Bertrand Mennecier

MET Gene Copy Number in Non-small Cell Lung Cancer: Molecular Analysis in a Targeted Tyrosine Kinase Inhibitor Naïve Cohort

Introduction: Recent clinical success of epidermal growth factor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) have raised hopes that targeting other deregulated growth factor signaling, such as the hepatocyte growth factor/MET pathway, will lead to new therapeutic options for NSCLC. Furthermore, NSCLC present secondary EGFR-TKIs resistance related to exons 20 and 19 EGFR mutations or more recently to MET amplification. The aim of this study was to determine MET copy number related to EGFR copy number and K-Ras mutations in a targeted TKI naive NSCLC cohort. Methods: We investigated 106 frozen tumors from surgically resected NSCLC patients. Genes copy number of MET and EGFR were assessed by quantitative relative real-time polymerase chain reaction and K-Ras mutations by sequencing. Results: MET is amplified in 22 cases (21%) and deleted in nine cases (8.5%). EGFR is amplified in 31 cases (29%). K-Ras is mutated in 11 cases (10.5%). As observed for EGFR amplification, MET amplification is never associated with K-Ras mutation. MET amplification could be associated with EGFR amplification. MET amplification is not related to clinical and pathologic features. MET amplification and EGFR amplification showed a trend toward poor prognosis in adenocarcinomas. Conclusion: In EGFR-TKIs naive NSCLC patients, MET amplification is a frequent event, which could be associated with EGFR amplification, but not with K-Ras mutation. MET amplification may identify a subset of NSCLC for new targeted therapy. It will also be important to evaluate MET copy number to properly interpret future clinical trials.

EGFR-TKI and lung adenocarcinoma with CNS relapse: interest of molecular follow-up

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) erlotinib improves survival of lung cancer as second- or third-line therapy. However, after an initial response, most patients will recur, particularly within the central nervous system. The present study reports the case of a 27-yr-old nonsmoking male presenting with a metastatic lung adenocarcinoma with EGFR exon 19 deletion, associated with sensitivity to EGFR-TKI. Gefitinib, followed by chemotherapy and finally erlotinib resulted in prolonged disease control, until multiple liver metastases were detected. After stopping EGFR-TKI, brain metastases with carcinomatous meningitis were diagnosed. A secondary T790M mutation, associated with resistance to EGFR-TKI, was found on the liver biopsy but not in the cerebrospinal fluid. Erlotinib was reintroduced and allowed a quick neurological improvement, even though the extra-cranial disease remained resistant to erlotinib. The present report underscores the interest of molecular monitoring in lung cancer. Persistent cerebral tyrosine kinase inhibitor sensitivity should be considered in patients presenting with an early central nervous system relapse after stopping epidermal growth factor receptor tyrosine kinase inhibitor, even with a T790M-resistant mutation in noncerebral metastases. Questions remain concerning the selection of sub-clones during epidermal growth factor receptor tyrosine kinase inhibitor therapy, which could differ according to metastatic sites, especially in the central nervous system.

Women and small cell lung cancer: social characteristics, medical history, management and survival: A retrospective study of all the male and female cases diagnosed in Bas-Rhin (Eastern France) between 1981 and 1994

The literature make it clear that lung cancer in women differs from that in men in several specific aspects. We conducted a retrospective study of the 967 consecutive recorded patients (696 men and 91 women after exclusions) diagnosed with small cell lung cancers (SCLC) between 1981 and 1994 in the Bas-Rhin population-based cancer registry to determine if such particularities could be observed in SCLC. Data included demographic and social characteristics, medical and smoking history, management (diagnosis and treatment), hospitalisation and survival. The end point for survival was 31 December 1998. Women were more frequently single, divorced, or widowed (P=0.007) and lived more often in urban areas (places with more than 10,000 inhabitants) (P=0.017). They differed significantly from men in their tobacco exposure (P=0.0001) and non-smoking rates (P=0.0003) but not in clinical presentation, except for more frequently elevated LDH levels (P=0.02). Bone marrow biopsies were more often performed in men (P=0.004), but management was otherwise comparable. The mean number of hospitalisations (for any reason) was comparable in both sexes but women tended to remain hospitalised longer (P=0.057). Overall survival did not differ, but women older than 70 years died sooner than their male counterparts (P=0.026). Our study confirms that some of gender differences reported in the lung cancer literature exist in SCLC. Sex-related differences in LDH levels have not previously been reported, to our knowledge. North American and European data concerning survival among women and men are discordant. Whether these gender differences are related to a real difference between the sexes or simply to differential exposure to carcinogens remains to be determined.

Overall survival with crizotinib and next-generation ALK inhibitors in ALK-positive non-small-cell lung cancer (IFCT-1302 CLINALK): a French nationwide cohort retrospective study

Overall survival (OS) with the anaplastic lymphoma kinase (ALK) inhibitor (ALKi) crizotinib in a large population of unselected patients with ALK-positive non-small-cell lung cancer (NSCLC) is not documented. We sought to assess OS with crizotinib in unselected ALK-positive NSCLC patients and whether post-progression systemic treatments affect survival outcomes. ALK -positive NSCLC patients receiving crizotinib in French expanded access programs or as approved drug were enrolled. We collected clinical and survival data, RECIST-defined progressive disease (PD) and post-PD systemic treatment efficacy. We performed multivariable analysis of OS from crizotinib initiation and PD under crizotinib. At time of analysis, 209 (65.7%) of the 318 included patients had died. Median OS with crizotinib was 16.6 months. The line of crizotinib therapy did not impact survival outcomes. Of the 263 patients with PD, 105 received best supportive care, 74 subsequent drugs other than next-generation ALKi and 84 next-generation ALKi. Next-generation ALKi treatment correlated with better survival outcomes in multivariate analysis. These patients had a median post-PD survival of 25.0 months and median OS from metastatic disease diagnosis of 89.6 months. Unselected ALK-positive NSCLC patients achieve good survival outcomes with crizotinib therapy. Next-generation ALKi may provide survival improvement after PD under crizotinib.

Concurrent cisplatin/etoposide chemotherapy plus twice daily thoracic radiotherapy in limited stage small cell lung cancer: a phase II study

Thirty-one previously untreated patients with limited stage small-cell lung cancer (LSCLC) were included in a prospective study, to investigate the feasability and the efficacy of a combined modality treatment using concurrent hyperfractionated chest irradiation and cisplatin (P) plus etoposide (E) chemotherapy. All patients received intravenously P=75 mg/m(2) at day 1, plus E=120 mg/m(2) days 1-3, at 3-week intervals for six cycles. Irradiated patients received 45 Gy in two daily fractions, 5 days a week, from week 4 to week 6. During week 5, prophylactic cranial irradiation was initiated, in one daily fraction of 2.5 Gy for a total dose of 25 Gy. Twenty-nine patients were evaluable for response. Twenty-two (76%) achieved a complete response, five (17%) had a partial response. Five patients are currently alive. The overall response rate was 93% (CI 95% (83.7-100)). The median survival time was 14 months and the 2-year survival rate was 25%. Main toxicities were grade 3-4 esophagitis in half of the patients and myelosuppression. The results are not as optimistic as other studies using a similar regimen.

Impact of EGFR mutations and KRAS amino acid substitution on the response to radiotherapy for brain metastasis of non-small-cell lung cancer

BACKGROUND Our study aimed to evaluate response rate (RR) to brain metastasis radiotherapy (RT), depending on the genomic status of non-small-cell lung cancer. MATERIAL & METHODS We retrospectively reviewed 1971 non-small-cell lung cancer files of patients with EGFR and KRAS testing and focused on 157 patients who had undergone RT for brain metastasis. RESULTS A total of 16 patients (10.2%) harbored EGFR mutations (mEGFR) and 45 patients (28.7%) KRAS (mKRAS). In univariate analysis, RR was significantly higher for mEGFR compared with wild-type EGFR/KRAS (odds ratio [OR]: 4.96; p = 0.05) or mKRAS (OR: 1.81; p = 0.03). In multivariate analysis, KRAS G12V or G12C status was associated with both poor RR (OR: 0.1; p < 0.0001) and overall survival (OR: 3.41; p < 0.0001). CONCLUSION mEGFR are associated with higher RR to brain RT than wild-type EGFR/RAS or mKRAS.

Patients with advanced lung cancer harboring oncogenic mutations should be admitted to intensive care units

Dear Editor, Lung cancer patients admitted to the intensive care unit (ICU) have a poor prognosis despite recent improvements. Recently, oncogenic mutation (EML4-ALK, EGFR, ROS1) targetable by specific drugs has been described in non-small-cell lung cancer (NSCLC). Patients with oncogenic mutations often had an adenocarcinoma with pleural or pericardial effusion and were never or former smokers [1, 2]. Only case reports on NSCLC patients with EML4-ALK translocation who were admitted to the ICU were published and suggested a better outcome [3, 4]. Our objective was to describe outcomes of NSCLC patients with oncogenic mutations admitted to the ICU. Consecutive NSCLC patients with oncogenic mutations admitted to ICUs between October 2012 and March 2014 in eight French hospitals were included. We confined the study to patients naive to targeted therapies or having initiated targeted therapy within 1 month before ICU admission. Study ethics approval was obtained on June 2014 (CECIC Rhône-Alpes-Auvergne, ClermontFerrand, IRB 5891). We compared mortality in the patients of the present study (cases) and in those included in a previous study by our group (controls) after careful matching according to tumor extension and histology [5]. Survival of cases and controls was analyzed using marginal Cox models. We identified 14 patients, with a median age of 60 years [interquartile range (IQR), 49–67 years] and a median SAPS II of 53 (IQR 38–67). Mutations were EML4-ALK (n = 8), EGFR (n = 5), and ROS1 (n = 1). They were identified before and during the ICU stay in respectively nine (64 %) and five (36 %) patients. The histological diagnosis was adenocarcinoma for 13 (93 %) patients. All but one patient had metastases. Of the EML4-ALK patients, seven had a pleural, pericardial, or peritoneal effusion. The ECOG-PS was three in seven patients. Targeted therapy was started before ICU admission in four patients and in the ICU in six patients. The most common reason for ICU admission was acute respiratory failure (ARF), with 11/14 (79 %) patients, including 6 in whom ARF was due to a cancer complication, namely, obstruction by the tumor, lymphangitis, pleural effusion, or one tracheoesophageal fistula. Nine (64 %) patients received mechanical ventilation and four (29 %) noninvasive ventilation. Median ICU length of stay was 10 days (IQR 3–17). ICU and in-hospital survivals were 8/14 (57 %) and 7/14 (50 %), respectively. Median survival in the

Germ-line exon 21 EGFR mutations, V843I and P848L, in nonsmall cell lung cancer patients

To the Editor: Somatic epidermal growth factor receptor ( EGFR ) mutations are now routinely integrated in the molecular diagnosis of nonsmall cell lung cancers (NSCLC) [1, 2]. Thus, germ-line EGFR mutations are rarely mentioned or looked for in the context of patients with a family history of cancer, as their association with NSCLC familial cancer risk is not well established. Moreover, the predictive value of these mutations for response to EGFR tyrosine kinase inhibitors (TKIs) is not well known [3]. We report here two different heterozygous germ-line EGFR variants identified in two Caucasian NSCLC patients, who demonstrated different responses to EGFR-TKI. A 63-year-old Caucasian, male former smoker with no family history of cancer (fig. 1a), was admitted for dyspnoea in August 2011, leading to discovery of a lower left lobe lung tumour and pleural effusion. Trans-thoracic biopsy diagnosed an invasive, acinar-predominant adenocarcinoma, classified cT2a N3 M1a (stage IV). Molecular analyses of the tumour by direct sequencing identified two concomitant heterozygous EGFR exon 21 mutations, L858R and V843I, confirmed in two independent experiments (fig. 1b). The V843I variant, but not L858R, was also detected in DNA obtained from a blood sample, with written informed consent, confirming a germ-line mutation (fig. 1c). Following treatment with cisplatin and pemetrexed, the patient relapsed in December 2012 with vertebral metastasis. An EGFR-TKI (erlotinib) was initiated, resulting in a stable disease for 9 months. Figure 1. a–c) Case 1, with epidermal growth factor receptor ( EGFR ) exon 21 mutations (V843I and L858R). a) Pedigree chart. The black case corresponds to the index patient. b) DNA sequencing electrophoretograms for DNA obtained from lung tumour tissue identifying EGFR exon 21 mutations; both mutations are present. c) DNA sequencing electrophoretograms for DNA obtained from blood, identifying one EGFR exon 21 mutation, the V834I variant, is present and confirming …

Second-line therapy in elderly patients with advanced nonsmall cell lung cancer

There is no dedicated study on second-line treatment for elderly patients with advanced nonsmall cell lung cancer (NSCLC). We report the results on second-line erlotinib therapy from our previously published phase III study comparing single-agent therapy with platinum-based doublet (carboplatin plus paclitaxel) therapy in 451elderly patients. Erlotinib was given to patients exhibiting disease progression or experiencing excessive toxicity during first-line therapy, until further progression or unacceptable toxicity. In total, 292 (64.7%) patients received erlotinib as second-line therapy. Initial performance status 0–1, stage IV NSCLC and an Activities of Daily Living score of 6 were independent factors for receiving erlotinib. Median (95% CI) overall survival was 4 (3.2–6.7) versus 6.8 (5.0–8.3) months in the single-agent and doublet arms, respectively (p=0.089). Performance status 0–1, never having smoked, adenocarcinoma and weight loss ≤5% were favourable independent prognostic factors of survival, whereas the randomisation arm had no significant impact. Among the 292 patients who received erlotinib, 60 (20.5%) experienced grade 3–4 toxic effects, the most frequent being rash. Erlotinib as second-line therapy is feasible, leading to efficacy results similar to those obtained in a previous randomised study that was not dedicated to elderly patients, with acceptable toxicity. Erlotinib is a feasible second-line therapy in elderly patients with advanced nonsmall cell carcinoma http://ow.ly/pz6ud

Correlation between MET protein expression and MET gene copy number in a Caucasian cohort of non-small cell lung cancers according to the new IASLC/ATS/ERS classification

Summary MET pathway is a promising target in non-small cell lung cancers (NSCLC) requiring companion tests. The aim of this study was to compare MET expression/gene copy number in a Caucasian population of NSCLC patients. We analysed 201 NSCLC, with 141 adenocarcinomas classified according to 2011 IASLC recommendations, for MET expression by immunohistochemistry (IHC) and gene copy number (GCN) by silver in situ hybridisation (SISH) on tissue microarrays. Mutations in EGFR, KRAS, BRAF, HER2, PIK3CA genes and ALK rearrangements were determined. MET overexpression was observed in 44% and a high MET GCN (≥5 copies) in 14%. MET CGN was correlated with MET expression, regardless of IHC scores (p < 0.001) but only 31% of MET overexpressed cases were SISH positive. MET overexpression/GCN number was more frequent in ADC than the other types (p < 0.001), the highest in high grade (74%/34%) and sarcomatoid ADC (86%/43%). Mutations of current genes or ALK rearrangements were identified in overexpressed or amplified MET cases. MET overexpression was an independent prognostic factor for overall survival in non-smoker NSCLC in univariate (p = 0.01) and multivariate (p = 0.01) analyses. MET overexpression is more frequent than MET high GCN, particularly in high grade ADC, regardless of EGFR, KRAS, BRAF, HER2, PIK3CA and ALK status in NSCLC.