EGFR Mutation Rate Research Articles

Clinical influence of switching companion diagnostic tests for EGFR-TKs from Therascreen to Cobas v2.

BackgroundSeveral companion diagnostic (CDx) tests for epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) have been approved. In our institute, the CDx test for EGFR‐TKIs was changed from the Therascreen test (Therascreen) to the Cobas EGFR v2 test (Cobas) because only Cobas was approved for the use of osimertinib in patients with EGFR‐mutated non‐small cell lung cancer (NSCLC) with T790M mutations. The clinical influence of switching the CDx test has not yet been examined comprehensively.MethodsAll serial patients with lung cancer tested for EGFR mutations with CDx tests between February 2014 and February 2016 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR) were enrolled in this analysis.ResultsTherascreen was used as a CDx test for EGFR‐TKI therapy in 607 patients between February 2014 and January 2015, and Cobas was used in 621 patients between February 2015 and February 2016. EGFR mutations were detected in 218 patients (35.9%) and 244 patients (39.3%) tested with Therascreen and Cobas, respectively. At the initial diagnosis, 400 and 459 patients were tested with Therascreen and Cobas, respectively. EGFR mutation subtypes, including del19, L858R, and others, were detected in 13.0%, 17.0%, and 2.5% of patients using Therascreen and 17.4%, 14.4%, and 1.5% of patients using Cobas, respectively.ConclusionsNo significant impact of switching from Therascreen to Cobas as the CDx test for EGFR mutations in clinical practice was observed. However, the detection pattern of the EGFR mutation subtypes between the two CDx tests was slightly different.Key pointsSignificant findings of the studyWe examined the influence of changing the EGFR test in 1228 patients in total. The detection rate of EGFR mutations was similar. However, the detection pattern for EGFR subtype mutations was slightly different between the two tests.What this study addsSwitching CDx tests from target polymerase chain reaction (PCR)‐ to next‐generation sequencing (NGS)‐based methods may lead to obvious changes in clinical practice. When the CDx test is required to change, the investigation of this influence is warranted in future studies.

Cell-free DNA from cerebrospinal fluid can be used to detect the EGFR mutation status of lung adenocarcinoma patients with central nervous system metastasis.

BackgroundEGFR tyrosine kinase inhibitors (TKIs) have revolutionized the therapeutic approach for EGFR mutated patients. However, acquired resistance to EGFR-TKI therapy is unavoidable. Repeat biopsy cannot be used, and peripheral blood detection shows a low positive rate in cases of brain-only disease progression.MethodsDroplet digital polymerase chain reaction (PCR) (ddPCR) was performed on the plasma and cerebrospinal fluid (CSF) samples of 79 lung adenocarcinoma (LUAD) patients with EGFR mutations and central nervous system (CNS) metastasis. The differences in the EGFR mutation status between the paired plasma and CSF samples were assessed, and the role of CSF testing as a predictor of overall survival was evaluated.ResultsThe CSF of patients with neurological symptoms, EGFR-TKI treatment, or leptomeningeal metastasis (LM) had a significantly higher positive rate of EGFR mutation compared to the plasma samples (P=0.001, P=0.035, P=0.019, respectively). Moreover, EGFR mutation status in CSF was consistent with neurological symptoms and LM (kappa =0.455, P<0.001; kappa =0.508, P<0.001; respectively). For the patients with brain metastasis, EGFR mutation-positive rate in CSF samples was lower than that in plasma samples (28.3% vs. 64.2%, P<0.001), while the patients with LM had the opposite result (84.6% vs. 38.5%, P=0.004). Moreover, patients with EGFR mutation in their CSF experienced worse survival [hazard ratio (HR) =2.93, 95% confidence interval (CI): 1.45–5.92; P=0.003, P adjust <0.0001].ConclusionsThe EGFR mutation status of CSF was different from that of plasma and is correlated with patient prognosis. CSF could be helpful in detecting the EGFR mutation status of patients, particularly in cases of LM.

Positive Mutation of EGFR Inhibitor Undergo Erlotinib, Gefitinib, Icotinib or Osimertinib Plus Chinese Medicine Versus EGFRTKIs Alone In Patients With NSCLC, A Regional Study East China

Management of non-small cell lung cancer has been changed dramatically since detection of EGFR mutation. The rate of EGFR mutation in East China is unknown. In China, lung cancer is the most frequently diagnosed cancer and the leading cause of cancer-related mortality. The five-year survival rate in patients with lung cancer varies from 3.7–32.9%, depending on stage and regional differences. The majority of the tumors were Stage IIIB or IV Advanced Lung Adenocarcinoma. The two year survival rate of the patients was 70.6%, the overall survival was 58.8%. Methods: We electronically searched CNKI, Pub Med, Cochrane from database inception and manually searched Chinese-language oncology journals to identify A Positive Mutation of EGFR Inhibitor Undergo Erlotinib, Gefitinib, Icotinib Or Osimertinib Plus Chinese Medicine Versus Erlotinib, Gefitinib, Icotinib Or Osimertinib Alone In Patients With NSCLC, A Regional Study East China. The quality of the included trials was assessed using the method of Cochrane. If heterogeneity existed among subgroups, then overall results (OS) were calculated based on a random-effects model; otherwise, a fixed effects model used. Results: Electronic database searches yielded 1450 citations with NSCLC. We identified full text articles retrieved for detailled evaluation 70. Sample size of each trial had calculated by Rev Man 5.3.

Genomic characteristics of driver genes in Chinese patients with non-small cell lung cancer.

BackgroundThe aim of this study was to determine the demographic profile of driver gene alterations, especially low‐frequency gene alterations in Chinese patients with non‐small cell lung cancer (NSCLC).MethodsA total of 7395 Chinese patients with NSCLC were enrolled in the study. Next‐generation sequencing (NGS) was performed on formalin‐fixed paraffin‐embedded specimens collected via either surgical resection or biopsy.ResultsThe frequent genomic alterations found in the study were EGFR mutations (51.7%), KRAS mutations (13.1%), MET alterations (5.6%; 3.2% copy number gains and 0.5% exon 14 skipping mutation), HER2 alterations (7.0%; 2.0% copy number gains and 5.4% mutations), ALK alterations (7.2%; 3.9% rearrangements), RET rearrangements (1.4%), ROS1 rearrangements (0.9%), and NTRK rearrangements (0.6%). The EGFR mutation rate was found to be significantly higher in women than in men (69.1% vs. 38.5%, P < 0.001), while the KRAS mutation (17.5% vs. 7.3%, P < 0.001) and MET alteration rates (6.5% vs. 4.5%, P < 0.001) were significantly higher in men than in women. The EGFR mutation rate tended to decrease with age in the group aged >40 years, while the KRAS mutation rate tended to increase with age. The HER2 mutation (13.9% vs. 6.7%, P < 0.001) and ALK alteration rates (14.3% vs. 6.9%, P < 0.001) were significantly higher in the group aged <40 years than in groups aged 40 years or older.ConclusionsThe frequency of different driver genes was diverse in different age‐gender groups, and the results of this study may assist clinicians in clinical decision‐making and the development of public healthcare strategies in the future.Key pointsSignificant findings of the study This study demonstrated that the frequency of different driver genes was diverse in different age‐gender groups. What this study adds It may enable clinicians to make clinical decisions, and assist government, pharmaceutical researchers and insurance companies develop public healthcare strategies.

Lung cancer in China: current and prospect.

To describe the current status of lung cancer in China, including incidence, prevention, molecular testing and treatment. Lung cancer presents a major public health issue and an enormous burden on society in China, because of its increasing incidence and high mortality. Several distinct gene profiles were associated with lung cancer in China: high EGFR mutation rate, low KRAS mutation rate and more comorbidity of HBV infection. Thus, local Chinese Society of Clinical Oncology Guidelines with more consideration of drug accessibility, regional development differences were highly recommended for clinical practice. For treatment, targeted therapy has achieved fruitful progress. Immunotherapy in China was a little bit lag behind previously and now there is a surge of immunotherapeutic drugs under investigation. For future, more preventive strategies and more trials considering chrematistics of Chinese lung cancer are needed. There are achievements and shortcomings for lung cancer prevention and treatment in China. More work considering distinct characteristic of lung caner in China are needed.

Oncogenic Genetic Alterations in Non-Small-Cell Lung Cancer (NSCLC) in Southwestern China.

PurposeTo investigate the impact of oncogenic genetic alterations (GAs) on non-small-cell lung cancer (NSCLC) in southwestern China.Patients and MethodsWe first collected 579 pathologically confirmed NSCLC specimens and then used next-generation sequencing (NGS) to evaluate the DNA samples for GAs. Both the tissue and plasma samples were provided by 28 patients. Furthermore, subgroup analyses based on sample type, concordance, and GA type were carried out.ResultsGAs were detected by NGS in 61.8% (358/579) of patients. Two hundred and twenty-nine patients (39.6%) harbored EGFR mutations, 63 (10.9%) harbored KRAS mutations, 13 (2.2%) harbored BRAF mutations, 30 (5.18%) harbored ALK fusions, and 13 (2.2%) had ROS1 fusions. We found that females (p < 0.01), nonsmokers (p < 0.001), adenocarcinoma (p < 0.001), and tissue (p = 0.03) had a relatively high EGFR mutation rate. Notably, NSCLC patients from Xuanwei had a significantly different mutational pattern for EGFR in comparison with that of non-Xuanwei patients (higher G719X + S768I mutations and multiple gene alterations, but fewer exon 19 deletion mutations and single gene alterations). We found that adenocarcinoma (p = 0.02), family history of malignancy (p = 0.03), Xuanwei origin (p < 0.001), and tissue (p = 0.04) were associated with a higher number of KRAS mutations. Subgroup analysis showed that ALK (p < 0.001) and ROS1 (p < 0.05) fusions and rare EGFR mutations (p < 0.001) were associated with non-Han ethnic patients.ConclusionYunnan NSCLC patients from Xuanwei and non-Han ethnic patients had an obviously unique prevalence of GAs.

A Multi-Center, Real-Life Experience on Liquid Biopsy Practice for EGFR Testing in Non-Small Cell Lung Cancer (NSCLC) Patients.

Background: circulating tumor DNA (ctDNA) is a source of tumor genetic material for EGFR testing in NSCLC. Real-word data about liquid biopsy (LB) clinical practice are lacking. The aim of the study was to describe the LB practice for EGFR detection in North Eastern Italy. Methods: we conducted a multi-regional survey on ctDNA testing practices in lung cancer patients. Results: Median time from blood collection to plasma separation was 50 min (20–120 min), median time from plasma extraction to ctDNA analysis was 24 h (30 min–5 days) and median turnaround time was 24 h (6 h–5 days). Four hundred and seventy five patients and 654 samples were tested. One hundred and ninety-two patients were tested at diagnosis, with 16% EGFR mutation rate. Among the 283 patients tested at disease progression, 35% were T790M+. Main differences in LB results between 2017 and 2018 were the number of LBs performed for each patient at disease progression (2.88 vs. 1.2, respectively) and the percentage of T790M+ patients (61% vs. 26%).

Analysis of EGFR mutation and clinical features of lung cancer in Yunnan

Objective: To analyze the EGFR mutation profile of lung cancer patients in Yunnan, and to provide evidence for clinical personalized treatment. Methods: Demographic and clinical data of 2 967 lung cancer patients undergoing EGFR identification were collected and analyzed from January 2014 to August 2019 in Yunnan Cancer Hospital. Results: The proportion of EGFR mutation in 2 967 patients with lung cancer was 46.2%. Univariate analysis showed that the proportion of EGFR mutation in women was higher than that in men (P<0.001) and displayed a downward trend with age (P=0.03). The mutation rate of ethnic minorities was higher than Han (P=0.012). Mutation rate in patients without smoking history was higher than those with smoking history (P<0.001), and patients without drinking history was higher than patients with drinking history (P<0.001). Mutation rate in patients without family history of lung cancer was higher than those with family history (P=0.008). The mutation rate of adenocarcinoma was higher than other pathological types (P<0.001). The mutation rate was different among stages, and it was higher in early patients than that in advanced patients (P<0.001). The mutation rate of tissue specimens was higher than those of cytology and peripheral blood samples (P<0.001). The mutation rate of Xuanwei area was lower than that in non-Xuanwei area (P<0.001). Multivariate analysis showed that gender (P<0.001), age (P=0.036), smoking history (P<0.001), pathological type (P<0.001), specimen type (P<0.001), and whether or not Xuanwei area (P<0.001) were the independent factors of EGFR mutation.The EGFR mutation was more common in female, non-smokers, adenocarcinoma, non-Xuanwei area, tissue specimen and young lung cancer patients.The mutation types of EGFR in 1 370 cases mainly included 19-Del and L858R. The predominant mutation of EGFR in Xuanwei area was L858R, while in non-Xuanwei area was 19-Del.The mutation rates of G719X, G719X+ L861Q, G719X+ S768I, and S768I in Xuanwei were higher while the mutation rates of 19-Del, L858R, and 20-ins were lower than non-Xuanwei area (P<0.05). The 19-Del mutation rate of ethnic minorities is higher than that of Han (P<0.001). The combined mutation rate of G719X, L861Q in Han was higher than that of ethnic minorities (P=0.005). Conclusions: The EGFR mutation rate in lung cancer patients in Yunnan is similar to Asian and Chinese, and higher in female, non-smokers, adenocarcinomas, young and non-Xuanwei area patients. The most common types of EGFR mutation in Yunnan are 19-Del and L858R. The predominant mutation of EGFR in Xuanwei area is L858R, while in non-Xuanwei area is 19-Del. The mutation rates of G719X, G719X+ L861Q, G719X+ S768I and S768I are higher in Xuanwei patients than those in non-Xuanwei patients. The combined mutation rate of G719X and L861Q in Han nationality is higher than that of ethnic minorities.

Status of 10 targeted genes of non-small cell lung cancer in eastern China: A study of 884 patients based on NGS in a single institution.

BackgroundThe status of targeted genes and the association between targeted genes and clinicopathological features in Chinese lung cancer patients remains to be elucidated.MethodsThe status of 10 targeted genes was evaluated by next‐generation sequencing (NGS) in 884 non‐small cell lung cancer (NSCLC) patients. The relationship between gene alterations and clinicopathological characters was analyzed.ResultsOverall, 684 (77.4%) patients harbored gene alterations, and EGFR (510, 57.7%) was found to be the most common type of mutation followed by KRAS (91, 10.3%), HER2 (38, 4.3%), PIK3CA (32, 3.6%), ALK (21, 2.4%), BRAF (10, 1.1%), ROS1 (5, 0.6%), RET (5, 0.6%), MET (4, 0.5%) and NRAS (1, 0.1%). Gene alterations were more frequent in females, non‐smokers and adenocarcinoma (P < 0.001). EGFR mutations were associated with women, non‐smokers, normal level of serum tumor markers, and adenocarcinoma (P < 0.001). Patients without lymph node metastasis (P = 0.012), or early stage disease (P < 0.001) exhibited a higher EGFR mutation rate. KRAS mutations tended to arise in men (P < 0.001), smokers (P < 0.001) and patients with higher levels of serum tumor markers (P = 0.048). A mucus‐producing component was associated with KRAS (P < 0.001), ROS1 (P = 0.033) and ALK (P < 0.001) alterations. ALK and ROS1 rearrangements were more frequent in micropapillary structures (P = 0.004, P = 0.012). BRAF mutation was associated with advanced disease patients and micropapillary structure (P < 0.001). PIK3CA mutation was more likely to be found in elderly patients (P = 0.014). Some patients had synchronous gene alterations, including EGFR/PIK3CA, EGFR/HER2, HER2/KRAS, EGFR/KRAS, EGFR/ROS1, EGFR/NRAS, KRAS/PIK3CA, KRAS/PIK3CA/HER2. ConclusionsMost patients had at least one genetic alteration, and individual patients harbored synchronous mutation. Each gene alteration had unique clinicopathological characteristics.Key pointsSignificant findings of the studyThis study revealed the frequency and distribution of 10 targeted gene abnormalities and their association with clinicopathological parameters of Chinese non‐small cell lung cancer (NSCLC) patients in eastern China.What this study addsSome rare synchronous mutations were detected in our study by next‐generation sequencing (NGS).

Co-mutation features in treatment-naïve EGFR-mutant lung adenocarcinoma.

e21616 Background: In Chinese patients with lung adenocarcinoma, the positive rate of EGFR mutation was 40% - 50%, EGFR-TKIs therapy for lung cancer was also aimed at this part of patients. However, different EGFR mutation types have different therapeutic effects, this study focuses on different EGFR mutation types to divide the population of lung adenocarcinoma. Methods: We retrospectively reviewed gene test results of two hundred and sixty-two treatment-naïve adenocarcinoma patients. Tumor tissues (199, 76%), plasma (46, 17.5%) and other samples (17, 6.5%) were subject to next-generation sequencing using a 59-gene panel, which enables simultaneously assess SNV, Indel, rearrangements and CNV variations. Results: There were 174 females. These patients were divided into four groups, which 139 were EGFR L858R, 99 were EGFR exon 19 deletion, 7 were EGFR 20 ins and 17 were uncommon EGFR mutations, the co-mutation proportions with EGFR were 84.9% (118/139), 76.8% (76/99), 71.4% (5/7) and 94.1% (16/17) respectively. The mean numbers of co-mutation genes in L858R and exon 19 deletion were 4.173 and 3.258 (p&lt;0.05). TP53 mutation was detected in 14.3% (1/7) 20ins group, which had a significant difference to L858R (59.7%, 83/139) and uncommon mutation groups (70.6%, 12/17) (p&lt;0.05). Meanwhile, EGFR amplification proportion in L858R (18%, 25/139) and exon 19 deletion (6.1%, 6/99) were significantly different (p&lt;0.05). The actionable mutations associated with target therapy involved in multiple pathways, for example, the HRR pathway and cell cycle pathway, related genes had no significant difference among the four groups. In these lung adenocarcinoma patients, we also found 6 EGFR T790M (2.3%, 6/262). Three cases accompanied with exon 19 deletion, and another three were L858R, no distribution in 20ins and uncommon groups. Conclusions: The phenomenon of concurrent gene mutation in treatment-naïve EGFR-mutant lung adenocarcinoma is common. EGFR mutant subgroups have different co-mutation features, like gene number and mutated genes. It may be the factor leading to different therapeutic effects of EGFR-TKIs, and indicate the importance of multiplex molecular test and further researches of target therapies.

Comprehensive investigation of mutational features of various lung adenocarcinoma histological subtypes among Chinese patients.

e21090 Background: Lung adenocarcinoma (LUAD) is further classified into several histological subtypes according to the World Health Organization classification; however, data on the molecular profile of these histological subtypes are limited. In this study, we aimed to investigate the mutational features of various LUAD histological subtypes among Chinese patients. Methods: We retrospectively analyzed clinical, histopathologic, and sequencing data from 3,425 consecutive patients diagnosed with stage IA-IVB LUAD between January 2017 to December 2019 at the Department of Pathology. Results: Based on histologic subtype, the cohort comprised of 0.2% atypical adenomatous hyperplasia (AAH, n = 6), 7.2% adenocarcinoma in situ (AIS, n = 246), 14.0% minimally invasive adenocarcinoma (MIA, n = 479), and 78.6% invasive adenocarcinoma (INV, n = 2,694), including 42.0% acinar (n = 1,438), 12.7% papillary (n = 435), 8.8% lepidic (n = 302), 8.5% solid (n = 290), 3.2% micropapillary (n = 109), 2.8% invasive mucinous (n = 95), 0.6% enteric (n = 21), 0.1% fetal (n = 3), and 0.1% colloid (n = 1). Analysis of mutation profiles revealed significantly higher mutation detection rates of ERBB2 ( P&lt; 0.01), BRAF ( P&lt; 0.01), and MAP2K1 ( P= &lt; 0.01) among patients with AIS, AAH and MIA as compared to patients with INV. Meanwhile, TP53 ( P&lt; 0.01) and EGFR ( P&lt; 0.01) mutations were significantly higher among patients with INV as compared to patients with AIS and MIA. Among the invasive subtypes, patients with invasive mucinous adenocarcinoma had significantly higher KRAS mutation rate (75%, P&lt; 0.01). Lepidic (81%), acinar (80%), papillary (77%), and micropapillary (66%) were the subtypes with the highest EGFR mutation rates. Conclusions: By analyzing the genomic data of a large cohort of patients, our study provides a more comprehensive outlook of gene mutations according to LUAD histological subtypes. Enrichement of actionable mutation in particular histological subtype contributes to more treatment option and better clinical outcomes as compared to other histological subtype, indicating the clinical relevance of performing comprehensive mutation profiling in addition to histopathologic analysis in all LUAD patients.

Clinicopathologic Features and Genetic Alterations in Adenocarcinoma In Situ and Minimally Invasive Adenocarcinoma of the Lung: Long-Term Follow-Up Study of 121 Asian Patients.

Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are both small tumors with good prognosis after surgical resection, and most of them present as ground glass opacities (GGOs) on computed tomography (CT) screening. However, the differences in clinicopathologic features and genetic alterations between AIS and MIA are poorly elaborated, and few studies have evaluated the prognosis of MIA with different invasive components. Meanwhile, the histological features of lung lesions presenting as unchanged pure GGOs are barely understood. Clinicopathologic features and genetic alterations of AIS (n = 59) and MIA (n = 62) presenting as GGOs were analyzed. Long-term preoperative observation (ranging from 2 to 1967 days) and postoperative follow-up (ranging from 0 to 92months) was conducted. The tumor size and consolidation/tumor ratio were significantly larger in the MIA cohort than those in the AIS cohort both on CT and microscopy images. Immunohistochemically, the expression of p53, Ki67, and cyclin D1 was higher in MIA than in AIS. The EGFR mutation rate was significantly higher in MIA, while other genetic alterations showed no differences. Six MIA cases showed recurrence or metachronous adenocarcinoma and all the cases with a predominant micropapillary invasive pattern demonstrated this feature. The current CT measurements may be helpful in distinguishing AIS from MIA, but show limited utility in predicting the histology of unchanged pure GGOs. The invasive pattern may have an influence on the postoperative process of MIA; therefore, further studies are needed to evaluate the current diagnostic criteria and treatment strategy for MIA.

Mutation of EGFR in Non-small Cell Lung Cancer, a Regional Study in Upper Egypt

Management of non-small cell lung cancer has been changed dramatically since detection of EGFR mutation. The rate of EGFR mutation in Upper Egypt is unknown. In this study; EGFR mutation in non-small cell lung cancer tissue was evaluated and correlated with clinicopathological features of the tumors. Tissue samples of non-small cell lung cancer that had been confirmed by histopathological and immunohistochemical examinations were evaluated for mutation of EGFR by StripAssay. Thirty four patients with non-small cell lung cancer; 21 males and 13 females with a mean age of 55.94 years were included in this study. The median tumor size was 6.0cm and more than half of the tumors were classified as T3. Fourteen patients had N2 nodal stage and 19 patients had either malignant pleural effusion or distant metastasis. The majority of the tumors were adenocarcinomas and half of them were grade II. The two year survival rate of the patients was 70.6% and the overall survival was 58.8%. EGFR mutation was recorded in 44.1% of the tumors; all of which were adenocarcinoma variant. The mutation was significantly more frequent in large sized tumors and it was relatively associated with poor survival. Mutation of EGFR was not associated with patients` age, sex, tumor grade, T stage, N stage or status of distant metastasis. The rate of EGFR gene mutation in non-small cell lung cancer in Upper Egypt is relatively high and target therapy based on these mutations could improve patients` outcome.

Mutational spectrum of tobacco associated oral squamous carcinoma and its therapeutic significance

Oral squamous cell cancer (OSCC) is a common malignancy attributed to use of chewing smokeless tobacco and smoking. Most of the targeted strategies are based on EGFR expression and mutation; however, none of them has shown significant improvement in survival and response rates. We carried out this study to evaluate mutational profile of tobacco associated oral carcinoma with special emphasis on EGFR and its downstream events.Patients and methodsA total of 46 histologically proven cases were recruited between January 2017 and January 2019. Apart from detailed clinical and histological studies, the paraffin-embedded tissue was submitted for expression of 50 genes using Next Generation Sequencing using Ion Ampliseq Cancer Hotspot Panel v2.ResultsThe mean age of patients was 47.8 ± 10.9 years. Majority had tumors on buccal mucosa (24) and tongue (13). Nineteen of these tumors were larger than 4 cm, and 5 had adjacent site involvement. Thirty one were node positive. TP53 mutations were commonest seen in 19 followed by CDKN2A in 11, HRAS in 8, PIK3CA in 3, SMARCB1 in 2, and KIT, EGFR, BRAF, STK11, ABL1, RB1 in one case each. Concomitant TP53 mutation was identified with other mutations like CDKN2A, HRAS, KIT, PIK3CA, STK11, SMARCB1, ABL1, and RB1 making tobacco-associated OSCC as a heterogeneous mutational tumor with multiple events. A patient with TP53 mutations has poor disease free survival (47.4 vs 63% p = 0.17); however, this was not statistically significant.ConclusionThe study shows a heterogeneous mutational spectrum with multiple mutational events in OSCC. The low EGFR mutation rates and higher mutations in EGFR downstream pathways including that in TP53 and HRAS suggest that anti EGFR strategies may not succeed in these tumors and newer agents and therapeutic combinations need to be tried.

P2.09-09 EGFR Is Highly Mutated in Lung Adenocarcinoma Patients with History of Breast Cancer

EGFR gene mutation has been reported to be frequent in the patients with specific clinical features such as female, adenocarcinoma, and East-Asian ethnicity. The mutation rate in lung adenocarcinoma is approximately 50% in Japan. Currently, the molecular mechanism which cause EGFR mutation has not been clarified. If the EGFR mutation in lung adenocarcinoma correlates with specific type of malignancy in the other organ, it could be a clue to find a mechanism which promote carcinogenesis of lung adenocarcinoma. In the current study, we focused on breast cancer. Patients with lung adenocarcinoma who underwent pulmonary resection in our hospital from January 2011 to December 2018 were analyzed. We retrospectively reviewed clinical information such as past illness, radiological findings, pathological diagnosis, and EGFR mutation status. Correlation was tested by chi-square test and p value of less than 0.05 was regarded as statistically significant. A total of 21 patients of lung adenocarcinoma had history of treatment for breast cancer. All patients were female. Among them, EGFR mutation was detected in 20 patients (95%). One patient who were negative for EGFR mutation had history of not only breast cancer but also cervical cancer of uterus and gastrointestinal stromal tumor, and developed angiosarcoma of the skin. Detected EGFR mutation types in 20 patients were as follows; deletion in exon 19 for 9 patients, L858R for 7 patients G719X for two patients, and L861Q for one patient. One patient showed multiple mutation (G719X and L861). In the same period, among 203 lung adenocarcinoma patients without other organ malignancy, 115 showed EGFR mutation (56.7%). There was significant difference in EGFR mutation rate between breast cancer group and no malignancy group (p=0.00058). Patients of lung adenocarcinoma with history of breast cancer showed extremely high positive rate for EGFR mutation in Japan, suggesting underlying common oncogenic molecular mechanism between lung adenocarcinoma and breast cancer. Elucidation of the mechanism may contribute to the diagnosis and treatment of carcinogenesis of breast cancer and lung cancer.

P2.14-52 The Results from Plasma EGFR Mutation Analysis in NEJ026 Study

EGFR mutation analysis of plasma circulating tumor DNA (ctDNA) has been reported to be useful to detect resistant mutations and to predict the efficacy of treatment. In NEJ026 study, we demonstrated the PFS of erlotinib plus bevacizumab (BE) treatment was significantly superior to the erlotinib alone (E) in NSCLC patients harboring EGFR mutation. Evaluation of plasma EGFR mutations included in NEJ026 study as preplanned analysis. At the time points of pretreated (P0), 6 weeks after study treatment started (P1), and confirmed progressive disease (P2), the plasma samples were collected from the patients enrolled to NEJ026 study. The number of enrolled patients were 112 in BE and 114 in E. Plasma ctDNA analysis for detection of the activating EGFR mutation and T790M mutation were performed by modified PNA-LNA PCR clamp method. The total numbers of collected plasma samples in BE and E were 108 (96.4%) and 107 (95.5%) at P0, 95 (84.8%) and 97 (86.6%) at P1, and 42 (37.5%) and 53 (47.3%) at P2, respectively. In eligible patients having EGFR activating mutation detected by cytohistological specimens, detection rate of plasma EGFR mutation at P0 was 68% (147/215). The detection ratio of T790M mutation at P2 were similar in both arms: 8 (19.0%) in BE and 11 (20.8%) in E. By detection pattern of activating EGFR mutation, PFS was evaluated among three groups: type A (P0 (-), P1 (-)), type B (P0 (+), P1(-)), and type C (P0 (+), P1(+)). Type A achieved the best response to both TKI [Type A BE: 18.1 M (n = 32, 95% CI, 11.5 to upper limit not reached (NR)), E: 16.7 M (n = 26, 95% CI, 11.2 to NR )]. Type B also had better PFS to TKI and BE is more favorable effect than E compared to other types [type B BE: 15.5 M (n = 48, 95% CI, 12.4 to 23.3), E: 11.1 M (n = 57, 95% CI, 8.5 to 13.7)]. Type C showed worse response to both treatment [type C BE: 6.0M. (n = 12, 95% CI 2.6 to NR), E: 4.3 M (n = 10, 95% CI, 2.8 to 20.2)]. BE had better PFS in all types. Frequency of T790M in P2 was similar among BE and E. When patients still had detectable activating EGFR mutation in plasma ctDNA after treatment for 6 weeks, you should consider that they might have poor response to both BE and E.

Lepidic, Papillary Components and EGFR Mutations are Frequent in Patients With Lung Adenocarcinoma Who are Over 75 Years Old.

Treatment for lung adenocarcinoma frequently diverges from standard treatment in older patients. Clinical, pathologic, and molecular characteristics of lung cancer in patients over 75 years old have not been fully described. The aim of our work was to describe the rate of EGFR, KRAS, BRAF, and HER2 mutations, and ALK rearrangement and pathologic characteristics in patients with lung adenocarcinoma over 75, compared with patients below 75 years old. This is a retrospective study from 2 cohorts: a histopathologic cohort of all consecutively resected lung adenocarcinoma in our institution for patients over 75 (n=54, from 2006 to 2017) compared with patients below 75 years old (n=148, from 2014 to 2017) and a molecular cohort of all stage IIIb or IV lung adenocarcinoma from 2009 to 2017 (n=1611). Papillary and lepidic components were more frequently found in patients over 75 years old (P=0.046 and 0.0078, respectively). The rate of current smokers was lower in older patients (P<0.0001). EGFR mutations were more frequent in patients over 75 than in younger patients: 17% versus 8.1% (P<0.0001). The mutually exclusive KRAS mutation was more frequent in patients below 75 years old than in older patients: 25.8% versus 12.8% (P<0.0001). There was no difference for the proportion of the 2 most frequent EGFR mutations (exon 19 deletion and L858R mutation) (P=0.85) or KRAS-mutated codon (P=0.22) between tumors in younger or older patients. There was no statistically significant difference for the presence of BRAF, HER2 mutations, and ALK rearrangement (P=0.44, 0.71, and 1, respectively). Our work highlights the fact that EGFR mutations are more frequent in patients over 75 years old in our population. We can hypothesize that this difference might be mainly caused by the less frequent occurrence of tobacco-smoking-related lung cancers in the elderly and the presence of a lepidic or papillary component in this age group.

P1.14-11 A Prospective Multicenter Study of Target-Capture Deep Sequencing in Paired Tissue and ctDNA to Guide EGFR-Mutated Lung Cancer Treatment

TKIs have significantly improved the survival of NSCLC pts carrying sensitive mutations. However, heterozygous responses were observed. We conducted a prospective multicenter clinical trial to explore factors associated with the efficacy of EGFR-TKI, and assess the mutation and TMB concordance between plasma and tissue NGS. Paired tumor and plasma samples were obtained from treatment naïve advanced NSCLC pts whenever applicable. DNA was sequenced by target-capture deep sequencing of 1021 tumor-related genes (pan-cancer panel). PFS was estimated using Kaplan-Meier method and compared using log-rank test. Tissue TMB (tTMB) and plasma TMB (bTMB) analysis interrogated SNVs/Indels with VAF ≥3% and ≥0.5%, respectively. TMB-H pts were identified with ≥9 muts/Mb. From Feb. 2017 to Jan. 2019, 262 advanced NSCLC pts were enrolled from 12 centers. In 224 pts with paired tumor and plasma samples, 144 had EGFR sensitive mutations in tumor samples (L858R, 46%; Ex19Indel, 42%), of whom, 106 (74%) had the identical mutations detected in plasma. The detection rate of tissue EGFR mutations in paired plasma was significantly higher in pts with extrathoracic metastasis (81% vs. 61%, p = 0.03). In 38 pts lacking paired samples, 20 pts had EGFR sensitive mutations detected. Thus, 164 pts were identified as EGFR positive by either plasma or tissue NGS. One hundred of them were treated EGFR TKIs (ORR: 70%, mPFS: 20 mo). The ORR was affected by EGFR subtypes (Ex19Indel vs. L858R: 72% vs. 45%, p = 0.02), concomitant CNV/fusion (with vs. without: 11% vs. 68%, p = 0.002) and CDKN2A mutations (with vs. without: 0% vs. 66%, p = 0.007). Mutations in p53 pathway (p = 0.02), CDK12/13 (p = 0.0002), concomitant CNV/fusion (p = 0.003), and high number of alterations (≥ 5) (p = 0.003) significantly shortened mPFS. tTMB was correlated with bTMB (rPearson = 0.9, p <0.0001), with a concordance rate of 90% for TMB-H and TMB-L classification. Interestingly, 9.8% of the EGFR positive pts were bTMB-H, and mPFS was shorter in bTMB-H pts (6 mo, 95% CI: 5 - NR) than in bTMB-L pts (NR, 95%: 13 - NR) (p = 0.2). Deep sequencing with the pan-cancer panel effectively detected mutations and evaluated TMB in both tissue and plasma with a high consistence. Moreover, the presence of structure variation, high tumor heterogeneity and concomitant mutations in genes such as CDKN2A were associated with worse prognosis. Further studies of predictive factors are ongoing (NCT03059641).

1564P - Liquid biopsy in clinical pratice of non-small cell lung cancer (NSCLC): A multi-institutional experience

BackgroundCirculating tumor DNA (ctDNA) from liquid biopsy is a source of tumor genetic material for EGFR testing in NSCLC when resistance to I-II generations TKI-therapies occurs or upfront, in absence of tissue biopsy. A multi-regional survey for patients treated with EGFR TKI from January to December 2018 was conducted regarding use of liquid biopsy for NSCLC in clinical practice. MethodsAim of the study was to describe EGFR testing workflow by liquid biopsy in clinical setting. Seven major lung-cancer centers in North Eastern Italy participated to the survey. ResultsOverall 316 patients (360 samples) have been screened for ctDNA EGFR, with a medium number of 1.1 samples/patient. All institutions reported EGFR as the main gene tested for clinical purposes in plasma samples of NSCLC, other genes (i.e. KRAS/BRAF) were occasionally tested upon oncologist request. Seven out of seven (100%) centers used commercially available real time CE-IVD tests. NGS or droplet digital PCR were used by one center each, as confirmation methods. In all institutions blood drawing was performed in the same hospital of EGFR testing (in 6/7 - 86%- centers in the Medical Oncology Unit), and plasma separated within 2hours. EGFR testing was performed in the Surgical Pathology Unit and report edited within 24hours in 3/7 (43%) centers and within 3-5 working days in 4/7 (57%) centers. Among all, 108 (34%) patients were tested at the time of diagnosis with an EGFR mutation rate of 15%. At progression to TKI treatment, 208 (66%) patients were tested. T790M positive rate was 55/122 (45%). Inconclusive cases (negative for both T790M and known actionable mutation) were 86 (41%). All centers declared that histo/cytological re-biopsy was suggested in these cases. ConclusionsReal-world experiences about EGFR testing in liquid biopsies revealed homogeneous habits among interviewed centers, according to national guidelines and literatures data. The consistent number of liquid biopsies at the time of diagnosis mainly refers to some reference centers that collect specimens from several institutions. However it might impose a revision of bronchoscopy workflows in order to obtain better samples suitable both for cito-histological diagnosis and molecular profiling. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

MA18.11 SNAI2 Is the Most Highly Differential Expressed Genes Between the Adenomatous and Squamous Components of Lung Adenosquamous Cell Carcinoma

Lung adenosquamous cell carcinoma is a hybrid tumor with adenomatous and squamous components in one tumor, it has the worst prognosis among the non small cell lung cancer. Our previous work has prooved that lung adenosquamous cell carcinoma has a similar EGFR mutation rate as lung adenocarcinoma which is 51.79% in 56 patients. Further squencing results showed that the majority of adnematous and squamous components had identical mutation type (34/37). EGFR mutated adenosquamous cell carcinoma patients are prone to be young, female and non-smokers, which are similar with the clinical charateristics of lung adenocarcinoma. Besides the corcodant mutation profile between the two different components of lung adenosquamous cell carcinoma, if there are any differentail expressed genes remained mysterious. our study will addressed this question. NanoString nCounter technology was employed in our study. it has been increasingly used for mRNA or miRNA differential expression studies because of its advantages of feasibility in formalin fixed paraffin embedded samples. We compared the differential expressed gene profiles between the paired matched adenomatous and squamous components in 24 adenosquamous cancer tissues. SNAI2 is found to be the most differential expressed genes between the two components in lung adenosquamous cell carcinoma. It is higher expressed in squamous component compared with the adenomatous component. SNAI2 is a member of epithelial to mesenchymal transition signalling pathway. Other research results showed that SNAI2 played a pivotal role in controlling the epithelial and mesenchymal transdifferentiation, stem cell property of cancer cell, and the metastasis ability. Our preliminary results showed that SNAI2 which is a member of EMT signalling pathway is highly expressed in the squamous component compared with the adenomatous component of lung ASC. It may contribute to the phenotype transdifferentiated and invasion of lung ASC.