Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicenter, retrospective analysis

Background: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC. Methods: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival. Findings: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0·010, 95% CI 3·29 × 10 −4–0·0282; p=0·0067) and overall survival (0·080, 0·017–0·373; p=0·0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0·330, 0·149–0·727; p=0·0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0·415, 0·209–0·802; p=0·0063) and overall survival (0·409, 0·220–0·780; p=0·0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy. Interpretation: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies

Factors of resistance to platinum-based chemotherapy in non-small cell lung cancers : Role of the Sonic Hedgehog pathway in chemoresistance

Le cancer bronchique non à petites cellules (CBNPC) est particulièrement chimiorésistant. Aucun marqueur robuste de chimiorésistance n'a été validé dans ce type de cancer. Nous avons cherché à décrire dans ce travail des marqueurs innovants de résistance à la chimiothérapie à base de platine dans les CBNPC. Après avoir étudié les caractéristiques cliniques et moléculaires habituelles des patients réfractaires à la chimiothérapie, nous avons étudié le rôle de la voie Sonic Hedgehog (Shh) dans le CBNPC et son impact en termes de chimiorésistance. Nous avons ainsi montré que cette voie de signalisation, connue comme liée aux cellules souches cancéreuses, est corrélée au caractère réfractaire à la chimiothérapie. L'expression de Gli2 est associée à la progression tumorale, à la survie sans progression et à la survie globale. Nous avons également démontré une corrélation entre l'activation de la voie Shh et la transition épithélio-mésenchymateuse, qui est liée à l'agressivité tumorale, le pouvoir métastasiant et la chimiorésistance. Nous avons aussi validé le rôle de la voie Shh dans la prolifération tumorale et la chimiorésistance dans un autre modèle de cancer thoracique, le mésothéliome pleural malin. Enfin, nous nous sommes intéressés à l'expression de hPAF1C (human polymerase II-associated factor 1 complex), facteur suractivé dans les cellules souches cancéreuses et lié à l'activation de la voie Shh. Nous avons montré que l'expression de hPAF1C est associée à un mauvais pronostic et à la prolifération tumorale par interaction avec c-Myc. Ces résultats soulignent le rôle important de la voie Shh dans le CBNPC en termes de chimiorésistance et d'agressivité tumorale.Non-small cell lung cancer (NSCLC) is known to be chemoresistant. Few robust markers of chemoresistance have been validated so far in this type of cancer. We have described in this work new innovative markers of resistance to cisplatin-based chemotherapy in NSCLC. After the study of usual clinical and molecular caracteristics of patients who were refractory to chemotherapy, we have then explored the role of the Sonic Hedgehog (Shh) pathway in NSCLC and its impact in term of chemoresistance. We have shown that Shh pathway, closely linked with cancer stem cells, was correlated with the refractory property to chemotherapy. Positive Gli2 immunohistochemistry score was associated with tumor progression et progression-free survival. We have also demonstrated a correlation between Shh activation and epithelial-mesenchymal transition, known to be linked with tumor aggressiveness, metastatic ability and chemoresistance. We have then validated the great role of Shh pathway in tumor proliferation and chemoresistance in another thoracic cancer, known to be chemoresistant, the malignant pleural mesothelioma. At last, the impact of ceancer stem cells on tumor aggressiveness and prognosis has been demonstrated through the study of the expression of hPAF1C (human polymerase II-associated factor 1 complex), described as overactivated in cancer stem cells and linked to Shh pathway activation. We have shown that hPAF1C expression was associated with poor prognosis and with tumor proliferation through an interaction with c-Myc. These results underline the major role of Shh pathway and cancer stem cells in SNCLC in term of chemoresistance and tumor aggressiveness

Facteurs de résistance à la chimiothérapie à base de sels de platine dans les cancers bronchiques non à petites cellules : Rôle de la voie Sonic Hedgehog dans la chimiorésistance

Non-small cell lung cancer (NSCLC) is known to be chemoresistant. Few robust markers of chemoresistance have been validated so far in this type of cancer. We have described in this work new innovative markers of resistance to cisplatin-based chemotherapy in NSCLC. After the study of usual clinical and molecular caracteristics of patients who were refractory to chemotherapy, we have then explored the role of the Sonic Hedgehog (Shh) pathway in NSCLC and its impact in term of chemoresistance. We have shown that Shh pathway, closely linked with cancer stem cells, was correlated with the refractory property to chemotherapy. Positive Gli2 immunohistochemistry score was associated with tumor progression et progression-free survival. We have also demonstrated a correlation between Shh activation and epithelial-mesenchymal transition, known to be linked with tumor aggressiveness, metastatic ability and chemoresistance. We have then validated the great role of Shh pathway in tumor proliferation and chemoresistance in another thoracic cancer, known to be chemoresistant, the malignant pleural mesothelioma. At last, the impact of ceancer stem cells on tumor aggressiveness and prognosis has been demonstrated through the study of the expression of hPAF1C (human polymerase II-associated factor 1 complex), described as overactivated in cancer stem cells and linked to Shh pathway activation. We have shown that hPAF1C expression was associated with poor prognosis and with tumor proliferation through an interaction with c-Myc. These results underline the major role of Shh pathway and cancer stem cells in SNCLC in term of chemoresistance and tumor aggressiveness.Le cancer bronchique non à petites cellules (CBNPC) est particulièrement chimiorésistant. Aucun marqueur robuste de chimiorésistance n'a été validé dans ce type de cancer. Nous avons cherché à décrire dans ce travail des marqueurs innovants de résistance à la chimiothérapie à base de platine dans les CBNPC. Après avoir étudié les caractéristiques cliniques et moléculaires habituelles des patients réfractaires à la chimiothérapie, nous avons étudié le rôle de la voie Sonic Hedgehog (Shh) dans le CBNPC et son impact en termes de chimiorésistance. Nous avons ainsi montré que cette voie de signalisation, connue comme liée aux cellules souches cancéreuses, est corrélée au caractère réfractaire à la chimiothérapie. L'expression de Gli2 est associée à la progression tumorale, à la survie sans progression et à la survie globale. Nous avons également démontré une corrélation entre l'activation de la voie Shh et la transition épithélio-mésenchymateuse, qui est liée à l'agressivité tumorale, le pouvoir métastasiant et la chimiorésistance. Nous avons aussi validé le rôle de la voie Shh dans la prolifération tumorale et la chimiorésistance dans un autre modèle de cancer thoracique, le mésothéliome pleural malin. Enfin, nous nous sommes intéressés à l'expression de hPAF1C (human polymerase II-associated factor 1 complex), facteur suractivé dans les cellules souches cancéreuses et lié à l'activation de la voie Shh. Nous avons montré que l'expression de hPAF1C est associée à un mauvais pronostic et à la prolifération tumorale par interaction avec c-Myc. Ces résultats soulignent le rôle important de la voie Shh dans le CBNPC en termes de chimiorésistance et d'agressivité tumorale

Crizotinib : enfin l’AMM en 1re ligne des cancers bronchiques non à petites cellules de stade avancé ALK+

International audienceLa présence d’un réarrangement de ALK concerne environ 4 % des cancers bronchiques non à petites cellules (CBNPC). Il induit une sensibilité des cellules tumorales aux inhibiteurs de tyrosine kinase (ITK) de ALK, tels que le crizotinib. L’essai de phase I publié en 2010 a testé le crizotinib (250 mg × 2/jour) en 2e ligne et plus chez 82 patients ayant un CBNPC de stade avancé avec un réarrangement de ALK [1]

Modalités d’utilisation du ceritinib (Zykadia™), inhibiteur de ALK de 2e génération, dans le cancer bronchique non à petites cellules de stade avancé

International audienceAround 4% of advanced non-small cell lung cancers (NSCLC) harbor a ALK rearrangement, with high sensitivity to ALK inhibitor as crizotinib. However, the vast majority of these tumors end with a tumor progression after several months of treatment with crizotinib. Ceritinib is a 2nd generation ALK inhibitor, which showed high efficiency in NSCLC with ALK rearrangement. Results from phase I trial showed a response rate at 58% in these tumors, with a similar rate for previously crizotinib-treated patients or crizotinib-naïve patients. Moreover, cerebral responses were observed with ceritinib. Preliminary date from a phase 2 trial confirmed these results. These promising results allowed a European marketing authorization (autorisation de mise sur le marché [AMM]) since May 2015 for the treatment of advanced NSCLC with ALK rearrangement and resistance or intolerance to crizotinib.Environ 4 % des cancers bronchiques non à petites cellules (CBNPC) de stade avancé ont un réarrangement de ALK, avec une forte sensibilité aux inhibiteurs de ALK comme le crizotinib. Cependant, la grande majorité de ces tumeurs vont avoir une progression tumorale après plusieurs mois de traitement par crizotinib. Le ceritinib est un inhibiteur de ALK de 2e génération, qui a montré une efficacité notable dans le traitement des CBNPC avec réarrangement de ALK. Les résultats d’une phase I ont objectivé un taux de réponse de 58 %, avec un taux similaire que les patients aient été traités ou non préalablement par le crizotinib. De plus, des réponses cérébrales ont été mises en évidence. Les résultats préliminaires de l’essai de phase II ont confirmé ces données. Ces résultats prometteurs ont permis l’autorisation de mise sur le marché (AMM) européenne du ceritinib dans le traitement des CBNPC de stade avancé avec réarrangement de ALK après échec ou intolérance du crizotinib

Old Sonic Hedgehog, new tricks: a new paradigm in thoracic malignancies.

The Sonic Hedgehog (Shh) pathway is physiologically involved during embryogenesis, but is also activated in several diseases, including solid cancers. Previous studies have demonstrated that the Shh pathway is involved in oncogenesis, tumor progression and chemoresistance in lung cancer and mesothelioma. The Shh pathway is also closely associated with epithelial-mesenchymal transition and cancer stem cells. Recent findings have revealed that a small proportion of lung cancer cells expressed an abnormal full-length Shh protein, associated with cancer stem cell features. In this paper, we review the role of the Shh pathway in thoracic cancers (small cell lung cancer, non-small cell lung cancer, and mesothelioma) and discuss the new perspectives of cancer research highlighted by the recent data of the literature

Old Sonic Hedgehog, new tricks: a new paradigm in thoracic malignancies.

The Sonic Hedgehog (Shh) pathway is physiologically involved during embryogenesis, but is also activated in several diseases, including solid cancers. Previous studies have demonstrated that the Shh pathway is involved in oncogenesis, tumor progression and chemoresistance in lung cancer and mesothelioma. The Shh pathway is also closely associated with epithelial-mesenchymal transition and cancer stem cells. Recent findings have revealed that a small proportion of lung cancer cells expressed an abnormal full-length Shh protein, associated with cancer stem cell features. In this paper, we review the role of the Shh pathway in thoracic cancers (small cell lung cancer, non-small cell lung cancer, and mesothelioma) and discuss the new perspectives of cancer research highlighted by the recent data of the literature