The Association of Acquired T790M Mutation with Clinical Characteristics after Resistance to First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma

Yen-Hsiang Huang; Kuo-Hsuan Hsu; Jeng-Sen Tseng; Kun-Chieh Chen; Chia-Hung Hsu; Kang-Yi Su; Jeremy J. W. Chen; Huei-Wen Chen; Sung-Liang Yu; Tsung-Ying Yang; Gee-Chen Chang

doi:10.4143/crt.2017.512

Articles

Page Path: HOME > Cancer Res Treat > Volume 50(4); 2018 > Article

Original Article The Association of Acquired T790M Mutation with Clinical Characteristics after Resistance to First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma: Yen-Hsiang Huang, MD¹, Kuo-Hsuan Hsu, MD^2,3, Jeng-Sen Tseng, MD, PhD^1,4, Kun-Chieh Chen, MD, PhD¹, Chia-Hung Hsu, MD¹, Kang-Yi Su, PhD^5,6, Jeremy J. W. Chen, PhD³, Huei-Wen Chen, PhD⁷, Sung-Liang Yu, PhD^5,6,8,9,10, Tsung-Ying Yang, MD, PhD^1,4,, Gee-Chen Chang, MD, PhD^1,4,11,; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2018;50(4):1294-1303.
DOI: https://doi.org/10.4143/crt.2017.512
Published online: January 4, 2018

¹Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan

²Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan

³Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan

⁴Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

⁵Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan

⁶Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan

⁷Graduate Institute of Toxicology, National Taiwan University, Taipei, Taiwan

⁸Center of Genomic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

⁹Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan

¹⁰Center for Optoelectronic Biomedicine, College of Medicine, National Taiwan University, Taipei, Taiwan

¹¹Comprehensive Cancer Center, Taichung Veterans General Hospital, Taichung, Taiwan

Correspondence: Gee-Chen Chang, MD, PhD Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, No. 1650, Sect. 4, Taiwan Boulevard, Taichung, 407 Taiwan, R.O.C.
Tel: 886-4-23592525 (ext. 3200) Fax: 886-4-23741320 E-mail: august@vghtc.gov.tw

Co-correspondence: Tsung-Ying Yang, MD, PhD Faculty of Medicine, School of Medicine, National Yang-Ming University, No. 155, Sect. 2, Linong Street, Taipei 11221, Taiwan, R.O.C.
Tel: 886-4-23592525 (ext. 3219) Fax: 886-4-23741320 E-mail: jonyin@gmail.com

*Yen-Hsiang Huang and Kuo-Hsuan Hsu contributed equally to this work.

• Received: October 25, 2017 • Accepted: January 2, 2018

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

12,594 Views
598 Download
47 Web of Science
43 Crossref
49 Scopus

prev next

Full Article

Download PDF

Abstract
Introduction
Materials and Methods
Results
Discussion
Electronic Supplementary Material
NOTES
REFERENCES

Abstract

Purpose
The main objective of this study was to investigate the relationship among the clinical characteristics and the frequency of T790M mutation in advanced epidermal growth factor receptor (EGFR)‒mutant lung adenocarcinoma patients with acquired resistance after firstline EGFR‒tyrosine kinase inhibitor (TKI) treatment.
Materials and Methods
We enrolled EGFR-mutant stage IIIB-IV lung adenocarcinoma patients, who had progressed to prior EGFR-TKI therapy, and evaluated their rebiopsy EGFR mutation status.
Results
A total of 205 patients were enrolled for analysis. The overall T790M mutation rate of rebiopsy was 46.3%. The T790M mutation rates among patients with exon 19 deletion mutation, exon 21 L858R point mutation, and other mutations were 55.0%, 37.3%, and 27.3%, respectively. Baseline exon 19 deletion was associated with a significantly higher frequency of T790M mutation (adjusted odds ratio, 2.14; 95% confidence interval [CI], 1.20 to 3.83; p=0.010). In the exon 19 deletion subgroup, there was a greater prevalence of T790M mutation than other exon 19 deletion subtypes in patients with the Del E746-A750 mutation (61.6% vs. 40.6%; odds ratio, 2.35; 95% CI, 1.01 to 5.49; p=0.049). The progression-free survival (PFS) of first-line TKI treatment > 11 months was also associated with a higher T790M mutation rate (54.1% vs. 39.3%; adjusted odds ratio, 1.82; 95% CI, 1.02 to 3.25; p=0.044). Patients who underwent rebiopsy at metastatic sites had more chance to harbor T790M mutation (52.6% vs. 33.8%; adjusted odds ratio, 1.97; 95% CI, 1.06 to 3.67; p=0.032).
Conclusion
PFS of first-line EGFR-TKI, rebiopsy site, EGFR exon 19 deletion and its subtype Del E746-A750 mutation are associated with the frequency of T790M mutation.
Key words: Lung neoplasms, Adenocarcinoma, Epidermal growth factor receptor mutation, T790M, Exon 19 deletion

Introduction

Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) accounts for about 80%-85% of all lung cancer. The treatment of lung cancer is individualized according to the results of molecular biology tests and histology. Epidermal growth factor receptor (EGFR) mutation is the most common driver mutation gene among lung cancer patients in East Asians, as well in Taiwan [1,2]. Previous clinical trials and studies had demonstrated that EGFR–tyrosine kinase inhibitors (TKI) had a better response rate and less adverse effect than platinum-based chemotherapy in EGFR-mutant NSCLC patients [3-9].

Although most EGFR-mutant NSCLC patients have a good response to EGFR-TKI initially, progressive disease (PD) eventually occurs due to acquired resistance. Various mechanisms of acquired resistance to first- and second-generation EGFR-TKIs have been identified, including secondary EGFR mutation, which involves a substitution of threonine to methionine at position 790 (T790M), small cell transformation, mesenchymal-epithelial transition (MET) amplification, epithelial-to-mesenchymal transition, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, and so on [10-12]. Among the above mechanisms, the T790M mutation accounts for 50%-60% of acquired resistance mechanisms [10,13].

The third-generation of EGFR-TKI had significantly greater efficacy than standard chemotherapy with platinum plus pemetrexed in advanced T790M-positive NSCLC patients who had PD after first-line EGFR-TKI treatment [14-16]. Thus, rebiopsy was needed to document the mechanism of acquired resistance for EGFR-mutant patients with PD after EGFR-TKI treatment. Although the mechanisms are yet to be fully elucidated, the clinical predictors for T790M mutation are important. Recent studies have discussed the association between exon 19 deletion (19Del) at baseline and the frequency of T790M mutation [17-19]. However, the results were not consistent and the studies had relatively low patient numbers.

Our previous study indicated that rebiopsy timing did not influence the detection rate of T790M and that the mutation could be identified in patients with a long EGFR-TKI–free interval [20]. Also, in that study, we did not fully explore the associations between patients’ clinical characteristics and the prevalence of T790M mutation in mixed lines of EGFR-TKI treatment. Therefore, in this study, we limited the scope of our investigation to advanced lung adenocarcinoma patients with acquired resistance after first-line EFGF-TKI treatment. The main objective of this study was to investigate the relationship among the clinical characteristics, EGFR mutation subtypes, and the frequency of T790M mutation.

Materials and Methods

1. Patients

This study was a retrospective, single-center, observational study at Taichung Veterans General Hospital (TCVGH) in Taiwan. We enrolled lung cancer frequency of the T790M mutation who received rebiopsy between July 2014 and August 2017. To be eligible for the study, patients had to fulfill the inclusion criteria as follows: histologically and cytologically confirmed EGFR-mutant lung adenocarcinoma, stage IIIB-IV, according to the seventh edition of the American Joint Committee for Cancer staging system [21], first-line EGFR-TKI treatment, rebiopsy after disease progression confirmed by the Response Evaluation Criteria in Solid Tumors ver. 1.1 [22]. Patients were excluded if they had primary treatment failure to EGFR-TKI, if the T790M mutation presented before EGFR-TKI treatment, or if they had been diagnosed with another active malignancy. Demographic characteristics and clinical data, including age, sex, smoking status, baseline EGFR mutation status, the type of first-line EGFR-TKI treatment, progression-free survival (PFS) of first-line EGFR-TKI, and rebiopsy site were collected for analysis. A never-smoker was defined as someone who had never smoked or smoked less than 100 cigarettes in his or her lifetime.

2. EGFR mutation test

EGFR mutations were assessed by matrix-assisted laser desorption ionization-time of flight mass spectrometry, as described in our previous study [2]. All tests were performed at the ISO15189-certified TR6 Pharmacogenomics Laboratory, as part of the National Research Program for Biopharmaceuticals, in the National Center of Excellence for Clinical Trial and Research of National Taiwan University Hospital.

3. Statistical analyses

Univariate analysis by Fisher exact test was performed for assessing the associations between the frequency of T790M mutation and patients’ characteristics, including age, sex, smoking status, baseline EGFR mutation status, the type of first-line EGFR-TKI treatment, PFS of first-line EGFR-TKI, and rebiopsy site. Multivariate analysis for the impact of baseline EGFR mutation status, PFS of first-line EGFR-TKI and rebiopsy site to the T790M mutation of rebiopsy was performed by logistic regression models. All statistical tests were done with SPSS ver. 23.0 (IBM Corp., Armonk, NY). Two-tailed tests and p-values of < 0.05 for significance were used.

4. Ethical statement

The study was approved by the Institutional Review Board (IRB) of TCVGH, Taiwan, and written informed consent for genetic testing and clinical data records were obtained from all patients (IRB No. CF12019).

Results

1. Patients’ characteristics

In total, 205 patients with advanced EGFR mutant lung adenocarcinoma met the study criteria and were enrolled for analysis (Fig. 1). The baseline characteristics are shown in Table 1. The median age of the patients was 60 years (range, 32 to 88 years). Seventy-six patients were male (37.1%), and 129 patients were female (62.9%). Most of the patients were never-smokers (n=162, 79.0%), and 43 patients were former or current smokers (21.0%). Regarding baseline EGFR mutation status, 111 patients harbored the exon 19 deletion mutation (19Del) (54.1%), 83 patients harbored the exon 21 L858R point mutation (L858R) (40.5%), and 11 patients had other mutations including mixed mutation (5.4%) (one patient with 19Del+L858R, one patient with 19Del+G719S, one patient with G719S+S768I, one patient with G719A+S861I, one patient with G719A+L861Q, two patients with G719S+L861Q, and four patients with L861Q). Ninety-four patients used gefitinib (45.9%) as the first-line EGFR-TKI treatment, and 98 patients were treated with erlotinib (47.8%). Concerning the best response of first-line EGFR-TKI, 176 patients had a partial response (85.9%), whereas 29 patients had stable disease (14.1%). With respect to the PFS of first-line EGFR-TKI, 98 patients had PFS > 11 months (47.8%), and 107 patients had PFS ≤ 11 months (52.2%). Rebiopsy of the primary tumor was performed in 68 patients (33.2%), and rebiopsy of metastatic lesions was performed in 137 patients (66.8%).

2. The T790M mutation status of rebiopsy

The results of T790M mutation status of rebiopsy and baseline EGFR mutation status are summarized in Fig. 2. The overall T790M mutation rate of rebiopsy was 46.3%. According to the baseline EGFR mutation status, 61 of 111 patients with the 19Del mutation had the T790M mutation (55.0%), 31 of 83 patients with the L858R mutation harbored the T790M mutation (37.3%), and three of 11 patients with other mutations (19Del+L858R, 19Del+G719S, and G719S+S768I) tested positive for the T790M mutation (27.3%).

3. The association between T790M mutation status of rebiopsy and patients’ characteristics

Univariate analyses of the associations between T790M mutation status and patients’ characteristics are summarized in Table 2. Patients with baseline 19Del mutation had a significantly higher positive rate of T790M mutation than patients with L858R or other mutations (p=0.022). Patients with a PFS of first-line EGFR-TKI > 11 months harbored a higher frequency of T790M mutation than that of patients with a PFS of first-line EGFR-TKI ≤ 11 months (p=0.036). Patients who underwent rebiopsy at metastatic site had higher incidence of T790M mutation than at primary site (p=0.012). There were no relationships of T790M mutation status of rebiopsy with age, sex, smoking status, the type of first-line EGFR-TKI treatment and best response of first-line EGFR-TKI. The detail of relationship between metastatic sites and the frequency of T790M mutation was presented in S1 Table. Additionally, we showed the rebiopsy methods in S2 Table.

4. The association between T790M mutation status of rebiopsy and exon 19 deletion

Not only univariate analysis but also multivariate analysis by logistic regression models demonstrated a significantly higher T790M mutation rate in patients with 19Del (adjusted odds ratio, 2.14; 95% confidence interval [CI], 1.20 to 3.83; p=0.010) (Table 3). Because the frequency of the T790M mutation was significantly different between patients with the baseline 19Del mutation and patients with other mutations, we performed a further detailed analysis of the relationship between the subtype of 19Del and T790M mutation of rebiopsy (Table 4). Six patients with the baseline 19Del did not have subtype data. Thus, only 105 patients were enrolled in the analysis. Seventy-three patients had the Del E746-A750 mutation, and the positive rate of T790M mutation was 61.6%. According to the univariate analysis, patients with the Del E746-A750 mutation had a significantly higher frequency of T790M mutation than that of patients with other mutations (odds ratio, 2.35; 95% CI, 1.01 to 5.49; p=0.049), and there was a trend by multivariate analysis (adjusted odds ratio, 2.37; 95% CI, 0.96 to 5.87; p=0.062).

5. The association between T790M mutation status of rebiopsy and PFS of first-line EGFR-TKI

Univariate analysis demonstrated patients with PFS of first-line EGFR-TKI > 11 months harbored a higher frequency of the T790M mutation (p=0.036) (Table 2). Multivariate analysis by logistic regression models showed patients with PFS > 11 months after first-line EGFR-TKI treatment had a higher T790M mutation positive rate with an adjusted odds ratio of 1.82 (95% CI, 1.02 to 3.25; p=0.044) (Table 3). We divided patients into three groups (PFS: ≤ 11 months, 11-20 months, and > 20 months), and it appeared that the frequency of T790M mutation and PFS of first-line EGFR-TKI treatment were directly correlated (Fig. 3).

The analysis of the major mutations (exon 19 deletion mutation and exon 21 L858R point mutation) revealed that the median PFS of first-line EGFR-TKI was 11.5 months in patients with the T790M mutation, and 9.1 months in patients without the T790M mutation. There was no statistically significant relationship between PFS and the T790M mutation status in patients harboring the exon 19 deletion and the L858R mutation (p=0.235) (Fig. 4A). Additionally, we divided the patients into four groups to evaluate the association between PFS of first-line EGFR-TKI therapy, baseline EGFR mutation status, and T790M mutation status of rebiopsy (19Del with T790M, 19Del without T790M, L858R with T790M, L858R without T790M), and no significant differences in PFS was found among these four groups (p=0.250) (Fig. 4B).

6. The association between clinical characteristics and the first-line EGFR-TKI treatment

We showed the relationship between clinical characteristics and the first-line EGFR-TKI in S3 Table. Fifty-three patients (54.1%) were female in erlotinib group, and seven patients (53.8%) were female in afatinib group. Sixty-nine patients (73.4%) were female in gefitinib group, and significant higher female percentage than other groups was noted by univariate analysis (p=0.015). There were no difference of age, smoking status, baseline EGFR mutation status, best response of first-line EGFR-TKI, PFS of first-line EGFR-TKI and rebiopsy site between three kinds of EGFR-TKI.

Discussion

Our study demonstrated that PFS of first-line EGFR-TKI > 11 months and rebiopsy at metastatic sites were correlated with a higher frequency of the T790M mutation. More importantly, not only the EGFR exon 19 deletion but also its subtype deletion E746-A750 at baseline was a predictor of the T790M mutation.

Nosaki et al. [17] stated that the frequency of the T790M mutation was higher in patients with the EGFR exon 19 deletion than in those with the L858R mutation (55.6% vs. 43.0%, p=0.05 by Fisher exact test). Matsuo et al. [18] also reported that patients with the 19Del mutation had a higher frequency of the T790M mutation than patients with the L858R mutation (63% vs. 38%, p=0.035). However, Oya et al. [19] demonstrated that there was no relationship between the baseline EFGRmutation and T790M mutation status (exon 19 deletion 49.5%, L858R 48.1%, p=0.240). Because the results were inconsistent, we designed the present study to include a relatively homogenous patient population and a larger total number of patients. We enrolled only adenocarcinoma patients who had acquired resistance after first-line EGFR-TKI treatment. Patients with primary T790M and patients who failed to respond to primary treatment with EGFR-TKI were excluded. We then compared the frequency of EGFR mutation between patients with 19Del and those with other mutations. A significantly higher T790M mutation positive rate in patients with 19Del was found in both the univariate and multivariate analysis. Additionally, in the present study, three patients with a complex EGFR mutation had the T790M mutation after first-line EGFR-TKI treatment. Two of them had the exon 19 deletion plus another mutation (19Del+L858R and 19Del+G719S). It appeared that the baseline 19Del was still the most influential mutation type.

Regarding the subtypes of EGFR exon 19 deletions, the most common subtype in our study was Del E746-A750, followed by Del L747-P753 ins S, which was consistent with the results of previous study [23,24]. Lee et al. [23] disclosed that patients with the exon 19 deletion starting on codon E746 had a better median PFS than those starting on L747 (14.2 months vs.6.5 months, p=0.021). Chung et al. [24] reported patients with LRE deletions in exon 19 had a better response to EGFR-TKIs, compared to patients with non-LRE deletions. In the present study, we evaluated the relationship between the subtype of baseline 19Del mutation and T790M mutation status after acquired resistance to first-line EGFR-TKI. Univariate analysis showed that patients with the Del E746-A750 mutation had a higher frequency of the T790M mutation than patients with other subtypes, and it had a trend by multivariate analysis also. This is the first study to demonstrate the association between the subtype Del E746-A750 of EGFR exon 19 deletion and positive T790M status.

Structural analyses showed an allosteric mechanism important for EGFR kinase domain activation in a previous report [25]. The deletions in EGFR exon 19, located between strand β3 and helix αC, could disrupt inactive conformation of the EGFR kinase domain and enhance the effectiveness of EGFR-TKIs [26]. However, because the deletions can occur in various fragments of exon 19 of the EGFR gene, the exon 19 deletion mutation is relatively complex compared with other EGFR mutations. Thus, it is challenging to elucidate the precise mechanism by which the pathophysiology of the subtype of exon19 deletion influences the frequency of the T790M mutation. Further research is needed to understand the underlying mechanisms involved.

Concerning the PFS of first-line EGFR-TKI treatment, Matsuo et al. [18] stated that the total duration of EGFR-TKI treatment was related to the frequency of patients with T790M mutation. Oya et al. [19] demonstrated patients with PFS less than 6 months were significantly less likely to harbor the T790M mutation than those with PFS ≥ 6 months. In our study, the median PFS was 10.7 months, and we found that patients with PFS > 11 months under first-line EGFR-TKI therapy had a higher prevalence of T790M mutation than patients with PFS ≤ 11 months. Although the area under curve in the receiver operating characteristic curve analysis of the association between the duration of PFS and T790M detection rate was only 0.594 (Fig. 5), we found there was a direct correlation between the PFS of first-line EGFR-TKI and the frequency of T790M mutation, as shown in Fig. 3. The above research may support the concept that longer EGFR-TKIs exposure induces a greater frequency of T790M mutation.

Moreover, previous studies demonstrated that the PFS of initial EGFR-TKI treatment was longer in patients with the T790M mutation [18,19]. In our study, the median PFS of first-line EGFR-TKI was 11.5 months in patients with the T790M mutation, and 9.1 months in patients without the T790M mutation. There was no statistically significant relationship between PFS and T790M mutation status (p=0.235). In the present study, we excluded patients who failed to respond to primary treatment with EGFR-TKIs, while other studies usually included patients with primary treatment failure. Patients with primary PD usually had a lower rate of T790M compared with patients with acquired resistance [19]. Patients with primary PD had a shorter PFS than patients with acquired resistance, which explains why there was no statistically significant result despite a difference in PFS of 2.4 months in this study. These findings are consistent with the idea that patients who acquired the T790M mutation have more indolent tumors than those without the T790M mutation. Compared with other studies, our patient group was relatively homogenous, had a higher number of patients, and our investigation was more clinically oriented.

Additionally, our study demonstrated a significantly higher T790M mutation positive rate in patients who received rebiopsy at metastatic site by both univariate and multivariate analysis (adjusted odds ratio, 1.97; 95% CI, 1.06 to 3.67; p=0.032). This could be explained by the tumor heterogeneity and the different characteristics between primary tumor and metastatic lesions [27,28]. Previous studies had suggested that tissue specimen should be obtained on new or progressing lesions after disease progression to determine the suitable treatments against the EGFR mutation profiles [28,29].

Concerning the relationship between prior EGFR-TKI treatment and the frequency of T790M mutation, patients who treated with afatinib as prior TKI had lower positive rate of T790M mutation (3/13, 23.1%) than gefitinib group (47/94, 50.0%) and erlotinib group (45/98, 45.9%) in present study. According to previous studies, the range of frequency of T790M mutation was from 25% to 47.6% [18,19,30,31]. However, the patient number and patient group were heterogeneous. We included only 13 patients with afatinib treatment, and it was difficult to make conclusion about the exact T790M mutation rate due to smaller patient numbers.

Our study had some limitations. First, it was a retrospective study, and thus more bias may have been present compared with a study that had been prospectively designed. Second, the research was undertaken at a single center, and therefore there may have been selection bias. Third, all patients in this study were Taiwanese, so our findings may not be generalizable to other ethnic populations. Although this study is the first to discuss the relationship between the subtypes of baseline 19Del and the frequency of T790M mutation status after acquired resistance to first-line EGFR-TKI treatment, further research is needed to confirm our results.

Our findings shed light on which patients may have a greater tendency to develop the T790M mutation after EGFR-TKIs treatment. Our study demonstrated that PFS of firstline EGFR-TKI and rebiopsy site influence the frequency of the T790M mutation. More importantly, both the exon 19 deletion and its subtype at baseline were predictors of the T790M mutation.

Electronic Supplementary Material

Supplementary materials are available at Cancer Research and Treatment website (http://www.e-crt.org).

crt-2017-512-suppl1.pdf

crt-2017-512-suppl2.pdf

crt-2017-512-suppl3.pdf

NOTES

Conflict of interest relevant to this article was not reported.

Acknowledgements

We would like to thank the Comprehensive Cancer Center of Taichung Veterans General Hospital for its assistance with the collection and management of the data.

Fig. 1.

The patient collection flow chart. PD, progressive disease; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.

Fig. 2.

The association between baseline epidermal growth factor receptor (EGFR) mutation status and T790M mutation status of rebiopsy.

Fig. 3.

The association between progression-free survival of first-line epidermal growth factor receptor-tyrosine kinase inhibitor and T790M mutation status of rebiopsy.

Fig. 4.

(A) Progression-free survival (PFS) of first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) versus T790M mutation status of rebiopsy by Kaplan-Meier survival curve analysis. (B) PFS of first-line EGFR-TKI versus T790M mutation status of rebiopsy and baseline EGFR mutation status by Kaplan-Meier survival curve analysis.

Fig. 5.

The relationship between the duration of progression-free survival and T790M detection rate by receiver operating characteristic curve analysis. AUC, area under curve.

Table 1.

Patients' characteristics and demographic data

Characteristic	No. (%) (n=205)
Age, median (range, yr)	60 (32-88)
Sex
Male	76 (37.1)
Female	129 (62.9)
Smoking status
Never smokers	162 (79.0)
Former smokers	23 (11.2)
Current smokers	20 (9.8)
*Baseline EGFR* mutation status**
Exon 19 deletions	111 (54.1)
Exon 21 L858R	83 (40.5)
Other mutations^a)	11 (5.4)
First-line TKI
Gefitinib	94 (45.9)
Erlotinib	98 (47.8)
Afatinib	13 (6.3)
Best response of first-line TKI
Stable disease	29 (14.1)
Partial response	176 (85.9)
PFS of first-line TKI
≤ 11 mo	107 (52.2)
> 11 mo	98 (47.8)
Rebiopsy site
Primary tumor	68 (33.2)
Metastases	137 (66.8)

EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; PFS, progression-free survival.

^a) Includes complex mutation.

Table 2.

Univariate analysis of the association between patients' characteristics and T790M status of rebiopsy

Characteristic	No.	T790M status		p-value^a)
Characteristic	No.	Positive	Negative	p-value^a)
Age (yr)
≤ 60	103	51 (49.5)	52 (50.5)	0.402
> 60	102	44 (43.1)	58 (56.9)
Sex
Male	76	33 (43.4)	43 (56.6)	0.563
Female	129	62 (48.1)	67 (51.9)
Smoking status
Non-smokers	162	79 (48.8)	83 (51.2)	0.229
Current/Former-smokers	43	16 (37.2)	27 (62.8)
*Baseline EGFR* mutation status**
19Del	111	61 (55.0)	50 (45.0)	0.022
L858R	83	31 (37.3)	52 (62.7)
Others	11	3 (27.3)	8 (72.7)
First-line TKI
Gefitinib	94	47 (50.0)	47 (50.0)	0.188
Erlotinib	98	45 (45.9)	53 (54.1)
Afatinib	13	3 (23.1)	10 (76.9)
Best response of first line TKI
Stable disease	29	12 (41.4)	17 (58.6)	0.688
Partial response	176	83 (47.2)	93 (52.8)
PFS of first-line TKI
≤ 11 mo	107	42 (39.3)	65 (60.7)	0.036
> 11 mo	98	53 (54.1)	45 (45.9)
Rebiopsy site
Primary	68	23 (33.8)	45 (66.2)	0.012
Metastases	137	72 (52.6)	65 (47.4)

Values are presented as number (%). EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; PFS, progression-free survival.

^a) By Fisher exact test.

Table 3.

Multivariate analysis of the association between patients' characteristics and T790M status of rebiopsy

Characteristic	Odds ratio (95% CI)	p-value^a)	Adjusted odds ratio (95% CI)	p-value^a)
*Baseline EGFR* mutation status**
19Del vs. others	2.15 (1.23-3.78)	0.008	2.14 (1.20-3.83)	0.010^b)
PFS of first-line TKI
> 11 mo vs. ≤ 11 mo	1.82 (1.05-3.18)	0.034	1.82 (1.02-3.25)	0.044^c)
Rebiopsy site
Metastasis vs. primary	2.17 (1.19-3.97)	0.012	1.97 (1.06-3.67)	0.032^d)

CI, confidence interval; EGFR, epidermal growth factor receptor; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

^a) By logistic regression model,

^b) Adjusted by age, sex, rebiopsy site, PFS of first-line TKI,

^c) Adjusted by age, sex, rebiopsy site, and baseline EGFR mutation status,

^d) Adjusted by age, sex, PFS of first-line TKI and baseline EGFR mutation status.

Table 4.

EGFR exon 19 deletions mutation patterns in relation to T790M status of rebiopsy^a)

Exon 19 deletions type	No.	T790M status
Exon 19 deletions type	No.	Positive	Negative
Del E746-A750	73	45 (61.6)	28 (38.4)
Del L747-P753 ins S	7	4 (57.1)	3 (42.9)
Del E746-S752 ins V	6	1 (16.7)	5 (83.3)
Del E746-T751	3	1 (33.3)	2 (66.7)
Del L747-T751	2	1 (50.0)	1 (50.0)
Del L747-T751 ins P	2	0	2 (100)
Del L747-E750	2	0	2 (100)
Del L747-A750	1	0	1 (100)
Del L747-P753	1	0	1 (100)
Mixed	8	6 (75.0)	2 (25.0)
Total	105	58	47

Values are presented as number (%). EGFR, epidermal growth factor receptor.

^a) Six patients without subtype data.

REFERENCES

1. Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol. 2014;9:154–62. Article PubMed PMC
2. Hsu KH, Ho CC, Hsia TC, Tseng JS, Su KY, Wu MF, et al. Identification of five driver gene mutations in patients with treatment-naive lung adenocarcinoma in Taiwan. PLoS One. 2015;10:e0120852Article PubMed PMC
3. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735–42. Article PubMed
4. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239–46. Article PubMed
5. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–8. Article PubMed
6. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121–8. Article PubMed
7. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327–34. Article PubMed
8. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39. Article PubMed
9. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500. Article PubMed
10. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240–7. Article PubMed PMC
11. Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786–92. Article PubMed
12. Ohashi K, Maruvka YE, Michor F, Pao W. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol. 2013;31:1070–80. Article PubMed PMC
13. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26.Article PubMed PMC
14. Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376:629–40. Article PubMed
15. Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372:1689–99. Article PubMed
16. Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4:1046–61. Article PubMed PMC
17. Nosaki K, Satouchi M, Kurata T, Yoshida T, Okamoto I, Katakami N, et al. Re-biopsy status among non-small cell lung cancer patients in Japan: a retrospective study. Lung Cancer. 2016;101:1–8. Article PubMed
18. Matsuo N, Azuma K, Sakai K, Hattori S, Kawahara A, Ishii H, et al. Association of EGFR exon 19 deletion and EGFR-TKI treatment duration with frequency of T790M mutation in EGFR-mutant lung cancer patients. Sci Rep. 2016;6:36458.Article PubMed PMC PDF
19. Oya Y, Yoshida T, Kuroda H, Shimizu J, Horio Y, Sakao Y, et al. Association between EGFR T790M status and progression patterns during initial EGFR-TKI treatment in patients harboring EGFR mutation. Clin Lung Cancer. 2017;18:698–705. Article PubMed
20. Tseng JS, Su KY, Yang TY, Chen KC, Hsu KH, Chen HY, et al. The emergence of T790M mutation in EGFR-mutant lung adenocarcinoma patients having a history of acquired resistance to EGFR-TKI: focus on rebiopsy timing and long-term existence of T790M. Oncotarget. 2016;7:48059–69. Article PubMed PMC
21. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471–4. Article PubMed
22. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47. Article PubMed
23. Lee VH, Tin VP, Choy TS, Lam KO, Choi CW, Chung LP, et al. Association of exon 19 and 21 EGFR mutation patterns with treatment outcome after first-line tyrosine kinase inhibitor in metastatic non-small-cell lung cancer. J Thorac Oncol. 2013;8:1148–55. Article PubMed
24. Chung KP, Wu SG, Wu JY, Yang JC, Yu CJ, Wei PF, et al. Clinical outcomes in non-small cell lung cancers harboring different exon 19 deletions in EGFR. Clin Cancer Res. 2012;18:3470–7. Article PubMed
25. Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell. 2006;125:1137–49. Article PubMed
26. Bose R, Zhang X. The ErbB kinase domain: structural perspectives into kinase activation and inhibition. Exp Cell Res. 2009;315:649–58. Article PubMed
27. Cadranel J, Zalcman G, Sequist L. Genetic profiling and epidermal growth factor receptor-directed therapy in non-small cell lung cancer. Eur Respir J. 2011;37:183–93. Article PubMed
28. Jekunen AP. Role of rebiopsy in relapsed non-small cell lung cancer for directing oncology treatments. J Oncol. 2015;2015:809835.Article PubMed PMC PDF
29. Kim E, Feldman R, Wistuba II. Update on EGFR mutational testing and the potential of noninvasive liquid biopsy in non-small-cell lung cancer. Clin Lung Cancer. 2018;19:105–14. Article PubMed
30. Wu SG, Liu YN, Tsai MF, Chang YL, Yu CJ, Yang PC, et al. The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients. Oncotarget. 2016;7:12404–13. Article PubMed PMC
31. Tanaka K, Nosaki K, Otsubo K, Azuma K, Sakata S, Ouchi H, et al. Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor-naive patients with non-small cell lung cancer harboring EGFR mutations. Oncotarget. 2017;8:68123–30. Article PubMed PMC

Figure & Data

REFERENCES

Citations

Citations to this article as recorded by

RELAY, Erlotinib Plus Ramucirumab in Untreated, EGFR-Mutated, Metastatic NSCLC: Outcomes by EGFR Exon 19 Deletion Variants
Kazumi Nishino, Jin-Yuan Shih, Kazuhiko Nakagawa, Martin Reck, Edward B. Garon, Michelle Carlsen, Tomoko Matsui, Carla Visseren-Grul, Ernest Nadal
JTO Clinical and Research Reports.2024; 5(2): 100624. CrossRef
Epidermal Growth Factor Receptor Exon 19 Deletion Subtypes Do Not Influence Survival Outcomes Following First-line Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitors in Advanced Nonsmall Cell Lung Cancer Patients
Yan-Jei Tang, John Wen-Cheng Chang, Chen-Yang Huang, Yueh-Fu Fang, Ching-Fu Chang, Cheng-Ta Yang, Chih-Hsi Scott Kuo, Ping-Chih Hsu, Chiao-En Wu
Journal of Cancer Research and Practice.2024; 11(1): 28. CrossRef
CRISPR-Based Fluorescent Reporter (CBFR) Assay for Sensitive, Specific, Inexpensive, and Visual Detection of a Specific EGFR Exon 19 Deletion in NSCLC
Pouya Salehipour, Mojdeh Mahdiannasser, Ghazal Sedaghat Shayegan, Kimia Shankaie, Mina Tabrizi, Majid Mojarrad, Mohammad Hossein Modarressi
Molecular Biotechnology.2023; 65(5): 807. CrossRef
Endobronchial ultrasound‐guided re‐biopsy of non–small cell lung cancer with acquired resistance after EGFR tyrosine kinase inhibitor treatment
Kyung Soo Hong, Jinmo Cho, Jong Geol Jang, Min Hye Jang, June Hong Ahn
Thoracic Cancer.2023; 14(4): 363. CrossRef
Monitoring of T790M in plasma ctDNA of advanced EGFR-mutant NSCLC patients on first- or second-generation tyrosine kinase inhibitors
Chun-Ta Huang, Chih-An Lin, Te-Jen Su, Ching-Yao Yang, Tzu-Hsiu Tsai, Chia-Lin Hsu, Wei-Yu Liao, Kuan-Yu Chen, Chao-Chi Ho, Chong-Jen Yu
BMC Cancer.2023;[Epub] CrossRef
Clinical outcomes of immune checkpoint inhibitors to treat non-small cell lung cancer patients harboring epidermal growth factor receptor mutations
Jinfei Si, Yue Hao, Jingwen Wei, Jing Xiang, Chunwei Xu, Qiuping Shen, Zhengbo Song
BMC Pulmonary Medicine.2023;[Epub] CrossRef
FRET probe for detecting two mutations in one EGFR mRNA
Myat Thu, Kouta Yanai, Hajime Shigeto, Shohei Yamamura, Kazunori Watanabe, Takashi Ohtsuki
The Analyst.2023; 148(11): 2626. CrossRef
Efficacy of Osimertinib in Patients with Lung Cancer Positive for Uncommon EGFR Exon 19 Deletion Mutations
Michael J. Grant, Jacqueline V. Aredo, Jacqueline H. Starrett, Paul Stockhammer, Iris K. van Alderwerelt van Rosenburgh, Anna Wurtz, Andrew J. Piper-Valillo, Zofia Piotrowska, Christina Falcon, Helena A. Yu, Charu Aggarwal, Dylan Scholes, Tejas Patil, Chr
Clinical Cancer Research.2023; 29(11): 2123. CrossRef
NSCLC presents metabolic heterogeneity, and there is still some leeway for EGF stimuli in EGFR-mutated NSCLC
Cindy Mendes, Isabel Lemos, Inês Francisco, Teresa Almodôvar, Fernando Cunha, Cristina Albuquerque, Luís G. Gonçalves, Jacinta Serpa
Lung Cancer.2023; 182: 107283. CrossRef
Clinical outcomes of advanced NSCLC patients with different EGFR exon 19 deletion subtypes treated with first‐line tyrosine kinase inhibitors: A single‐center ambispective cohort study
Yangchun Gu, Jinyu Yu, Haifeng Hu, Hua Zhang, Baoshan Cao, Li Liang
Thoracic Cancer.2023; 14(31): 3147. CrossRef
Brain metastasis, EGFR mutation subtype and generation of EGFR-TKI jointly influence the treatment outcome of patient with EGFR-mutant NSCLC
Jia-Shiuan Ju, Allen Chung-Cheng Huang, Pi-Hung Tung, Chi-Hsien Huang, Tzu-Hsuan Chiu, Chin-Chou Wang, How-Wen Ko, Fu-Tsai Chung, Ping-Chih Hsu, Yueh-Fu Fang, Yi-Ke Guo, Chih-Hsi Scott Kuo, Cheng-Ta Yang
Scientific Reports.2023;[Epub] CrossRef
Afatinib treatment in a large real‐world cohort of nonsmall cell lung cancer patients with common and uncommon epidermal growth factor receptor mutation
Chi‐Hsien Huang, Jia‐Shiuan Ju, Tzu‐Hsuan Chiu, Allen Chung‐Cheng Huang, Pi‐Hung Tung, Chin‐Chou Wang, Chien‐Ying Liu, Fu‐Tsai Chung, Yueh‐Fu Fang, Yi‐Ke Guo, Chih‐Hsi Scott Kuo, Cheng‐Ta Yang
International Journal of Cancer.2022; 150(4): 626. CrossRef
The Clinical Outcomes of Different First-Line EGFR-TKIs Plus Bevacizumab in Advanced EGFR-Mutant Lung Adenocarcinoma
Yen-Hsiang Huang, Kuo-Hsuan Hsu, Chun-Shih Chin, Jeng-Sen Tseng, Tsung-Ying Yang, Kun-Chieh Chen, Kang-Yi Su, Sung-Liang Yu, Jeremy J.W. Chen, Gee-Chen Chang
Cancer Research and Treatment.2022; 54(2): 434. CrossRef
Impact of EGFR exon 19 deletion subtypes on clinical outcomes in EGFR-TKI-Treated advanced non-small-cell lung cancer
Le-Tian Huang, Shu-Ling Zhang, Cheng-Bo Han, Jie-Tao Ma
Lung Cancer.2022; 166: 9. CrossRef
Risk Stratification Using a Novel Nomogram for 2190 EGFR-Mutant NSCLC Patients Receiving the First or Second Generation EGFR-TKI
John Wen-Cheng Chang, Chen-Yang Huang, Yueh-Fu Fang, Ching-Fu Chang, Cheng-Ta Yang, Chih-Hsi Scott Kuo, Ping-Chih Hsu, Chiao-En Wu
Cancers.2022; 14(4): 977. CrossRef
Impact of sequential therapy with osimertinib on the overall survival in patients with EGFR-mutant non-small cell lung cancer
Minehiko Inomata, Masahiro Matsumoto, Isami Mizushima, Kana Hayashi, Zenta Seto, Kotaro Tokui, Chihiro Taka, Seisuke Okazawa, Kenta Kambara, Shingo Imanishi, Toshiro Miwa, Ryuji Hayashi, Shoko Matsui, Kazuyuki Tobe
The Egyptian Journal of Bronchology.2022;[Epub] CrossRef
Pretreatment Neutrophil-to-Lymphocyte Ratio and Smoking History as Prognostic Factors in Advanced Non–Small Cell Lung Cancer Patients Treated with Osimertinib
Ji Young Park, Seung Hun Jang, Chang Youl Lee, Taehee Kim, Soo Jie Chung, Ye Jin Lee, Hwan Il Kim, Joo-Hee Kim, Sunghoon Park, Yong Il Hwang, Ki-Suck Jung
Tuberculosis and Respiratory Diseases.2022; 85(2): 155. CrossRef
Optimizing Patient Outcomes Through Sequential EGFR TKI Treatment in Asian Patients With EGFR Mutation-Positive NSCLC
Rong Liu, Jianying Zhou, Xia Ling
Clinical Medicine Insights: Oncology.2022;[Epub] CrossRef
State-of-the-Art Molecular Oncology of Lung Cancer in Taiwan
Yung-Hung Luo, Kung-Hao Liang, Hsu-Ching Huang, Chia-I Shen, Chi-Lu Chiang, Mong-Lien Wang, Shih-Hwa Chiou, Yuh-Min Chen
International Journal of Molecular Sciences.2022; 23(13): 7037. CrossRef
Real-World Testing Practices, Treatment Patterns and Clinical Outcomes in Patients from Central Eastern Europe with EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Retrospective Chart Review Study (REFLECT)
Urška Janžič, Nina Turnšek, Mircea Dediu, Ivan Shterev Donev, Roxana Lupu, Gabriela Teodorescu, Tudor E. Ciuleanu, Adam Pluzanski
Current Oncology.2022; 29(8): 5833. CrossRef
Efficacy and Failure Patterns of Early SBRT to the Primary Tumor in Advanced EGFR-Mutation-Positive Lung Cancer with EFGR-TKI Treatment: A Prospective, Single Arm, Phase II Study
Yangyang Shi, Hailing Xu, William Y. Raynor, Jiapei Ding, Ling Lin, Chao Zhou, Wei Wang, Yinnan Meng, Xiaomai Wu, Xiaofeng Chen, Dongqing Lv, Haihua Yang
Life.2022; 12(12): 1954. CrossRef
Association of hOGG1‐Cys variants with occurrence of p53 and EGFR deletion mutations in non‐small cell lung cancer
Ming‐Jenn Chen, Ching‐Ju Shen, Lee Wang, Po‐Ming Chen, Chih‐Yi Chen, Huei Lee
Thoracic Cancer.2021; 12(4): 534. CrossRef
The Impact of Acquired EGFR T790M Mutation and EGFR Circulating Cell-Free DNA on Survival in Patients with Lung Adenocarcinoma Following EGFR-TKI Therapy
Wen-Chien Cheng, Te-Chun Hsia, Chih-Yen Tu, Hung-Jen Chen
OncoTargets and Therapy.2021; Volume 13: 13425. CrossRef
EGFR-TKI plus bevacizumab versus EGFR-TKI monotherapy for patients with EGFR mutation-positive advanced non-small cell lung cancer-A propensity score matching analysis
Jeng-Shiuan Tsai, Po-Lan Su, Szu-Chun Yang, Chao-Chun Chang, Chia-Ying Lin, Yi-Ting Yen, Yau-Lin Tseng, Wu-Wei Lai, Chien-Chung Lin, Wu-Chou Su
Journal of the Formosan Medical Association.2021; 120(9): 1729. CrossRef
The impact of different first-line EGFR-TKIs on the clinical outcome of sequential osimertinib treatment in advanced NSCLC with secondary T790M
Yen-Hsiang Huang, Jeng-Sen Tseng, Kuo-Hsuan Hsu, Kun-Chieh Chen, Kang-Yi Su, Sung-Liang Yu, Jeremy J. W. Chen, Tsung-Ying Yang, Gee-Chen Chang
Scientific Reports.2021;[Epub] CrossRef
First- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors in a large, real-world cohort of patients with non-small cell lung cancer
Allen Chung-Cheng Huang, Chi-Hsien Huang, Jia-Shiuan Ju, Tzu-Hsuan Chiu, Pi-Hung Tung, Chin-Chou Wang, Chien-Ying Liu, Fu-Tsai Chung, Yueh-Fu Fang, Yi-Ke Guo, Chih-Hsi Scott Kuo, Cheng-Ta Yang
Therapeutic Advances in Medical Oncology.2021;[Epub] CrossRef
Association of EGFR Tyrosine Kinase Inhibitor Treatment With Progression-Free Survival Among Taiwanese Patients With Advanced Lung Adenocarcinoma and EGFR Mutation
Po-Yen Chen, Chin-Chou Wang, Chien-Ning Hsu, Chung-Yu Chen
Frontiers in Pharmacology.2021;[Epub] CrossRef
Elevated exosome-derived miRNAs predict osimertinib resistance in non-small cell lung cancer
Xinying Li, Cen Chen, Zimu Wang, Jiaxin Liu, Wei Sun, Kaikai Shen, Yanling Lv, Suhua Zhu, Ping Zhan, Tangfeng Lv, Yong Song
Cancer Cell International.2021;[Epub] CrossRef
Liquid Biopsy for EGFR Mutation Analysis in Advanced Non-Small-Cell Lung Cancer Patients: Thoughts Drawn from a Real-Life Experience
Paola Ulivi, Elisabetta Petracci, Matteo Canale, Ilaria Priano, Laura Capelli, Daniele Calistri, Elisa Chiadini, Paola Cravero, Alice Rossi, Angelo Delmonte, Lucio Crinò, Giuseppe Bronte
Biomedicines.2021; 9(10): 1299. CrossRef
Real-world efficacy and safety of lorlatinib in treating advanced ALK-positive non–small cell lung cancer patients
Po-Hsin Lee, Kun-Chieh Chen, Kuo-Hsuan Hsu, Yen-Hsiang Huang, Jeng-Sen Tseng, Tsung-Ying Yang, Gee-Chen Chang
Anti-Cancer Drugs.2021; 32(10): 1099. CrossRef
Clinical Features and Progression Pattern of Acquired T790M-positive Compared With T790M-negative EGFR Mutant Non–small-cell Lung Cancer: Catching Tumor and Clinical Heterogeneity Over Time Through Liquid Biopsy
Alessandro Dal Maso, Martina Lorenzi, Elisa Roca, Sara Pilotto, Marianna Macerelli, Valentina Polo, Fabiana Letizia Cecere, Alessandro Del Conte, Giorgia Nardo, Vanessa Buoro, Daniela Scattolin, Sara Monteverdi, Loredana Urso, Elisabetta Zulato, Stefano F
Clinical Lung Cancer.2020; 21(1): 1. CrossRef
Association between programmed death-ligand 1 expression, immune microenvironments, and clinical outcomes in epidermal growth factor receptor mutant lung adenocarcinoma patients treated with tyrosine kinase inhibitors
Ching-Yao Yang, Wei-Yu Liao, Chao-Chi Ho, Kuan-Yu Chen, Tzu-Hsiu Tsai, Chia-Lin Hsu, Kang-Yi Su, Yih-Leong Chang, Chen-Tu Wu, Chia-Chi Hsu, Bin-Chi Liao, Wei-Hsun Hsu, Jih-Hsiang Lee, Chia-Chi Lin, Jin-Yuan Shih, James C.-H. Yang, Chong-Jen Yu
European Journal of Cancer.2020; 124: 110. CrossRef
Comparison detection methods for EGFR in formalin-fixed paraffin-embedded tissues of patients with NSCLC
Xiaojie Fan, Xiaoxiao Wang, Meng Zhang, Huiyan Deng, Yueping Liu
Pathology - Research and Practice.2020; 216(1): 152783. CrossRef
Clinical implication and usefulness of de novo EGFR T790M mutation in lung adenocarcinoma with EGFR-tyrosine kinase inhibitor sensitizing mutation
Sang Hoon Lee, Eun Young Kim, Arum Kim, Yoon Soo Chang
Cancer Biology & Therapy.2020; 21(8): 741. CrossRef
Post-Progression Survival in Secondary EGFR T790M-Mutated Non-Small-Cell Lung Cancer Patients With and Without Osimertinib After Failure of a Previous EGFR TKI
Chi-Lu Chiang, Hsu-Ching Huang, Chia-I Shen, Yung-Hung Luo, Yuh-Min Chen, Chao-Hua Chiu
Targeted Oncology.2020; 15(4): 503. CrossRef
An Observational Study of Acquired EGFR T790M-Dependent Resistance to EGFR-TKI Treatment in Lung Adenocarcinoma Patients in Taiwan
Shang-Gin Wu, Chi-Lu Chiang, Chien-Ying Liu, Chin-Chou Wang, Po-Lan Su, Te-Chun Hsia, Jin-Yuan Shih, Gee-Chen Chang
Frontiers in Oncology.2020;[Epub] CrossRef
Refined Stratification Based on Baseline Concomitant Mutations and Longitudinal Circulating Tumor DNA Monitoring in Advanced EGFR-Mutant Lung Adenocarcinoma Under Gefitinib Treatment
Jianchun Duan, JiaChen Xu, Zhijie Wang, Hua Bai, Ying Cheng, Tongtong An, Hongjun Gao, Kai Wang, Qing Zhou, Yanping Hu, Yong Song, Cuimin Ding, Feng Peng, Li Liang, Yi Hu, Cheng Huang, Caicun Zhou, Yuankai Shi, Jiefei Han, Di Wang, Yanhua Tian, Zhenlin Ya
Journal of Thoracic Oncology.2020; 15(12): 1857. CrossRef
A Highly Sensitive Next-Generation Sequencing-Based Genotyping Platform for EGFR Mutations in Plasma from Non-Small Cell Lung Cancer Patients
Jung-Young Shin, Jeong-Oh Kim, Mi-Ran Lee, Seo Ree Kim, Kyongmin Sarah Beck, Jin Hyoung Kang
Cancers.2020; 12(12): 3579. CrossRef
Association of Tumor PD-L1 Expression with the T790M Mutation and Progression-Free Survival in Patients with EGFR-Mutant Non-Small Cell Lung Cancer Receiving EGFR-TKI Therapy
Minehiko Inomata, Kenji Azechi, Naoki Takata, Kana Hayashi, Kotaro Tokui, Chihiro Taka, Seisuke Okazawa, Kenta Kambara, Shingo Imanishi, Toshiro Miwa, Ryuji Hayashi, Shoko Matsui, Kazuyuki Tobe
Diagnostics.2020; 10(12): 1006. CrossRef
Rare Mechanism of Acquired Resistance to Osimertinib in Korean Patients with EGFR-mutated Non-small Cell Lung Cancer
Jiyun Lee, Joon Ho Shim, Woong-Yang Park, Hee Kyung Kim, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
Cancer Research and Treatment.2019; 51(1): 408. CrossRef
Clinical outcomes and secondary epidermal growth factor receptor (EGFR) T790M mutation among first‐line gefitinib, erlotinib and afatinib‐treated non‐small cell lung cancer patients with activating EGFR mutations
Yen‐Ting Lin, Jin‐Shing Chen, Wei‐Yu Liao, Chao‐Chi Ho, Chia‐Lin Hsu, Ching‐Yao Yang, Kuan‐Yu Chen, Jih‐Hsiang Lee, Zhong‐Zhe Lin, Jin‐Yuan Shih, James Chih‐Hsin Yang, Chong‐Jen Yu
International Journal of Cancer.2019; 144(11): 2887. CrossRef
Prior EGFR-TKI Treatment in EGFR-Mutated NSCLC Affects the Allele Frequency Fraction of Acquired T790M and the Subsequent Efficacy of Osimertinib
Chih-Hsi Scott Kuo, Chi-Hsien Huang, Chien-Ying Liu, Stelios Pavlidis, Ho-Wen Ko, Fu-Tsai Chung, Tin-Yu Lin, Chih-Liang Wang, Yi-Ke Guo, Cheng-Ta Yang
Targeted Oncology.2019; 14(4): 433. CrossRef
Frecuencia de mutación T790M determinada por biopsia líquida en pacientes con cáncer pulmonar de células no pequeñas después de la progresión a inhibidores de tirosina cinasa contra EGFR en primera línea
Jorge Arturo Alatorre-Alexander, Patricio Santillán-Doherty, María del Rosario Flores-Soto, Luis Manuel Martínez-Barrera, Jerónimo Rafael Rodríguez-Cid, Carla Paola Sánchez-Ríos
NCT Neumología y Cirugía de Tórax.2019; 78(4): 348. CrossRef

PubReader
ePub Link

Cite

CITE: export Copy Download Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format:

RIS — For EndNote, ProCite, RefWorks, and most other reference management software
BibTeX — For JabRef, BibDesk, and other BibTeX-specific software

Include:

Citation for the content below
Citation and abstract for the content below

The Association of Acquired T790M Mutation with Clinical Characteristics after Resistance to First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma

Cancer Res Treat. 2018;50(4):1294-1303. Published online January 4, 2018

DOI: https://doi.org/10.4143/crt.2017.512

XML Download

Figure

Related articles

Targeting CD73 to Overcomes Resistance to First-Generation EGFR Tyrosine Kinase Inhibitors in Non–Small Cell Lung Cancer

The Association of Acquired T790M Mutation with Clinical Characteristics after Resistance to First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma

Fig. 1. The patient collection flow chart. PD, progressive disease; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.

Fig. 2. The association between baseline epidermal growth factor receptor (EGFR) mutation status and T790M mutation status of rebiopsy.

Fig. 3. The association between progression-free survival of first-line epidermal growth factor receptor-tyrosine kinase inhibitor and T790M mutation status of rebiopsy.

Fig. 4. (A) Progression-free survival (PFS) of first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) versus T790M mutation status of rebiopsy by Kaplan-Meier survival curve analysis. (B) PFS of first-line EGFR-TKI versus T790M mutation status of rebiopsy and baseline EGFR mutation status by Kaplan-Meier survival curve analysis.

Fig. 5. The relationship between the duration of progression-free survival and T790M detection rate by receiver operating characteristic curve analysis. AUC, area under curve.

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

The Association of Acquired T790M Mutation with Clinical Characteristics after Resistance to First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma

Characteristic	No. (%) (n=205)
Age, median (range, yr)	60 (32-88)
Sex
Male	76 (37.1)
Female	129 (62.9)
Smoking status
Never smokers	162 (79.0)
Former smokers	23 (11.2)
Current smokers	20 (9.8)
*Baseline EGFR* mutation status**
Exon 19 deletions	111 (54.1)
Exon 21 L858R	83 (40.5)
Other mutations^a)	11 (5.4)
First-line TKI
Gefitinib	94 (45.9)
Erlotinib	98 (47.8)
Afatinib	13 (6.3)
Best response of first-line TKI
Stable disease	29 (14.1)
Partial response	176 (85.9)
PFS of first-line TKI
≤ 11 mo	107 (52.2)
> 11 mo	98 (47.8)
Rebiopsy site
Primary tumor	68 (33.2)
Metastases	137 (66.8)

Characteristic	No.	T790M status		p-value^a)
Characteristic	No.	Positive	Negative	p-value^a)
Age (yr)
≤ 60	103	51 (49.5)	52 (50.5)	0.402
> 60	102	44 (43.1)	58 (56.9)
Sex
Male	76	33 (43.4)	43 (56.6)	0.563
Female	129	62 (48.1)	67 (51.9)
Smoking status
Non-smokers	162	79 (48.8)	83 (51.2)	0.229
Current/Former-smokers	43	16 (37.2)	27 (62.8)
*Baseline EGFR* mutation status**
19Del	111	61 (55.0)	50 (45.0)	0.022
L858R	83	31 (37.3)	52 (62.7)
Others	11	3 (27.3)	8 (72.7)
First-line TKI
Gefitinib	94	47 (50.0)	47 (50.0)	0.188
Erlotinib	98	45 (45.9)	53 (54.1)
Afatinib	13	3 (23.1)	10 (76.9)
Best response of first line TKI
Stable disease	29	12 (41.4)	17 (58.6)	0.688
Partial response	176	83 (47.2)	93 (52.8)
PFS of first-line TKI
≤ 11 mo	107	42 (39.3)	65 (60.7)	0.036
> 11 mo	98	53 (54.1)	45 (45.9)
Rebiopsy site
Primary	68	23 (33.8)	45 (66.2)	0.012
Metastases	137	72 (52.6)	65 (47.4)

Characteristic	Odds ratio (95% CI)	p-value^a)	Adjusted odds ratio (95% CI)	p-value^a)
*Baseline EGFR* mutation status**
19Del vs. others	2.15 (1.23-3.78)	0.008	2.14 (1.20-3.83)	0.010^b)
PFS of first-line TKI
> 11 mo vs. ≤ 11 mo	1.82 (1.05-3.18)	0.034	1.82 (1.02-3.25)	0.044^c)
Rebiopsy site
Metastasis vs. primary	2.17 (1.19-3.97)	0.012	1.97 (1.06-3.67)	0.032^d)

Exon 19 deletions type	No.	T790M status
Exon 19 deletions type	No.	Positive	Negative
Del E746-A750	73	45 (61.6)	28 (38.4)
Del L747-P753 ins S	7	4 (57.1)	3 (42.9)
Del E746-S752 ins V	6	1 (16.7)	5 (83.3)
Del E746-T751	3	1 (33.3)	2 (66.7)
Del L747-T751	2	1 (50.0)	1 (50.0)
Del L747-T751 ins P	2	0	2 (100)
Del L747-E750	2	0	2 (100)
Del L747-A750	1	0	1 (100)
Del L747-P753	1	0	1 (100)
Mixed	8	6 (75.0)	2 (25.0)
Total	105	58	47

Table 1. Patients' characteristics and demographic data

EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; PFS, progression-free survival.

Includes complex mutation.

Table 2. Univariate analysis of the association between patients' characteristics and T790M status of rebiopsy

Values are presented as number (%). EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; PFS, progression-free survival.

By Fisher exact test.

Table 3. Multivariate analysis of the association between patients' characteristics and T790M status of rebiopsy

CI, confidence interval; EGFR, epidermal growth factor receptor; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

By logistic regression model,

Adjusted by age, sex, rebiopsy site, PFS of first-line TKI,

Adjusted by age, sex, rebiopsy site, and baseline EGFR mutation status,

Adjusted by age, sex, PFS of first-line TKI and baseline EGFR mutation status.

Table 4. EGFR exon 19 deletions mutation patterns in relation to T790M status of rebiopsya)