EGFR-mutant Tumors Research Articles

Italian Nivolumab Expanded Access Program inNonsquamous Non-Small Cell Lung Cancer Patients: Results in Never-Smokers and EGFR-Mutant Patients.

Nivolumab is the first checkpoint inhibitor approved for the treatment of nonsquamous NSCLC. We report results from the nivolumab Italian expanded access program focusing on never-smokers and patients with EGFR-mutant nonsqamous NSCLC. Nivolumab (3 mg/kg intravenously every 2 weeks) was administered upon physicians' request to patients who had relapsed after one or more prior systemic treatments for stage IIIB/IV nonsquamous NSCLC. Efficacy and safety were evaluated in patients who received at least one dose of nivolumab. Of 1588 patients with nonsquamous NSCLC, 305 (19.2%) were never-smokers. EGFR status was available for 1395 patients. Of the 102 patients (6.4%) with EGFR mutation-positive tumors, 51 (50%) were never-smokers. The objective response rate was significantly higher in patients with wild-type EGFR than patients with EGFR-mutant tumors (19.6% versus 8.8% [p= 0.007]), in former and current smokers than in never-smokers (21.5% versus 9.2% [p= 0.0001]), and in never-smokers with wild-type EGFR than in never-smokers with mutant EGFR (11.0% versus 1.9% [p= 0.04]). There was no significant difference in objective response rate between smokers with wild-type EGFR and smokers with mutant EGFR (22.0% versus 20.6%). There was no statistically significant difference in median progression-free survival or in median overall survival. The median overall survival times were 11 months in patients with EGFR wild-type tumors versus 8.3 months in patients with EGFR-mutant tumors, 11.6 months in smokers versus 10.0 months in never-smokers, 11.0 months in never-smokers with EGFR wild-type tumors versus 5.6 months in never-smokers with EGFR-mutant tumors, and 14.1 months in smokers with EGFR-mutant tumors versus 11.3 months in smokers with EGFR wild-type tumors. The data on the Italian expanded access program in populations with nonsquamous NSCLC suggest that subgroups of patients could benefit differently from nivolumab according to their EGFR mutational status and smoking habits. These results warrant further investigation.

Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions.

EGFR exon 20 insertions (Ex20Ins) account for 4% to 10% of EGFR activating mutations in non-small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to first- and second-generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset. Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M; however, the activity of osimertinib in EGFR Ex20Ins NSCLC has yet to be fully assessed. Using CRISPR-Cas 9 engineered cell lines carrying the most prevalent Ex20Ins mutations, namely Ex20Ins D770_N771InsSVD (22%) or Ex20Ins V769_D770InsASV (17%), and a series of patient-derived xenografts, we have characterized osimertinib and AZ5104 (a circulating metabolite of osimertinib) activities against NSCLC harboring Ex20Ins. We report that osimertinib and AZ5104 inhibit signaling pathways and cellular growth in Ex20Ins mutant cell lines in vitro and demonstrate sustained tumor growth inhibition of EGFR-mutant tumor xenograft harboring the most prevalent Ex20Ins in vivo The antitumor activity of osimertinib and AZ5104 in NSCLC harboring EGFR Ex20Ins is further described herein using a series of patient-derived xenograft models. Together these data support clinical testing of osimertinib in patients with EGFR Ex20Ins NSCLC. Mol Cancer Ther; 17(5); 885-96. ©2018 AACR.

An EGFR ligand promotes EGFR-mutant but not KRAS-mutant lung cancer in vivo.

EGFR ligands (e.g., EGF and TGFA) have been shown to be clinically associated with poor survival in lung cancer. Since TGFA itself initiates autochthonous tumors in liver, breast, and pancreas but not in the lung in transgenic mice in vivo, it would appear that an EGFR ligand may not initiate but rather promote lung cancer. However, it has not been proven in vivo whether lung cancer is promoted by an EGFR ligand. Using transgenic mouse models conditionally expressing EGFRL858R or KrasG12D with TGFA (an EGFR ligand) in lung epithelium, we determined that TGFA promoted the growth of EGFRL858R-lung tumors in airway regions but not that of KrasG12D-lung tumors. Analysis of TCGA datasets identified ΔNp63 and AGR2 as potential key tumor-promoting regulators, which were highly induced in the TGFA-induced EGFRL858R-lung tumors. The expression of AGR2 was positively correlated with the expression of TGFA in human EGFR-mutant lung adenocarcinomas. The expression of TGFA in human EGFR-mutant lung adenocarcinomas but not in the EGFR wild-type lung adenocarcinoma was associated with poor survival. These results suggest that targeting EGFR ligands may benefit patients who carry EGFR-mutant lung tumors but will not benefit patients with KRAS-mutant lung tumors.

Brain Metastases in Oncogene-Addicted Non-Small Cell Lung Cancer Patients: Incidence and Treatment.

Brain metastases (BM) are common in non-small cell lung cancer patients including in molecularly selected populations, such as EGFR-mutant and ALK-rearranged tumors. They are associated with a reduced quality of life, and are commonly the first site of progression for patients receiving tyrosine kinase inhibitors (TKIs). In this review, we summarize incidence of BM and intracranial efficacy with TKI agents according to oncogene driver mutations, focusing on important clinical issues, notably optimal first-line treatment in oncogene-addicted lung tumors with upfront BM (local therapies followed by TKI vs. TKI monotherapy). We also discuss the potential role of newly emerging late-generation TKIs as new standard treatment in oncogene-addicted lung cancer tumors compared with sequential strategies.

Pulmonary Non-Small Cell Carcinoma With Morphologic Features of Adenocarcinoma or "Non-Small Cell Carcinoma Favor Adenocarcinoma" in Cytologic Specimens Share Similar Clinical and Molecular Genetic Characteristics.

Define if the presence of morphologic features of adenocarcinoma (ACA) in non-small cell lung carcinoma (NSCLC) on cytology specimens correlates with clinical and biologic features. A total of 209 cases of NSCLC diagnosed on fine-needle aspiration in a 3-year period were included. After morphologic review, the cases were classified as ACA (n = 115), NSCLC favor ACA (n = 43), and NSCLC-not otherwise specified (NOS) (n = 18). Squamous cell (SCC) (n = 14) and NSCLC favor SCC (n = 19) were excluded from further analysis. Patients with EGFR-mutated tumors had longer overall survival than those with EGFR wild-type tumors (P = .01). When comparing cases with morphologic features of ACA, NSCLC favor ACA, and NSCLC-NOS, there were no differences in the presence or absence of tested mutations, clinical stage, or survival. Patients diagnosed with pulmonary ACA, NSCLC favor ACA, or NSCLC-NOS in cytology specimens have similar clinical stage, survival, and molecular alterations.

Impact of Pulmonary Tuberculosis on the EGFR Mutational Status and Clinical Outcome in Patients with Lung Adenocarcinoma.

PurposeAlthough it has been suggested that pulmonary tuberculosis (TB) is associated with increased risk of lung cancer, the exact mechanism is not clearly identified. We investigated the effect of pulmonary TB on the epidermal growth factor receptor (EGFR) mutational status and clinical outcome in patients with pulmonary adenocarcinoma.Materials and MethodsWe reviewed data of patients diagnosed with pulmonary adenocarcinoma harboring EGFR mutations and treated at our institution from 2008 to 2015. We divided our population into two groups: patients with pre-existing TB lesions on chest computed tomography scan (TB group) and those without the lesions (non-TB group). We compared the differences in EGFR mutational status, response to tyrosine kinase inhibitors (TKIs) and survival between the two groups.ResultsA total of 477 patients with pulmonary adenocarcinoma were analyzed. One hundred eighty-three patients (39%) had EGFR-mutated tumors and 100 (21%) patients had pre-existing TB lesions. The frequency of EGFR mutation was significantly higher in the TB group compared with the non-TB group (56% vs. 34%, p=0.038). Pre-existing TB lesions were independently associated with more frequent EGFR mutations in multivariate analysis (odds ratio, 1.43). In addition, both the progression-free survival (9.1 months vs. 11.6 months, p=0.020) and the overall survival (19.4 months vs. 24.5 months, p=0.014) after first-line EGFR-TKIs were significantly shorter in the TB group than in the non-TB group.ConclusionPrevious pulmonary TB may be associated with more frequent EGFR mutations and poorer treatment response to EGFR-TKIs in patients with pulmonary adenocarcinoma.

Making progress in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer by surpassing resistance: third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs).

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) represent the standard of care for advanced non-small cell lung cancer (NSCLC) patients whose tumours harbor an activating EGFR mutation. Unfortunately, resistance to first- and second-generation EGFR-TKIs inevitably occurs in all patients with EGFR-mutant disease approximately within a year of treatment. At least half of these cases are attributed to the emergence of a secondary mutation in exon 20 of the EGFR gene, namely the T790M mutation. Third-generation EGFR-TKIs, including osimertinib and rociletinib, target this epigenic mutation, thus re-sensitizing cancer cells to EGFR-TKI inhibition. Osimertinib to date represents the standard of care in EGFR-mutant tumors after failure of first-line EGFR-TKIs by over-performing platinum-based chemotherapy in the recently reported AURA-3 randomized phase III clinical trial. The aim of this review is to describe the different treatment strategies that have been developed to reverse resistance to first- and second-line EGFR-TKIs, the corresponding mechanisms of resistance and the development of novel-generation EGFR-TKIs. We also discuss the challenge posed by the implementation of third-generation EGFR-TKIs earlier in the course of the disease in first-line treatment of EGFR-mutant NSCLC.

Subjecting appropriate lung adenocarcinoma samples to next-generation sequencing-based molecular testing: challenges and possible solutions.

Next‐generation sequencing (NGS) has recently been rapidly adopted in the molecular diagnosis of cancer, but it still faces some obstacles. In this study, 665 lung adenocarcinoma samples (558 TKI‐naive and 107 TKI‐relapsed samples) were interrogated using NGS, and the challenges and possible solutions of subjecting appropriate tissue samples to NGS testing were explored. The results showed that lower frequencies of HER2/BRAF/PIK3CA and acquired EGFR T790M mutations were observed in biopsy samples with <20% tumor cellularity than in those with ≥20%, but there were no significant differences in the frequencies of EGFR or KRAS mutations. Moreover, tumor heterogeneity was assessed by heterogeneity score (HS), which was calculated through multiplying by 2 the mutant allele frequency (MAF) of tumor cells. In TKI‐naive samples, intratumor heterogeneity could occur in EGFR,KRAS,HER2,BRAF, and PIK3CA mutant tumors, but the degree was variable. Higher EGFR, but lower BRAF and PIK3CA HS values were observed compared with KRAS HS. In TKI‐relapsed samples, analysis of concomitant sensitizing EGFR and T790M MAFs showed that intratumor heterogeneity was common in acquired EGFR T790M mutant tumors. The mutational status between primary and metastatic tumors was usually concordant, but KRAS,HER2, and PIK3CA HS were significantly higher in metastatic tumors than in primary tumors. Additionally, the discordance rate of mutational status in multifocal lung adenocarcinomas diagnosed as equivocal or multiple primary tumors was high. Together, our findings demonstrate that a comprehensive quality assessment is necessary during tissue process to mitigate the challenges of poor tumor cellularity, tumor heterogeneity, and multifocal clonally independent tumors.

Prognostic value of the expression of immunomodulatory targets in surgically resected lung adenocarcinoma.

173 Background: Therapies targeting immune checkpoints have recently shown encouraging activity in patients with non-small cell lung cancer. T-cell activation is controlled by the balance of co-stimulatory molecules that act positively in concert with T-cell receptor (TCR) signaling induced by antigen stimulation and co-inhibitory molecules (immune checkpoint molecules) that negatively regulate TCR signaling. Methods: We performed a Cap Analysis of Gene Expression (CAGE) analysis to quantify the gene expression of PD-L1, PD-L2, co-inhibitory molecules (CTLA-4, PD-1, TIM-3, BTLA, VISTA and LAG-3) and co-stimulatory molecules (CD28, OX40, GITR, CD317, CD27 and HVEM) using RNA extracted from 71 frozen tumor tissue samples of surgically resected lung adenocarcinomas, including 35 EGFR-mutated, 11 KRAS-mutated and 25 wild-type tumors. The correlations between the expression of the above immunomodulatory targets and the overall survival were analyzed. None of patients received immunotherapy. Results: Lung adenocarcinomas in this study were divided into two groups: tumors showing high expression of almost all immunomodulatory targets and those with low expression. The expression of CTLA-4, PD-1 and PD-L1 was not prognostic. The prognosis of patients with tumors showing high expression of TIM-3 was significantly worse than that of those with low expression, regardless of the EGFR and KRAS mutation status. The prognosis of patients with tumors showing high expression of VISTA was significantly better than that of those with low expression, regardless of the EGFR and KRAS mutation status. The prognosis of patients with tumors showing high expression of LAG-3 was significantly worse than that of those with low expression among overall patients. However, high expression of LAG-3 was an unfavorable prognostic factor in patients with EGFR-mutated or wild-type tumors, and it was a favorable prognostic factor in patients with KRAS-mutated tumors. Conclusions: Lung adenocarcinomas may be divisible into immunogenic and nonimmunogenic tumors. The prognostic value differs according to the immunomodulatory target and driver oncogene status.

Cell of origin markers identify different prognostic subgroups of lung adenocarcinoma

Strong prognostic markers able to stratify lung adenocarcinoma (ADC) patients are lacking. We evaluated whether a six-immunohistochemical markers panel (TTF1, SP-A, Napsin A, MUC5AC, CDX2 and CK5), defining the putative neoplastic "cell of origin," allows to identify prognostic subgroups among lung ADC. We screened a large cohort of ADC specimens (2003-2013) from Torino Institutional Repository identifying: (i) marker positivity by immunohistochemistry, (ii) main morphological appearance by light microscopy, (iii) presence of "hotspot" mutations of candidate genes by Sequenom technology. To evaluate possible predictors of survival and time to recurrence, uni- and multivariable-adjusted comparisons were performed. We identified 4 different subgroups: "alveolar," "bronchiolar," "mixed" and "null type." Alveolar-differentiated ADC were more common in young (P=.065), female (P=.083) patients, frequently harboring EGFR-mutated (P=.003) tumors with acinar pattern (P<.001). Bronchiolar-differentiated ADC were more associated with mucinous and solid pattern (P<.001), higher degree of vascular invasion (P=.01) and KRAS gene mutations (P=.07). Bronchiolar, mixed, and null types were independent negative predictors for overall survival, and the latter two had a shorter time to recurrence. This "Cell of Origin" classifier is more predictable than morphology and genetics and is an independent predictor of survival on a multivariate analysis.

PCR-based detection of EGFR, ALK, KRAS and BRAF mutations in Russian patients with lung adenocarcinoma: a single-center experience.

In contrast to other countries with predominantly white populations, Russian smoking-related lung cancers (LC) are mainly squamous cell carcinomas and approximately half lung adenocarcinomas (AdCa) are not related to tobacco consumption. Given that smoking significantly influences the probability of presence of actionable mutations in LC, one would expect that Russian lung AdCa patients would differ from other white populations in distribution of EGFR, ALK, KRAS and BRAF mutations. Herein, 2,336 consecutive lung AdCa cases, including 1,203 patients with known smoking status, were subjected to sequential testing for the above mutations. One quarter of lung AdCa patients carried either EGFR or ALK mutation with combined prevalence of 42% in those who had never smoked but only 8% in smokers. There was only a moderate difference in KRAS mutation frequency between ever- and never-smokers in EGFR/ALK-negative cases (31% vs. 23%), and this was mainly attributed to increased prevalence of G12C substitution in the former group. The occurrence of BRAF V600E mutation was 1.7% and 4% in EGFR/ALK/KRAS mutation-negative ever- and never-smokers, respectively. ALK testing of 470 EGFR-mutated tumors revealed only 1 (0.2%) instance of translocation. Similarly, KRAS testing identified 1 (1.25%) mutation in 80 EGFR-mutated AdCa and none in 48 ALK-rearranged AdCa. Therefore, concurrent actionable mutations in lung adenocarcinoma are exceptionally rare and sequential gene testing can be regarded as a reliable option.

Clinical and Molecular Characteristics Associated With Survival Among Patients Treated With Checkpoint Inhibitors for Advanced Non–Small Cell Lung Carcinoma

Checkpoint inhibitors have replaced docetaxel as the new standard second-line therapy in advanced non-small cell lung carcinoma (NSCLC), but little is known about the potential predictive value of clinical and molecular characteristics. To estimate the relative efficacy of checkpoint inhibitor vs docetaxel overall and in subgroups defined by clinicopathological characteristics. This systematic review and meta-analysis searched MEDLINE, Embase, PubMed, and the Cochrane Central Register of Controlled Trials for randomized clinical trials published in the English language between January 1, 1996, and January 30, 2017. Randomized clinical trials that compared a checkpoint inhibitor (nivolumab, pembrolizumab, or atezolizumab) with docetaxel. For each trial included in this study, the trial name, year of publication or conference presentation, patients' clinicopathological characteristics, type of chemotherapy, and type of checkpoint inhibitor were extracted. Data collection for this study took place from February 1 to March 31, 2017. Two reviewers performed study selection, data abstraction, and risk of bias assessment. Hazard ratios (HR) and 95% CIs for the overall population and subgroups were extracted. Pooled treatment estimates were calculated using the inverse-variance-weighted method. In total, 5 trials involving 3025 patients with advanced NSCLC were included in this meta-analysis. These patients were randomized to receive a checkpoint inhibitor (nivolumab, 427 [14.1%]; pembrolizumab, 691 [22.8%]; or atezolizumab, 569 [18.8%]) or docetaxel (1338 [44.2%]). Checkpoint inhibitors were associated with prolonged overall survival, compared with docetaxel (HR, 0.69; 95% CI, 0.63-0.75; P < .001). They prolonged overall survival in the EGFR wild-type subgroup (HR, 0.67; 95% CI, 0.60-0.75; P < .001), but not in the EGFR mutant subgroup (HR, 1.11; 95% CI, 0.80-1.53; P = .54; interaction, P = .005), and they prolonged overall survival in the KRAS mutant subgroup (HR, 0.65; 95% CI, 0.44-0.97; P = .03) but not in the KRAS wild-type subgroup (HR, 0.86; 95% CI, 0.67-1.11; P = .24; interaction, P = .24). The relative treatment benefits were similar according to smoking status (never smokers [HR, 0.79] vs ever smokers [HR, 0.69]; interaction, P = .40), performance status (0 [HR, 0.69] vs 1 [HR, 0.68]; interaction, P = .85), age (<65 years [HR, 0.71] vs ≥65 years [HR, 0.69]; interaction, P = .74), histology (squamous [HR, 0.67] vs nonsquamous [HR, 0.70]; interaction, P = .71), or sex (male [HR, 0.69] vs female [HR, 0.70]; interaction, P = .82). Checkpoint inhibitors, compared with docetaxel, are associated with significantly prolong overall survival in second-line therapy in NSCLC. The finding of no overall survival benefit for patients with EGFR mutant tumors suggests that checkpoint inhibitors should be considered only after other effective therapies have been exhausted. The findings of this meta-analysis could also assist in the design and interpretation of future trials and in economic analyses.

PD-L1 confers resistance to EGFR mutation-independent tyrosine kinase inhibitors in non-small cell lung cancer via upregulation of YAP1 expression.

Programmed death ligand (PD-L1) expression was associated with tumor immune escape and subsequent poor prognosis in non-small cell lung cancer (NSCLC). This expression was higher in patients with EGFR-mutated NSCLC tumors than in those with EGFR-wild-type (WT) NSCLC tumors. We therefore hypothesized that poor prognosis mediated by higher PD-L1 may be partially through conferring resistance to tyrosine kinase inhibitor (TKI) in NSCLC regardless of EGFR mutation. The change in PD-L1 expression following gene manipulation corresponded with changes in expression of HIF-1α and YAP1. The expression of HIF-1α and YAP1 was concomitantly decreased by PD-L1 silencing or by ROS scavenger treatment (N-acetylcysteine, NAC); however, a ROS inducer treatment (pyocyanin) completely reversed the decreased expression of both genes in EGFR-mutated and -wild-type (WT) NSCLC cells. The MTT assay indicated that the inhibitory concentration of gefitinib yielding 50% cell viability (IC50) depended on PD-L1-mediated YAP1 expression. Mechanistic studies indicated that upregulation of YAP1 by PD-L1 might be responsible for EGFR mutation-independent TKI resistance via the ROS/HIF-1α axis. An unfavorable TKI response was more common in patient tumors with high PD-L1 or YAP1 mRNA expression than in patient tumors with low mRNA expression of these genes. In conclusion, PD-L1 might confer EGFR mutation-independent TKI resistance in NSCLC cells via upregulation of YAP1 expression.

A method of high-throughput functional evaluation of EGFR gene variants of unknown significance in cancer.

Numerous variants of unknown significance (VUS) have been identified through large-scale cancer genome projects, although their functional relevance remains uninvestigated. We developed a mixed-all-nominated-mutants-in-one (MANO) method to evaluate the transforming potential and drug sensitivity of oncogene VUS in a high-throughput manner and applied this method to 101 nonsynonymous epidermal growth factor receptor (EGFR) mutants. We discovered a number of mutations conferring resistance to EGFR tyrosine kinase inhibitors (TKIs), including gefitinib- and erlotinib-insensitive missense mutations within exon 19 and other gefitinib-resistant mutations, such as L833V, A839T, V851I, A871T, and G873E. L858R-positive tumors (12.8%) harbored compound mutations primarily in the cis allele, which decreased the gefitinib sensitivity of these tumors. The MANO method further revealed that some EGFR mutants that are highly resistant to all types of TKIs are sensitive to cetuximab. Thus, these data support the importance of examining the clinical relevance of uncommon mutations within EGFR and of evaluating the functions of such mutations in combination. This method may become a foundation for the in vitro and in vivo assessment of variants of cancer-related genes and help customize cancer therapy for individual patients.

Cancer stem cell-like population is preferentially suppressed by EGFR-TKIs in EGFR-mutated PC-9 tumor models

AimsAlthough the epidermal growth factor receptor (EGFR) and Wnt/β-catenin signaling systems synergistically regulate many essential developmental and regenerative processes in lung cancer, the mechanisms of their crosstalk remain poorly defined. Our study aimed to investigate an interaction between EGFR and the β-catenin signal. ResultsIn this study, we described a potent activation of β-catenin by EGFR, which is dependent of the PtdIns3K/AKT pathway. We found EGF activated β-catenin signaling via phosphorylation of EGFR and AKT in EGFR-mutated PC-9 lung cancer cells. Meanwhile, EGFR tyrosine kinase inhibitors (EGFR-TKIs) regulated cancer stem-like cells (CSCs) by inhibiting autophosphorylation of EGFR and downstream signaling proteins, as well as β-catenin. Further, β-catenin depletion by RNA interference virtually eliminated cancer stem cell-like population in PC-9 cells in vitro. The nude mice transplantation model was also performed to confirm EGFR-TKIs strongly inhibited the β-catenin signal and decreased CSCs. Importantly, the reduction of CSCs that sorted out by side population (SP) cells significantly reduced the migration capability. Thus, our results improved the understanding of this process to provide insights into mechanisms of responding to EGFR-TKIs. ConclusionsOur discoveries raise an intriguing question of the role of β-catenin in EGFR-TKIs-treated cancer stem cell-like population(s) and its potential as a new therapeutic target for NSCLC in the future.

PIK3CA mutation is associated with increased local failure in lung stereotactic body radiation therapy (SBRT)

ObjectivesHyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway has been associated with radioresistance. It is unclear whether such mutations confer suboptimal local control for patients who receive lung stereotactic body radiation therapy (SBRT). Our objective was to examine whether mutations in the EGFR/AKT/PIK3CA signaling pathway are associated with local failure (LF) after lung SBRT. MethodsWe retrospectively reviewed 166 patients who underwent SBRT to primary or metastatic lung lesions from 2007 to 2015 for whom genetic testing data was available for EGFR, AKT, and PIK3CA genes. Association between clinical factors, including molecular mutation status, and LF was evaluated. ResultsSix patients (4%) had PIK3CA mutation, 36 patients (22%) had EGFR mutation, and one patient (0.6%) had AKT1 mutation. Median lesion size was 2.0 cm (range, 0.6–5.6 cm); median dose was 48 Gy in 4 fractions (range, 30–70 Gy in 3–10 fractions). Median follow-up for survivors was 27.3 months (range, 3.8–66.7 months). LF occurred in 16 patients (10%). On univariate analysis, PIK3CA mutation was associated with LF (HR 10.44 [95% CI 2.16–50.46], p = .003), while tumor histology, tumor size, primary tumor site, BED and EGFR mutation were not. At one year, probability of LF in lesions with PIK3CA mutation was 20.0% vs. 2.9% in lesions without mutation (p < .001 by log rank test). ConclusionAlthough the number of patients affected was small, PIK3CA mutation was significantly associated with higher risk of LF in patients undergoing lung SBRT. This association has not previously been reported for lung SBRT and indicates the need for further validation.

OA 07.02 Characteristics of Lung Cancer Cell-Free Tumor DNA (CfDNA) Shedding and Correlation with Tumor Burden as Measured by RECIST

cfDNA is a promising biomarker for early recurrence detection and disease monitoring in the NSCLC curative setting. However, less is known about cfDNA shedding characteristics and correlation with tumor burden in advanced NSCLC. We reviewed cfDNA results of NSCLC patients tested at our institution between November 2015 and December 2016 with Guardant 360, a comprehensive cfDNA assay that detects genomic alterations in 70-73 cancer genes. 141 cases with evaluable imaging were selected for this analysis, enriching for EGFR and KRAS mutated cases to facilitate comparisons of major genomic subtypes (Table 1). Tumor burden was approximated using the sum of longest diameters (SLD), per RECIST v1.1. There was a statistically significant correlation of moderate strength between cfDNA maximum variant allele frequency (VAF) detected and SLD (Spearman’s rho = 0.35, p <0.001). This correlation was strongest in KRAS mutant cases (rho = 0.52, p = 0.001) and weakest in EGFR mutated tumors (rho = 0.21, p <0.24). Multi-variate regression that included stage, histology, and mutation status confirmed the predictive value of cfDNA VAF for SLD (p = 0.03). TP53 mutants had higher cfDNA VAF (Wilcox p <0.001), even after accounting for SLD. Increased cfDNA VAF was also seen with EGFR mutants and patients with visceral metastasis, though possibly confounded by concomitant EGFR amplification and increased tumor burden, respectively. CNS metastasis was not associated with differential cfDNA shedding. In this primarily metastatic cohort, cfDNA VAF correlated with radiographic assessment of tumor burden by RECIST. This correlation was partially mediated by the presence of key driver mutations. TP53 and EGFR mutant tumors and the presence of visceral metastasis are associated with higher cfDNA VAF. These findings have potential implications for the use of cfDNA in advanced-stage NSCLC disease monitoring, where RECIST is more clinically applicable than formal volumetrics.

PIK3CA Mutation is Associated With Increased Local Failure in Lung Stereotactic Body Radiation Therapy

Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway has been associated with radioresistance. It is unclear whether such mutations also confer suboptimal local control for patients who receive lung stereotactic body radiation therapy (SBRT). Our objective was to examine whether mutations in the EGFR/AKT/PIK3CA signaling pathway are associated with local failure (LF) after lung SBRT. We retrospectively reviewed 168 patients who underwent SBRT to primary or metastatic lung lesions from 2007-2015 for whom molecular testing data was available for EGFR, AKT, and PIK3CA genes. For tumors of lung origin (n = 156), molecular testing data was included from the lung tumor. For metastatic tumors to the lung (n = 12), molecular testing data from either a primary or metastatic tumor site was used. Association between clinical factors, including molecular mutation status, and LF was evaluated with Cox regression analysis. The Kaplan-Meier method was used to assess differences in LF rates based on PIK3CA mutation status. The most common histology was adenocarcinoma (92%) among all tumors. Six patients (4%) had PIK3CA mutation, 36 patients (21%) had EGFR mutation, and one patient (0.6%) had AKT mutation. Median lesion size was 2.0 cm (range, 0.6–5.6 cm), median dose was 48 Gy (range 30–70 Gy), and median number of fractions was 4 (range, 3–10). Median follow-up was 21 months (range, 0.2–70 months). LF was observed for 16 patients (10%). On univariate analysis, PIK3CA mutation presence was associated with LF (HR 11.0 [95% CI 2.3-52.6], P = 0.003), while tumor histology (adenocarcinoma vs. other), tumor size (≤2 cm vs. >2 cm), primary tumor site (lung vs. other), BED (<100 Gy versus ≥100 Gy) and EGFR mutation presence were not. At one year, probability of LF in lesions with PIK3CA mutations was 25.0% vs. 3.1% in lesions without mutations (P < 0.001). Lesions with PIK3CA mutations were associated with a decreased time to LF (mean 17.4 months [95% CI 11.1-12.8 months]) compared to those without PIK3CA mutation (mean 61.3 months [95% CI 57.0-65.7 months]). Although the number of patients affected was small, PIK3CA mutation was significantly associated with a much higher risk of LF in patients undergoing lung SBRT. This association has not previously been reported for lung SBRT and indicates the need for further validation and study.

Les traitements péri-opératoires des carcinomes bronchiques non à petites cellules

Perioperative treatments have been developed to reduce the risk of recurrence after complete resection for non-small cell lung cancer (NSCLC). Chemotherapy and radiotherapy have been integrated within routine care. Perioperative chemotherapy leads to a 5% improvement in 5-year survival. It should be delivered in stage pII and pIIIA NSCLC, and can be administered in stage pIB≥4 cm. Preoperative chemoradiation does not improve outcomes when compared to preoperative chemotherapy. Mediastinal radiotherapy can be discussed after surgery of pN2 NSCLC.Innovative treatments which have demonstrated activity in advanced disease have been evaluated in the perioperative setting. Antiangiogenic agents have no interest in this situation. Studies of EGFR tyrosine kinase inhibitors in all-comers are negative. The first phase lll results of adjuvant EGFR tyrosine kinase inhibitors in EGFR-mutated tumors are promising. Preliminary data of immune checkpoint inhibitors given as neoadjuvant therapy highly justify further study. Several ongoing large trials should help to better define the place of these agents within the future therapeutic perioperative panel.

1339P - A large prospective cohort study of the clinical features of advanced lung cancer harboring HER2 aberrations (HER2-CS STUDY)

Background: HER2 is a potential driver oncogene. HER2-targeted precision therapy has been tested in NSCLC. However, the demographics of HER2-positive NSCLC have not been defined systematically. Methods: Pts with advanced NSCLC were registered. HER2-IHC and FISH assays were performed with commercial kits. HER2 mutations were identified by the direct sequencing. The aim of this study was to clarify the frequency, characteristics and outcome of HER2-positive NSCLC. Results: Of 1,126 tumors screened (Table A), 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 EGFR wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775_G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female pts had HER2 mutant tumors more frequently, while IHC/FISH+ tumors were detected more often in males (Table B). HER2-positive tumors had similar survival outcome to triple negative tumors, but significantly worse prognoses than EGFR-mutant and ALK-positive tumors (p < 0.05 each).Table1339PA. The Genotype-Specific Subsets*including 22 pts with HER2-positive tumors with EGFR mutations, 2 with both HER2- and ALK-positive tumors, and 2 had ALK-positive tumors with EGFR-mutations.HER2 (n = 88)EGFR (n = 358)ALK (n = 44)Triple negative/ unknown (n = 664)Total (n = 1,126)Age, median Sex (male) Smoking habit Non-Sq Stage III/IV696962696961 (69%) 58 (66%) 78 (89%) 51 (58%)142 (40%) 142 (40%) 351 (98%) 220 (61%)21 (48%) 19 (43%) 44 (100%) 35 (80%)516 (78%) 544 (82%) 503 (76%) 423 (64%)726 (64%) 754 (67%) 951 (84%) 714 (63%)MST (mo) 1-yr OS rate17.5 59%NR 85%NR 79%15.1 59%19.8 67%B. The Subsets of HER2 aberrations**1 had an IHC2+/FISH+ tumor with mutation.IHC3 + (n = 34)IHC2+/FISH + (n = 34)Mutant (n = 21)Age, median Sex (male) Smoking habit Non-Sq Stage III/IV71716527 (79%) 24 (71%) 30 (88%) 17 (50%)27 (79%) 26 (76%) 28 (82%) 21 (62%)8 (38%) 9 (43%) 21 (100%) 14 (67%)MST (mo) 1-yr OS rate10.5 46%16.0 70%NR 59%* including 22 pts with HER2-positive tumors with EGFR mutations, 2 with both HER2- and ALK-positive tumors, and 2 had ALK-positive tumors with EGFR-mutations.** 1 had an IHC2+/FISH+ tumor with mutation. Open table in a new tab Conclusions: This is the first prospective study showing a small fraction of NSCLC possessed HER2 aberrations. HER2-positive tumors had relatively poor prognosis. NSCLCs with HER2 IHC3+ and mutation seemed to be distinct subsets. Clinical trial identification: UMIN registration number 000017003 Legal entity responsible for the study: HER2-CS Network Funding: Japan Agency for Medical Research and Development Disclosure: H. Yoshioka: Honoraria: Eli Lilly, Chugai Pharma., Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, AstraZeneca, Bristol-Myers Squibb, Ono Pharmaceutical, Takeda Pharma. T. Shibayama: Honoraria: Meiji Seika Pharma Co., Ltd. Astra Zeneca K.K. Boehringer Ingelheim Pharmaceuticals, Inc. Eli Lilly Japan K.K. K. Aoe: Eli Lilly, Astrazeneca, BMS, Ono Pharmaceutical Co., Ltd. T. Kozuki: Honoraria: Chugai Pharma., AstraZeneca, Eli lilly Japan, Pfizer, Ono Pharm., Bristol-Myers Squibb, Kyowa-Hakko Kirin, Boehringer Ingelheim. N. Fujimoto: Honoraria: Kissei Co. Ltd. S. Kuyama: Honoraria: Chugai Pharma., AstraZeneca, Pfizer, Ono Pharm., Boehringer Ingelheim, Meiji Seika Pharma. H. Yanai: Honoraria: Bayer Yakuhin, Ltd, Janssen Pharmaceutical K.K., Kyowa Hakko Kirin Co., Ltd., Becton, Dickinson and Company, Fujiyakuhin Co., Ltd. K. Kiura: Honoraria: Chugai Pharmaceutical Co., Ltd. Pfizer Japan Inc. Novartis Pharma K.K. Taiho Pharmceutical Co., Ltd. Eli Lilly Japan K.K. All other authors have declared no conflicts of interest.