a previous history of SCLC or neuroendocrine tumor of the lung were excluded as well as patients with combined Small cell/ Non-small cell lung cancer on the initial pathology sample. Study ethics approval was obtained on December 8th of 2015 (CECIC Rhône-Alpes-Auvergne, Clermont-Ferrand, IRB 5891). Anonymized data were collected at each center then centrally analyzed at the Albert Bonniot Institute, Inserm U 823, Grenoble Alpes University, in Grenoble, France. The primary objective of this study was to analyze survival data after transformation to SCLC. The secondary objectives were to define: the epidemiological characteristics at the time of diagnosis of NSCLC, the histomolecular characteristics at the time of diagnosis of NSCLC and at the time of diagnosis of SCLC; the clinical characteristics at the time of diagnosis of NSCLC and SCLC and the treatment characteristics before and after transformation from NSCLC to SCLC. All identified cases will be analyzed. This concerns about sixty two patients because the transformation into small cell lung cancer is a rare mechanism of resistance, it is for this reason that all the cases will be included in order to obtain the most exhaustive data possible. Continuous variables were described as median (25%-75% interquartile range [IQR]) and categorical variables as number (%). Associations between categorical variables were compared using the chi-2 test or Fisher's exact test and those between continuous variables using the Wilcoxon test. Patients were followed until November of 2017. Overall survival (OS) is the time from the initial diagnosis of lung cancer to death and survival after SCLC transformation is from the rebiopsy to death. Kaplan-Meier plots of survival curves were compared between groups using the log-rank test. All tests were two-sided, and P values <0.05 were considered statistically significant. All statistical analyses were performed using SAS 9.3 (SAS Institute, Cary, NC, USA).

Official Title
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Retrospective Study of Cases of Small Cell Lung Cancer (SCLC) That Appeared During Treatment of Another Lung Carcinoma With or Without Oncogenic Activation (TransCPC)

Conditions
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Small Cell Lung Cancer

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with no history of small cell cancer or Neuroendocrine cancer Patients with non-small cell lung cancer at baseline, stage IIIB or IV Transformation during treatment of non small cell lung cancer, in small cell cancer proven by biopsy Exclusion Criteria: History of small cell cancer or Neuroendocrine cancer Absence of histological evidence of the transformation into small cell lung cancer after treatment of non small cell lung cancer Patients with non-small cell lung cancer at initial biopsy, stage I, II, IIIA
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| EGFR MUTATED<br>patient with lung cancer with EGFR mutation before transformation into small cell lung cancer | |
| EGFR NON MUTATED<br>patient with lung cancer without driver oncogenic before transformation into small cell lung cancer | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| survival time after transformation to small cell lung cancer (SCLC) | months of survival after transformation into small cell lung cancer | 2005 to 2017 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| time from initial diagnosis of non small cell lung cancer (NSCLC) to small cell lung cancer transformation | median of months between initial diagnosis of non small cell lung cancer and small cell lung cancer transformation | 2005 to 2017 | 
| histology type at the time of diagnosis of NSCLC and at the time of diagnosis of small cell lung cancer (SCLC) | histology on biopsy at the initial diagnosis and at transformation according with OMS classification | 2005 to 2017 | 
| type of specific treatments administered before and after transformation from non small cell lung cancer into small cell lung cancer | The type of treatment administered before and after SCLC transformation. percentage of patients in each type of specific treatment used | 2005 to 2017 | 
| sexe of patients | sexe female or male in percentage of patients | 2005 to 2017 | 
| stage of NSCLC at initial diagnosis | percentage of patients with stage III and with IV of NSCLC | 2005 to 2017 | 
| smocking status at diagnosis initial of non small cell lung cancer | percentage of patients in never, former or active smokers | 2005 to 2017 | 
| type of mutations at the diagnostic initial NSCLC and at transformation | the mutation on initial biopsy and on biopsy at transformation in SCLC in percentage of patients | 2005 to 2017 | 
| treatment lines before transformation into small cell lung cancer (SCLC) | Median number of lines of treatment for the NSCLC before transformation into SCLC | 2005 to 2017 | 
| response rates to first line treatment after transformation into small cell lung cancer | response rate in percentage of patients after transformation into SCLC according with the RECIST criteria | 2005 to 2017 | 
| lines of treatment after transformation into SCLC | median number of lines of treatment after transformation into SCLC | 2005 to 2017 | 
| age of patients | the median in years at the he diagnosis initial of non small cell lung cancer | 2005 to 2017 |