Single EGFR Mutation Research Articles

EGFR co-mutation is associated with the risk of recurrence in invasive lung adenocarcinoma with the micropapillary component

BackgroundInvasive lung adenocarcinoma (LUAD) patients with the micropapillary (MPP) component tend to have extremely poor prognosis. To optimize clinical outcomes, a better understanding of specific concurrent gene alterations and their impact on the prognosis of patients with the MPP component is necessary. MethodA total of 621 Chinese patients with surgically resected invasive LUAD who underwent genetic testing for lung cancer were enrolled in this retrospective study. The genomic profiling of major lung cancer-related genes based on next-generation sequencing (NGS) was carried out on formalin-fixed paraffin-embedded tumor samples. ResultAmong 621 patients with invasive LUAD, 154 (24.8%, 154/621) had the MPP component. We found that PIK3CA (4.5% vs 1.3%), KRAS (9.1% vs 4.7%), and ROS1 (2.6% vs 0.4%) were more frequent in patients with the MPP component than those without the MPP component (P < 0.05). The co-mutation occurred in 66 patients (10.6%, 66/621), of which 19 patients with the MPP component. Most of them were EGFR co-mutations (89.5%, 17/19), including EGFR and PIK3CA, EGFR and ERBB2, and other types. Patients with the MPP component who harbored EGFR co-mutations showed significantly worse recurrence-free survival (RFS) than single EGFR mutation (median RFS 20.1 vs 30.5 months; hazard ratio [HR]: 8.008; 95% confidence interval [CI]: 1.322–48.508). ConclusionsPatients with the MPP component harbored the co-mutation of driver genes had a higher risk of recurrence after surgery, especially in patients with EGFR co-mutation. EGFR co-mutation was a significant prognostic factor for RFS in patients with the MPP component.

Role of molecular testing for malignant pleural effusion in targeted therapy for advanced non‐small cell lung cancer

To confirm the predictive value of targeted therapies for oncogenic driver gene mutations detected in malignant pleural effusion (MPE) cell blocks from patients with advanced non-small cell lung cancer (NSCLC). For patients with NSCLC whose tumor tissues could not be used to detect oncogenic driver gene status, molecular mutation status in 101 MPE cell blocks was tested using amplification refractory mutation system polymerase chain reaction prior to treatment. Corresponding targeted therapies were adopted based on the detection results. Mutations observed in MPE cell blocks included epidermal growth factor receptor mutation (EGFR) (60.4% [61/101]), anaplastic lymphoma kinase fusion (6.3% [5/80]), and ROS proto-oncogene 1 receptor tyrosine kinase fusion (3% [2/70]). Other mutations that were found in <5% of patients included epidermal growth factor receptor-2, rat sarcoma-filtered germ carcinogenic homologous B1, neuroblastoma RAS viral oncogene homolog, and mesenchymal epithelial transition factor exon 14. The median follow-up time was 23.5 months for the 41 patients with a single EGFR mutation and who received tyrosine kinase inhibitor monotherapy as the first-line treatment; in these patients, the objective response rate was 78% (95% confidence intervals (CI), 62% to 89%), progression-free survival was 10.8 months (95% CI, 8.7 to 13.0 months), and overall survival was 31.7 months (95% CI, 13.9 to 49.4 months). Malignant pleural effusion cell blocks are recommended for mutation testing for targeted therapies in patients with NSCLC.

Inter- and Intratumor Heterogeneity of EGFR Compound Mutations in Non–Small Cell Lung Cancers: Analysis of Five Cases

BackgroundSeveral clinical and preclinical studies suggest that non–small cell lung cancers (NSCLCs) with EGFR compound mutations were associated with lower efficacies of first-generation EGFR inhibitors than tumors with single EGFR mutation. Some researchers hypothesize that EGFR mutation status is heterogeneous in such tumors and that second-generation EGFR inhibitors may eliminate cancer cells with uncommon EGFR mutations from tumors with EGFR compound mutations. However, this hypothesis is currently unproven; therefore, we performed the current study to determine if tumor cells with EGFR compound mutations are present in heterogeneous or homogeneous manners. Patients and MethodsMultiregion analysis was performed for surgically resected primary NSCLC tumors with EGFR compound mutations to examine the intratumor heterogeneity of EGFR compound mutations. In addition, we evaluated the intertumor heterogeneity of EGFR compound mutations using 2 pleural disseminations obtained from a patient with NSCLC at exploratory thoracotomy and 9 primary or metastatic lesions obtained from 2 autopsied NSCLC patients. Digital polymerase chain reaction, target sequencing, or direct sequencing were used to detect EGFR mutations. ResultsThis study included 5 NSCLC cases; their compound mutations were L858R+S768I, G719X+S768I, G719A+R776H, L858R+E709G, and L858R+I759M. Noncancerous pulmonary tissues from each patient did not harbor EGFR mutations, which revealed that all mutations were somatic. We did not detect any intra- or intertumor heterogeneity in these EGFR compound mutations. ConclusionNo intra- or intertumor heterogeneity was observed for EGFR compound mutations. Our results indicate that both EGFR mutations were truncal and selective elimination of cancer cells with uncommon EGFR mutations is unrealistic.

Abstract 5896: Targeted NGS analysis to predict recurrence in resected EGFR- mutated lung adenocarcinoma

Abstract Background: Targeted next-generation sequencing (NGS) is widely applied in personalized therapy of NSCLC patients by identifying driver oncogenes. Another important application of targeted NGS analysis is to predict recurrence in resected early stage NSCLC patients. We investigated targeted NGS analysis to identify the genetic alterations related to the recurrence in resected EGFR-mutated lung adenocarcinoma. Methods: Tissues from 130 patients who had complete resection of stage I to IIIA EGFR mutated adenocarcinoma (median follow-up: 45 months), were analyzed by targeted NGS with 170 cancer-related genes. The DFS according to the numbers and types of gene alterations were estimated using the Kaplan-Meier method. The independent biomarkers related to recurrence were identified by Cox proportional hazard regression analysis. Results: The relapses after surgical resections were observed in 32 patients of 130 (24.6%). The relapses were associated not with sex and smoking history but with visceral-pleural invasion (p=0.001), lympho-vascular invasion (p=0.002), and stage(p=0.001). Relapse rates were increased in order by L858R (11/59, 18.6%), exon 19 deletion (16/56, 28.6%), compound EGFR mutation (3/10, 30%) and exon 20 mutation (2/5, 40%), but there was no statistical difference. 13 of 16 (81%) relapse patients with 19 deletion had E746_A750 del. It indicates that the hot spot of exon 19 deletion related to recurrence is E746_A750 del. In the aspect of the number of mutations, the patients with single mutation were 68(51.5%). 44(33.8%) had dual mutation, 13(10.8%) had triple mutation. DFS was associated with the number of genetic mutations (p=0.025). The 5-year DFS rates were 83%, 62% and 25% for single, dual and triple mutation respectively(p&amp;lt;0.001). Besides, we found the CTNNB1 mutation was associated with worse DFS in a multivariate analysis adjusted by sex, age, stage, smoking history and operation methods (hazard ratio [HR]: 5.4, 95% confidence interval: 2.1-14.4; p=0.001). The patients with CTNNB1/EGFR co-mutation were expected to have shorter DFS than the patients with single EGFR mutation (p=0.003). Conclusions: The number of co-occurring mutations, CTNNB1 mutation and del E746_A750 in exon19 was negative prognostic factors for DFS in resected EGFR-mutated lung adenocarcinoma. We recommend that the targeted NGS should be performed to identify the genetic alterations so we can predict the outcome and plan adjuvant chemotherapy or EGFR tyrosine kinase inhibitor therapy to patients with a higher risk of recurrence. Citation Format: In Ae Kim, Hee Jung Kim, Jae Young Hur, Seung En Lee, Jung Hoon Park, Song Am Lee, Jae Jun Hwang, Wan Seop Kim, Kye Young Lee. Targeted NGS analysis to predict recurrence in resected EGFR- mutated lung adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5896.

Impact of Somatic Mutations in Non-Small-Cell Lung Cancer: A Retrospective Study of a Chinese Cohort.

BackgroundSomatic mutations are important biomarkers for selecting an optimal targeted therapy and predicting outcomes for non-small-cell lung cancer (NSCLC) patients that are often detected from tissue samples. However, tissue samples are not always readily available from these patients. The exploration of using circulating tumor DNA (ctDNA) to identify somatic mutations offers an alternative source that should be explored.MethodsIn this retrospective study, we included 280 patients diagnosed with adenocarcinoma between 2017 and 2018 in a hospital in eastern China. Tissue or ctDNA was collected, and a wide spectrum of somatic mutations was analyzed by targeted next-generation sequencing platforms. Associations among the mutation status, biomarkers, screening methods, disease stages, and interaction with treatment with overall survival (OS) were investigated.ResultsWe found that the EGFR L858R mutation was the most frequently identified mutation in adenocarcinoma in this population by both methods, followed by KRAS (p=3.7e-09), PIK3CA (p=5e-04), and HER2 mutations (p=6.3e-03). We observed that EGFR mutations were significantly mutually exclusive with KRAS, HER2, and MET. FGFR1 mutations were significantly more abundantly detected in the ctDNA group. We found an interaction effect between EGFR mutation and target therapies. The ability of the targeted therapy to improve OS in patients with a single EGFR mutation (HR=0.069, p=0.07) approached significance, but this was not the case for the patients with more than one EGFR mutation or without an EGFR mutation (HR=0.813, p=0.725). Furthermore, the effect of chemotherapy was more predominant in the EGFR group in comparison to the control group.ConclusionThese findings provide useful information on the distribution of somatic mutations via different screening methods and how this related to the optimal treatment selection in Chinese patients with NSCLC.

Clinical features and therapeutic options in non-small cell lung cancer patients with concomitant mutations of EGFR, ALK, ROS1, KRAS or BRAF.

BackgroundAlthough oncogenic driver mutations were thought to be mutually exclusive in non‐small cell lung cancer (NSCLC), certain tumors harbor co‐occurring mutations and represent a rare molecular subtype. The evaluation of the clinical features and therapeutic response associated with this NSCLC subtype will be vital for understanding the heterogeneity of treatment response and improving the management of these patients.MethodsThis retrospective study included 3774 samples from patients diagnosed with NSCLC. All samples were screened for EGFR, ALK, ROS1, KRAS, and BRAF mutation using the amplification‐refractory mutation system. The relationship between concomitant driver mutations and clinicopathologic characteristics, and patient clinical outcomes were evaluated.ResultsSixty‐three (1.7%) samples had more than one driver gene mutation. Among these, 43 were coalterations with an EGFR mutation, 20 with an ALK rearrangement, and eight with an ROS1 rearrangement. Except for ROS1 concomitant mutations that were more frequent in male patients (87.5%, P = 0.020), the clinicopathological features of the concomitant mutation patients were not significantly different from those harboring a single EGFR, ALK, or ROS1 mutation. Furthermore, first‐line EGFR‐TKI treatment did not significantly improve the progression‐free survival (PFS) of patients harboring EGFR concomitant mutation, compared to patients harboring a single EGFR mutation. However, for EGFR concomitant mutation patients, TKI therapy was more effective than chemotherapy (median PFS of 10.8 vs 5.2 months, P = 0.023). Lastly, KRAS mutations did not influence the EGFR‐TKI therapy treatment effect.ConclusionIn this study, concomitant mutations were found in 1.7% of the NSCLC. EGFR‐TKI therapy was more effective than chemotherapy for patients harboring EGFR concomitant mutation, and ROS1 concomitant mutations were more frequent in male patients. For patients harboring coalterations with an ALK or ROS1 rearrangement, we should be cautious when considering the therapeutic options.

Concurrent gene alterations with EGFR mutation and treatment efficacy of EGFR-TKIs in Chinese patients with non-small cell lung cancer.

PurposeWe investigated the frequency of concurrent genes in EGFR-mutant non-small cell lung cancer patients and determined its value in predicting the efficacy of EGFR-TKIs treatment.MethodsThree hundred and twenty patients, who harbored EGFR activating mutations and received EGFR-TKIs treatment, were examined for another eight genes including KRAS, NRAS, PIK3CA, BRAF, and HER2 mutations and ALK, ROS1, and RET fusion genes based on reverse transcription PCR. Progression-free survival and overall survival with EGFR-TKIs treatment were evaluated using Kaplan-Meier methods and compared between different patients using log-rank tests.RESULTSTwenty-one (6.6%) of 320 EGFR mutant samples with additional gene alterations were identified. The most common concurrent gene was PIK3CA mutation (n = 9), followed by EML4-ALK rearrangement (n = 6), HER2 mutation (n = 3), RET rearrangement (n = 1), ROS1 rearrangement (n = 1) and KRAS mutation (n = 1). Patients with single EGFR mutation had a significantly longer progression-free survival than those with concurrent genes (10.9 vs. 6.0 months, P = 0.002). Among the 21 cases, patients with PIK3CA mutation had the longest median progression-free survival (7.6 months), followed by ALK rearrangement (5.0 months) and other gene types (1.2 months). No overall survival difference was found between patients with single EGFR mutation and concurrent gene alterations (21.0 vs.17.6 months, P = 0.17).ConclusionWe demonstrated that concurrent gene alterations occurred in some patients with EGFR mutations. Concurrent gene alterations decreased the efficacy of EGFR-TKIs.