EGFR and KRAS status of primary sarcomatoid carcinomas of the lung: Implications for anti‐EGFR treatment of a rare lung malignancy

Sarcomatoid carcinomas (SC) of the lung are uncommon malignant tumors composed of carcinomatous and sarcomatous cell components and characterized by a more aggressive outcome than other histological subtypes of nonsmall cell lung cancer (NSCLC). Although epidermal growth factor receptor (EGFR)‐targeted therapies have emerged as a promising therapeutic approach in patients with advanced typical NSCLC such as adenocarcinoma, the potential clinical activity of these drugs in lung SC is still unknown. To investigate this point, we have analyzed the status of 4 EGFR pathways biomarkers in a series of lung SC. EGFR protein expression, EGFR gene copy number, EGFR mutational status and KRAS mutational status were assessed in a series of 22 consecutive cases of primary lung SC. EGFR protein overexpression was observed in all the cases. High level of polysomy (≥4 copies of the gene in >40% of cells) was detected in 5 cases (23%). No EGFR mutation was detected. KRAS mutations were found in 8 patients (38%; Gly12Cys in 6 cases and Gly12Val in 2 cases). The consistent EGFR protein overexpression and the high rate of KRAS mutation may contribute to the poorer outcome of lung SC in comparison with typical NSCLC. The rare incidence of increased EGFR gene copy number, the lack of EGFR mutation and the high rate of KRAS mutation observed in our series also suggest that most patients with lung SC are not likely to benefit from anti‐EGFR therapies. © 2009 UICC     

Clinical Outcome With Platinum-Based Chemotherapy in Patients With Advanced Nonsquamous EGFR Wild-Type Non–Small-Cell Lung Cancer Segregated According to KRAS Mutation Status

BackgroundWe hypothesized that KRAS mutations function as a marker of poor sensitivity to first-line platinum-based chemotherapy in patients with advanced nonsquamous EGFR wild-type (WT) non–small-cell lung cancer (NSCLC).Patients and MethodsConsecutive advanced nonsquamous EGFR WT NSCLCs treated at the Medical Oncology of Perugia with simultaneous assessment of KRAS mutation status were eligible. Anaplastic lymphoma kinase (ALK) gene status was known in roughly half of the patients who had KRAS WT.ResultsTwo hundred four patients were included. Among them, the 77 individuals carrying a KRAS-mutant phenotype experienced a significantly inferior outcome in terms of response rate (P = .04), disease control rate (P = .05), and progression-free survival (PFS) (P = .05) compared with the EGFR WT/KRAS WT population. The association between KRAS mutation and shorter PFS remained statistically significant at multivariate analysis (hazard ratio [HR], 1.45). In addition, patients with KRAS mutations reported a significantly shorter overall survival (OS) compared with patients with EGFR WT/KRAS WT/ALK negativity (n = 64) (P = .02). Among patients with KRAS mutations, those harboring a mutation at codon 13 (n = 12) performed worse than those with a mutation at codon 12 (n = 62) in terms of both PFS and OS (P = .09 for both).ConclusionKRAS mutation appears to negatively affect sensitivity to first-line platinum-based chemotherapy in patients with advanced nonsquamous EGFR WT NSCLC. Studies on larger case series are needed to address differences in clinical outcome according to the type of mutation.     

Comprehensive investigation of oncogenic driver mutations in Chinese non-small cell lung cancer patients

Purpose

To determine the frequency of driver mutations in Chinese non-small cell lung cancer (NSCLC) patients.

Methods

Comprehensive mutational analysis was performed in 1356 lung adenocarcinoma, 503 squamous cell carcinoma, 57 adenosquamous lung carcinoma, 19 large cell carcinoma and 8 sarcomatoid carcinoma. The effect of EGFR tyrosine kinase inhibitors (TKIs) on EGFR-mutated lung adenocarcinoma patients after disease recurrence was investigated.

Results

Mutations in EGFR kinase domain, HER2 kinase domain, KRAS, BRAF, ALK, ROS1 and RET were mutually exclusive. In lung adenocarcinoma cases “pan-negative” for the seven above-mentioned driver mutations, we also detected two oncogenic EGFR extracellular domain mutations (A289D and R324L), two HER2 extracellular and transmembrane domain mutations (S310Y and V659E), one ARAF S214C mutation and two CD74-NRG1 fusions. Six (1.2%) FGFR3 activating mutations were identified in lung squamous cell carcinoma (five S249C and one R248C). There were three (15.8%) EGFR mutations and four (21.1%) KRAS mutations in large cell carcinoma. Three (37.5%) KRAS mutations were detected in sarcomatoid carcinoma. In EGFR-mutated lung adenocarcinoma patients who experienced disease recurrence, treatment with EGFR TKIs was an independent predictor of better overall survival (HR = 0.299, 95% CI: 0.172–0.519, P < 0.001).

Conclusion

We determined the frequency of driver mutations in a large series of Chinese NSCLC patients. EGFR TKIs might improve the survival outcomes of EGFR-mutated lung adenocarcinoma patients who experienced disease recurrence.     

Determinants of Survival in Advanced Non–Small-Cell Lung Cancer in the Era of Targeted Therapies

BackgroundMolecular profiling of non–small-cell lung cancer (NSCLC) samples has a profound impact on choice of therapy. However, it is less clear whether EGFR and KRAS mutations are prognostic outside of a trial-based treatment paradigm.MethodsWe performed a retrospective chart review of 513 patients with NSCLC undergoing EGFR and KRAS mutational analysis at the Hospital of the University of Pennsylvania between May 2008 and November 2011. Survival analysis was based on the 376 patients who received systemic treatment, and their survival was determined from the date of initiation of systemic therapy.ResultsThe median overall survival (OS) was 30.8 months (95% confidence interval [CI], 24.7-36.9). Neither EGFR mutational status (P = .09) nor KRAS mutational status (0.69) was associated with OS. Female sex (P < .001), never smoker status (P = .01), better performance status (PS) (P < .001), lower Charlson Comorbidity Index (P < .001), and lower age-weighted index (P < .001) were associated with prolonged survival. The presence of bone metastases (P = .001) and liver metastases (P = .004) was also associated with a shortened survival. In a multivariable regression that adjusted for stage, we demonstrated that male gender (P = .002), worse Eastern Cooperative Oncology Group PS (P = .01), metastases to bone (P = .03), and higher age-weighted comorbidity index (P = .001) were independent prognostic factors for shorter survival. EGFR mutation status was not prognostic (P = .85).ConclusionIn our series, EGFR and KRAS do not function as prognostic determinants for NSCLC.     

High mesothelin expression in advanced lung adenocarcinoma is associated with KRAS mutations and a poor prognosis

Mesothelin is a cell surface glycoprotein which is highly expressed in several epithelial cancers and may have a role in cell adhesion and metastases. In this study, we used prospectively obtained clinical and pathological data to characterize mesothelin expression in advanced lung adenocarcinoma. Tissue was obtained from patients who underwent molecular profiling of potentially actionable genes on a trial of molecular profiling and targeted therapies in advanced thoracic malignancies. We immunohistochemically evaluated the intensity, and the percentage of cells expressing mesothelin in 93 advanced lung adenocarcinomas. The evaluation was blinded for molecular data and outcome. Mutations of EGFR, KRAS, BRAF, AKT1, PIK3CA and HER2 were assessed by pyrosequencing; HER2 amplification and ALK translocation were assessed by fluorescence in situ hybridization. 53% of advanced lung adenocarcinomas expressed mesothelin to some degree; high mesothelin expression, defined as mesothelin positivity in more than 25% of cells, was found in 24% of patients. High mesothelin expression was associated with inferior survival (median 18.2 months vs. 32.9 months; P = 0.014). High mesothelin expression was strongly associated with mutant KRAS (P < 0.0001) and wild-type EGFR (P = 0.002). Our results provide strong rationale to explore anti-mesothelin targeted therapies in advanced lung adenocarcinoma especially in the KRAS-mutant subgroup.     

Mutation of TP53 and Alteration of p14arf Expression in EGFR- and KRAS-Mutated Lung Adenocarcinomas

BackgroundIn lung adenocarcinoma, inactivation of the tumor suppressor p53 may abrogate a safeguard mechanism preventing the development of tumors with activating mutations in EGFR or KRAS. To assess this hypothesis, we analyzed TP53 mutations and downregulation of p14^arf, a negative regulator of p53 activated by oncogenic signals, in a retrospective series of 96 patients with primary adenocarcinoma of the lung.Patients and MethodsMutations in TP53 (exons 4-9), KRAS (exon 1), and EGFR (exons 18-21) were identified by direct sequencing of DNA from formalin-fixed, paraffin-embedded resected tumors. Expression of p14^arf was semiquantitatively evaluated by immunohistochemical analysis.ResultsTP53, KRAS, and EGFR mutations were detected in 42 of 93 (45.2%), 15 of 95 (15.8%), and 31 of 90 (34.4%) cases, respectively. Low p14^arf expression was observed in 19 of 91 cases (20.9%). Disruption of the p53/p14^arf pathway (defined as TP53 mutation or decreased p14^arf expression, or both) was observed in 18 of 31 EGFR-mutated (58.1%) tumors and in 9 of 13 KRAS-mutated (69.2%) tumors.ConclusionInactivation of the p53/p14^arf pathway is common but not systematic in EGFR- or KRAS-mutated lung adenocarcinomas. Our work highlights the need to better investigate the association between EGFR and KRAS mutations and alterations in tumor suppressor pathways.     

ROS1 Fusions Rarely Overlap with Other Oncogenic Drivers in Non–Small Cell Lung Cancer

IntroductionChromosomal rearrangements involving the gene ROS1 define a distinct molecular subset of NSCLCs with sensitivity to ROS1 inhibitors. Recent reports have suggested a significant overlap between ROS1 fusions and other oncogenic driver alterations, including mutations in EGFR and KRAS.MethodsWe identified patients at our institution with ROS1-rearranged NSCLC who had undergone testing for genetic alterations in additional oncogenes, including EGFR, KRAS, and anaplastic lymphoma receptor tyrosine kinase gene (ALK). Clinicopathologic features and genetic testing results were reviewed. We also examined a separate database of ROS1-rearranged NSCLCs identified through the commercial FoundationOne assay (Foundation Medicine, Cambridge, MA).ResultsAmong 62 patients with ROS1-rearranged NSCLC evaluated at our institution, none harbored concurrent ALK fusions (0%) or EGFR activating mutations (0%). KRAS mutations were detected in two cases (3.2%), one of which harbored a concurrent noncanonical KRAS I24N mutation of unknown biological significance. In a separate ROS1 fluorescence in situ hybridization–positive case, targeted sequencing failed to confirm a ROS1 fusion but instead identified a KRAS G13D mutation. No concurrent mutations in B-Raf proto-oncogene, serine/threonine kinase gene (BRAF), erb-b2 receptor tyrosine kinase 2 gene (ERBB2), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), AKT/serine threonine kinase 1 gene (AKT1), or mitogen-activated protein kinase kinase 1 gene (MAP2K1) were detected. Analysis of an independent data set of 166 ROS1-rearranged NSCLCs identified by FoundationOne demonstrated rare cases with co-occurring driver mutations in EGFR (one of 166) and KRAS (three of 166) and no cases with co-occurring ROS1 and ALK rearrangements.ConclusionsROS1 rearrangements rarely overlap with alterations in EGFR, KRAS, ALK, or other targetable oncogenes in NSCLC.     

Clinicopathological and prognostic significance of interleukin-8 expression and its relationship to KRAS mutation in lung adenocarcinoma

Background:

On the basis of our recent findings of oncogenic KRAS-induced interleukin-8 (IL-8) overexpression in non-small cell lung cancer, we assessed the clinicopathological and prognostic significances of IL-8 expression and its relationship to KRAS mutations in lung adenocarcinomas.

Methods:

IL-8 expression was examined by quantitative RT–PCR using 136 of surgical specimens from lung adenocarcinoma patients. The association between IL-8 expression, clinicopathological features, KRAS or EGFR mutation status and survival was analysed.

Results:

IL-8 was highly expressed in tumours from elderly patients or smokers and in tumours with pleural involvement or vascular invasion. In a non-smokers'' subgroup, IL-8 level positively correlated with age. IL-8 was highly expressed in tumours with KRAS mutations compared with those with EGFR mutations or wild-type EGFR/KRAS. Lung adenocarcinoma patients with high IL-8 showed significantly shorter disease-free survival (DFS) and overall survival (OS) than those with low IL8. DFS and OS were significantly shorter in the patients with mutant KRAS/high IL-8 than in those with wild-type KRAS/low IL-8. Cox regression analyses demonstrated that elevated IL-8 expression correlated with unfavourable prognosis.

Conclusions:

Our findings suggest that IL-8 expression is associated with certain clinicopathological features including age and is a potent prognostic marker in lung adenocarcinoma, especially in oncogenic KRAS-driven adenocarcinoma.     

Spectrum of gene mutations detected by next generation exome sequencing in brain metastases of lung adenocarcinoma

BackgroundBrain metastases (BM) are a life-threatening complication. We aimed to analyse gene mutations in lung adenocarcinoma BM.MethodsWe performed next generation sequencing (NGS) of a pre-defined set of 48 cancer-related genes in a cohort of 76 neurosurgical lung adenocarcinoma BM specimens using a cancer specific gene panel on the MiSeq platform (Illumina, San Diego, CA). NGS results were statistically correlated to patient characteristics. Data on ALK, ROS1, MET and FGFR1 gene status assessed by FISH were available from previous studies in the majority of patients.ResultsTwenty-nine (60.4%) of the 48 investigated cancer-related genes were mutated in at least one BM sample and 64 (84.2%) of the 76 BM samples carried at least one mutated gene. The number of mutated genes per sample ranged from 0 to 9 (median 2). The most commonly mutated genes were TP53, KRAS and CDKN2A, which were affected in 35/76 (46.1%), 29/76 (38.2%) and 17/76 (22.4%) samples, respectively. Other potentially druggable alterations included EGFR mutations (3/76, 3.9% of samples), PIK3CA mutation (2/76, 2.6%), BRAF mutation (1/76, 1.3%) and SMO mutation (1/76, 1.3%). Presence of KRAS mutations was associated with positive smoking history (p = 0.015, Chi square test) and presence of EGFR mutation correlated with unfavourable overall survival time from BM diagnosis (p = 0.019, log rank test).ConclusionsDeleterious gene mutations, some of them with potential therapeutic implications, are found in a high fraction of lung adenocarcinoma BM.     

High Expression of Dihydropyrimidine Dehydrogenase in Lung Adenocarcinoma is Associated With Mutations in Epidermal Growth Factor Receptor: Implications for the Treatment of Non–Small-Cell Lung Cancer Using 5-Fluorouracil

BackgroundIt has been shown that 5-fluorouracil (5-FU) sensitivity in patients with non–small-cell lung cancer (NSCLC) is associated with epidermal growth factor receptor (EGFR) mutation status. However, the relationship between dihydropyrimidine dehydrogenase (DPD), a 5-FU degrading enzyme, and EGFR mutation status is unknown. Here, we focus on clinicopathologic factors and in vitro correlations between DPD expression and EGFR mutation status.Patients and MethodsEGFR mutations and messenger RNA (mRNA) levels of DPD and thymidylate synthase (TS) were analyzed in 47 resected NSCLC tumors by laser-capture microdissection. In addition, relationships between EGFR mutation status and the immunohistochemical expression of DPD and TS in 49 patients with primary NSCLC who were treated with a 5-FU derivative of S-1 postoperatively were examined. Correlations among clinicopathologic factors were evaluated. The effect of epidermal growth factor on DPD expression was also investigated in vitro in various cell lines.ResultsAdenocarcinoma in situ showed significantly higher DPD mRNA levels and more EGFR mutation frequency than other histological types (P < .05). DPD immunopositive cases were more frequently observed in adenocarcinoma, in females, and in nonsmokers. DPD immunopositive cases were correlated with EGFR mutation status (P < .003). The prognoses of wild-type EGFR and mutated EGFR populations were similarly favorable with postoperative S-1 treatment, which overcomes the problem of 5-FU degradation in mutated EGFR. In vitro, EGFR-mutated cell lines showed high DPD mRNA and protein expression.ConclusionHigh DPD expression was shown to be correlated with EGFR mutation in adenocarcinoma cells and tissues. Clinicians should take this finding into consideration when using 5-FU to treat patients with NSCLC.     

Clinical Relevance of EGFR- or KRAS-mutated Subclones in Patients With Advanced Non–small-cell Lung Cancer Receiving Erlotinib in a French Prospective Cohort (IFCT ERMETIC2 Cohort - Part 2)

IntroductionEvaluation of EGFR Mutation status for the administration of EGFR-TKIs in non-small cell lung Carcinoma (ERMETIC) was a prospective study designed to validate the prognostic value of EGFR/KRAS mutations in patients with advanced non–small-cell lung cancer (NSCLC), all receiving a first-generation tyrosine kinase inhibitor, erlotinib. ERMETIC2 was an ancillary project evaluating the clinical value of common EGFR/KRAS-mutated subclones regarding prognosis using highly sensitive molecular detection methods.Materials and MethodsTumor samples from 228 patients with NSCLC (59% adenocarcinoma, 37% women, and 19% never/former smokers) were available for reanalysis using alternative highly sensitive molecular techniques. A multivariate Cox model was used for prognostic analysis.ResultsUsing alternative highly sensitive techniques, 16 EGFR and 51 KRAS supplementary mutations were newly identified, all still exclusive, leading to an overall rate of 12.3% (n = 28) and 33.3% (n = 76), respectively. Using real-time polymerase chain reaction (hybridization probe), they were significantly associated with progression-free survival (P = .02) and overall survival (OS) (P = .01), which were better for EGFR-mutated patients for progression-free survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.28-0.78) and OS (HR, 0.56; 95% CI, 0.31-1), and worse for KRAS mutations and OS (HR, 1.63; 95% CI, 1.09-2.44). Using the most sensitive technique detection for KRAS–clamp polymerase chain reaction–KRAS mutated subclones did not impact OS.ConclusionsKRAS and EGFR mutations were detected in higher proportions by alternative highly sensitive molecular techniques compared with direct Sanger sequencing. However, minor KRAS-mutated subclones offered no prognostic value when representing less than 1% of the tumor cells.     

Additional prognostic role of EGFR activating mutations in lung adenocarcinoma patients with brain metastasis: Integrating with lung specific GPA score

ObjectiveWhile several prognostic models have been presented in NSCLC patients with brain metastasis, none of these models have included molecular markers as an index. The aim of our study was to evaluate the prognostic value of EGFR mutations and to integrate these EGFR mutations into the prognostic index in NSCLC patients with brain metastasis.Materials and methodsWe analyzed retrospectively 292 lung adenocarcinoma patients with brain metastasis. Clinico-pathological features and overall survival (OS) were compared between patients with EGFR mutations and patients with EGFR wild type. EGFR mutation status was integrated with lung specific graded prognostic assessment (GPA) score.ResultsAmong 292 patients, EGFR mutation status was tested in 183 patients. One hundred and five patients (57.4%) had EGFR activating mutations, 14 (7.7%) had EGFR non-activating mutations and 64 (35.0%) had EGFR wild type. OS was significantly longer in patients with EGFR activating mutations than in those with EGFR wild type patients (20.4 vs. 10.1 months, p = 0.002). However, patients with EGFR non-activating mutations did not show superior OS compared with EGFR wild type patients (14.6 vs. 10.1 months, p = 0.83). Multivariate analysis revealed that the presence of EGFR activating mutation is an independent positive prognostic factor for OS (adjusted hazard ratio 0.56, p = 0.002).ConclusionsEGFR activating mutations have a prognostic role in lung adenocarcinoma patients with brain metastasis that is independent of other known prognostic factors. The frequency of EGFR mutation was higher than expected. The presence of EGFR activating mutations should be included as an index in the prognostic models for lung adenocarcinoma patients with brain metastasis.     

Frequent EGFR Mutations and Better Prognosis in Positron Emission Tomography-Negative,Solid-Type Lung Cancer

BackgroundThe differential diagnosis of a solitary solid-type lung nodule is diverse. 18F-fluorodeoxyglucose positron emission tomography (PET) has a high sensitivity in the diagnosis of solid-type lung cancers; however, PET-negative, solid-type lung cancers are rarely observed. In this study, we analyzed the clinical/genetic features and prognosis of PET-negative, solid-type lung cancers.Patients and MethodsBetween January 2007 and February 2020, 709 patients with solid-type lung cancers (tumor size ≥2.0 cm) underwent pulmonary resection. Clinical, genetic, and prognostic features were evaluated in 27 patients (3.8%) with tumors showing negative PET results defined as SUVmax <2.0.ResultsAll 27 patients had lung adenocarcinoma; 23 had invasive adenocarcinomas and 4 had invasive mucinous adenocarcinomas. The PET-negative group showed high frequencies of females and never-smokers. Recurrence-free survival was significantly better in the PET-negative group compared with PET-positive counterparts extracted using propensity score matching from patients who underwent pulmonary resection during the same period (P = .0052). Furthermore, 83% of PET-negative, solid-type invasive lung adenocarcinoma patients harbored EGFR mutation, which was significantly higher than that of PET-positive, solid-type invasive lung adenocarcinoma patients (38%, n = 225) who received EGFR mutation testing in our cohort (P < .0001). PET-negative, solid-type lung adenocarcinoma patients with EGFR mutations had significantly better recurrence-free survival compared with PET-positive, solid-type lung adenocarcinoma patients with EGFR mutations extracted using propensity score matching (P = .0030).ConclusionPET-negative, solid-type lung cancers are characterized with a high incidence of EGFR mutation and a better prognosis compared with PET-positive, solid-type lung cancer.     

High Prevalence of Concomitant Oncogene Mutations in Prospectively Identified Patients with ROS1-Positive Metastatic Lung Cancer

ObjectivesChromosomal rearrangements involving ROS1 define a rare entity of lung adenocarcinomas with exquisite sensitivity to molecularly targeted therapy. We report clinical outcomes and genomic findings of patients with ROS1-positive lung cancer who were prospectively identified within a multiplex biomarker profiling program at the West German Cancer Center.MethodsStandardized immunohistochemical (IHC) analysis, fluorescence in situ hybridization (FISH), and hotspot mutation analyses were performed in 1345 patients with advanced cancer, including 805 patients with metastatic lung adenocarcinoma. Clinical and epidemiological data were retrieved from the institutional database.ResultsROS1 positivity by IHC analysis was detected in 25 patients with lung cancer (4.8% of lung adenocarcinomas), including 13 patients (2.5%) with ROS1 FISH positivity with a cutoff of at least 15% of events. Of the ROS1 IHC analysis–positive cases, 36% presented with concomitant oncogenic driver mutations involving EGFR (six cases, five of which were clinically validated by response to EGFR-targeting agents), KRAS (two cases), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), and BRAF. Three cases initially classified as ROS1 FISH–negative passed the threshold of 15% positive events when repeat biopsies were analyzed at progression. The median overall survival of the ROS1-positive patients (104 months) was significantly superior to that of the 261 patients with EGFR/anaplastic lymphoma kinase/ROS1–negative lung adenocarcinoma (24.4 months, p = 0.044). Interestingly, the overall survival of the 13 ROS1-positive patients with lung cancer from initiation of pemetrexed-based chemotherapy was significantly prolonged when compared with that of 169 pemetrexed-treated patients with EGFR/anaplastic lymphoma kinase/ROS1–negative adenocarcinoma (p = 0.01).ConclusionsROS1-positive metastatic lung adenocarcinomas frequently harbor concomitant oncogenic driver mutations. Levels of ROS1 FISH–positive events are variable over time. This heterogeneity provides additional therapeutic options if discovered by multiplex biomarker testing and repeat biopsies.     

Effect of gefitinib on the survival of patients with recurrence of lung adenocarcinoma after surgery: A retrospective case-matching cohort study

BackgroundPatients with lung adenocarcinoma who carry epidermal growth factor receptor (EGFR) gene mutations respond remarkably well to EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib, or erlotinib. However, the effect of EGFR-TKI treatment on the prolongation of overall survival (OS) of these patients remains uncertain, although several recent studies have shown prolongation of progression free survival compared with cytotoxic chemotherapy.MethodsA total of 304 patients with lung adenocarcinoma who had postoperative recurrent disease were studied. To eliminate potential biases as possible, the matching of four potential predictive factors of responsiveness to EGFR-TKI led to the identification of 81 pairs of patients (those who were treated with gefitinib and those who were not). A deletion mutation in exon 19 and a point mutation (L858R) in exon 21 of the EGFR gene were also analyzed. We compared the OS between the two groups.ResultsOS in the gefitinib group was significantly longer than in the control group (median, 63 vs. 41 months; p = 0.015). EGFR mutations were detected in 65 out of 129 patients (50%) in the whole sample. EGFR mutational status was not an independent prognostic factor of gefitinib benefit; rather, it was a predictive factor.ConclusionsThis study strongly suggested that gefitinib treatment improved OS of lung adenocarcinoma patients who had postoperative recurrence, especially those carrying EGFR mutations.     

EGFR biomarkers predict benefit from vandetanib in combination with docetaxel in a randomized phase III study of second-line treatment of patients with advanced non-small cell lung cancer

BackgroundZODIAC was a randomized phase III study of second-line treatment in patients with advanced non-small cell lung cancer (NSCLC) that evaluated the addition of vandetanib to docetaxel. The study showed a statistically significant improvement in progression-free survival and objective response rate, but not in overall survival for unselected patients. This study evaluated epidermal growth factor receptor (EGFR) gene mutation, copy number gain, and protein expression, and KRAS gene mutation, in pretreatment tumor samples as potential biomarkers predicting benefit from vandetanib as second-line treatment of NSCLC.Patients and methodsAfter progression following first-line chemotherapy, 1391 patients with locally advanced or metastatic (stage IIIB/IV) NSCLC were randomized 1 : 1 to receive vandetanib (100 mg/day) plus docetaxel (75 mg/m² every 21 days) or placebo plus docetaxel in the ZODIAC study. Archival tumor samples (n = 570) were collected from consenting patients (n = 958) for predefined, prospective biomarker analyses.ResultsOf evaluable samples, 14% were EGFR mutation positive, 35% were EGFR FISH positive, 88% were EGFR protein expression positive, and 13% were KRAS mutation positive. Compared with the overall study population, in which progression-free survival (PFS) [hazard ratio (HR) = 0.79] but not OS (HR = 0.91) were significantly improved with vandetanib, there was greater relative clinical benefit for patients with EGFR mutation-positive tumors [PFS HR 0.51, confidence interval (CI) 0.25–1.06 and OS HR 0.46, CI 0.14–1.57] and EGFR FISH-positive tumors (PFS HR 0.61, CI 0.39–0.94 and OS HR 0.48, CI 0.28–0.84). Similarly, patients with EGFR mutation or FISH-positive tumor samples who received vandetanib had an increased chance of objective tumor response (odds ratios 3.34, CI 0.8–13.89, and 3.90, CI 1.02–14.82, respectively). There did not appear to be benefit for vandetanib in patients with KRAS mutation-positive tumors.ConclusionsHigh EGFR gene copy number or activating EGFR mutations may identify patient subgroups who receive increased clinical benefit from vandetanib in combination with docetaxel in second-line NSCLC.ClinicalTrials.govNCT00312377.     

PD-L1 Expression and Comprehensive Molecular Profiling Predict Survival in Nonsmall Cell Lung Cancer: A Real-World Study of a Large Chinese Cohort

BackgroundProgrammed death ligand 1 (PD-L1) expression is the current standard biomarker used to predict non-smallcell lung cancer (NSCLC) response to immunotherapy. Gene expression signatures also seem to be related to the response to immunotherapy. Understanding the clinical and prognostic impact of molecular phenotype and tumor features on PD-L1 expression in NSCLC patients may improve the prediction of immunotherapy response.Materials and MethodsA total of 819 consecutive surgically resected NSCLC specimens from one institution were analyzed in our study. We determined PD-L1 expression by immunohistochemistry (IHC) using the 22C3 clone and the molecular phenotype by targeted next-generation sequencing with a 68-gene panel.ResultsHigh PD-L1 expression was significantly associated with wild-type EGFR (P < .001), KRAS mutation (P < .001), ROS1 rearrangement (P < .001), ALK rearrangement (P = .007), RET rearrangement (P = .041) and MET gene alterations (P = .003). Mutations in TP53 and Rb1 were also significantly associated with high PD-L1 expression (both P < .001). High PD-L1 expression was significantly associated with EGFR co-mutation with tumor suppressor genes such as TP53, Rb1, while EGFR mutation alone was not associated with high PD-L1 expression. Poor survival appeared to be linked to high PD-L1 expression or PD-L1 negative expression with concomitant mutations of tumor suppressor genes, especially multiple tumor suppressor genes.ConclusionPD-L1 expression is highly correlated with major driver and suppressor gene alterations. High PD-L1 expression and patients with negative PD-L1 expression harboring suppressor gene mutation are associated with poor prognosis in patients with NSCLC.     

Programmed Cell Death Ligand 1 Expression in Resected Non–Small Cell Lung Cancer

BackgroundRecently, anti–programmed cell death 1 (PD-1) and anti–programmed cell death ligand 1 (PD-L1) immunotherapies have yielded promising outcomes for patients with advanced non–small cell lung cancer (NSCLC) and led to great interest in applying these agents to treat resectable early-stage NSCLC. The objective of our study was to evaluate PD-L1 protein expression in resectable early-stage NSCLC specimens from a large Northern European cohort, examine the relationship to clinical characteristics, and demonstrate the prognostic role in resected NSCLC.Materials and MethodsA large cohort of 875 NSCLC tumors consisted of 337 patients from Sweden and 538 patients from Norway was studied. All the patients had undergone pulmonary resection, and most patients had had early-stage NSCLC. PD-L1 protein expression was assessed by immunohistochemistry using the Dako PD-L1 22C3 pharmDx kit. The tumor proportion score for PD-L1 protein expression was compared with comprehensive demographic and clinicopathologic data.ResultsThe overall prevalence of PD-L1 protein expression in the resectable NSCLC cohort was 9.5% at a tumor proportion score cutoff of ≥ 50%. Stage I NSCLC had lower PD-L1 expression compared with that of the other stages (P = .0012). PD-L1 expression correlated with wild-type EGFR gene expression (P = .0156) and mutated KRAS gene expression (P = .0004). No significant association was found between PD-L1 expression and mortality after multivariable adjustment for clinical characteristics, although the survival curves showed PD-L1 expression significantly correlated with a poor prognosis in the total NSCLC cohort and in the adenocarcinoma subgroup.ConclusionPD-L1 expression in the present large cohort of resectable NSCLC was relatively low compared with data from clinical trials of advanced NSCLC. PD-L1 expression correlated positively with tumor stage, wild-type EGFR, and KRAS mutation. PD-L1 expression was not found as an independent prognostic factor in the present study. These findings could be important in the future when evaluating the role of anti–PD-1/PD-L1 immunotherapy in the setting of neoadjuvant or adjuvant trials for early-stage resectable NSCLC.