Abstract
Background/Aim: The significance of epidermal growth factor receptor (EGFR) mutation in untreated patients with non-small cell lung cancer (NSCLC) remains uncertain. We aimed to determine the significance of EGFR mutation in patients who received best supportive care (BSC) alone, and compare the outcomes of only EGFR- tyrosine kinase inhibitors (TKI)-treated vs. BSC patients. Patients and Methods: Between April 1991–August 2018, 1,197 patients diagnosed with unresectable NSCLC at our institutions were enrolled in the study. Results: Among 226 patients who underwent EGFR mutation analysis and received BSC alone, 35 and 191 did and did not harbor the mutation, and the median survival times (MST) did not differ significantly between these groups. A comparison of only EGFR-TKI-treated and BSC patients with EGFR mutation revealed that the former had a three times longer MST than the latter. Conclusion: Our results may help explain the benefit of EGFR-TKI for patients who would be directed towards BSC.
- Epidermal growth factor receptor gene mutation
- best supportive care
- non-small-cell lung cancer
- prognosis
- anti-tumor effects
Lung cancer is the leading cause of cancer-related deaths worldwide (1). In a 1994 meta-analysis, patients who underwent chemotherapy had longer survival times than those who received best supportive care (BSC) alone (2). Accordingly, BSC is no longer used as the control arm in clinical trials of first-line treatment. Moreover, few retrospective studies have explored the prognosis of untreated patients with NSCLC (3, 4). In recent years, novel chemotherapy drugs, immune therapies, and molecular targeted therapies have been developed for the treatment of non-small cell lung cancer (NSCLC) (5-7). Although these new agents are considered less toxic than conventional chemotherapy drugs, some patients remain unable to undergo systemic treatment because of a poor performance status (PS), older age, or severe comorbidities.
Approximately 40-50% or 10-15% of patients with lung adenocarcinoma in Asia or Western countries harbor an activating mutation in the gene encoding epidermal growth factor receptor (EGFR) (8). EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy has yielded remarkable responses in these patients (9-11), as even those with a poor PS (e.g., 3-4) were found to receive survival benefit with this therapy (12). Consequently, a few patients who harbor an EGFR mutation do not receive targeted therapy. Still, studies of cancer cell lines and experimental animal models revealed that EGFR mutation increases the proliferative and metastatic activities of NSCLC cells (13). However, the significance of this mutation itself in untreated patients with NSCLC remains uncertain.
Several prospective clinical trials showed the EGFR-TKI prolonged the progression-free survival compared to patients treated by chemotherapy (9, 10). In addition, EGFR TKI treatment showed that these drugs exhibited anti-tumor activity against the EGFR-mutated NSCLC cells comparing untreated group both in vitro and in vivo (14-17). However, there has not been a study to examine the difference of survival durations between the patients with EGFR-mutated NSCLC who received EGFR-TKI monotherapy and BSC alone.
Therefore, we retrospectively compared the survival duration of patients with or without EGFR-mutated NSCLC who received BSC alone, as well as of survival durations of patients with EGFR-mutated NSCLC who received EGFR-TKI monotherapy or BSC alone. Through these analyses, we aimed to clarify the significance of EGFR mutation in patients with NSCLC as well as explain the benefit of EGFR-TKI therapy.
Patients and Methods
Study design and participants. We retrospectively reviewed the medical records of patients with unresectable NSCLC who were diagnosed at Higashihiroshima Medical Center between April 1991 and January 2019, and at Hiroshima University Hospital between April 2008 and August 2018. This retrospective analysis was approved by the Hiroshima University Institutional Review Board (No. E939). All procedures associated with studies involving human participants were performed in accordance with the ethical standards of the institutional research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Regarding patient consent, the opt-out method was applied in this retrospective study.
EGFR mutation analysis. Some patients were diagnosed with NSCLC before EGFR mutational analyses became available. In such cases, we extracted DNA from samples that had been confirmed cytologically or histologically to contain cancer cells, using the phenol-chloroform extraction method or DNeasy Blood & Tissue Kit (QIAGEN, Valencia, CA, USA) according to the manufacturer’s instructions. Subsequently, the extracted DNA was subjected to a polymerase chain reaction assay using the peptide nucleic acid-locked nucleic acid clamp PCR method, Cycleave-PCR method, or Cobas DNA Sample Preparation Kit (Roche Molecular Systems, Pleasanton, CA, USA) according to the manufacturer’s instructions to detect activating EGFR mutations. For patients diagnosed with NSCLC after EGFR mutation analytical products were made commercially available, genomic samples were subjected to mutation testing (peptide nucleic acid-locked nucleic acid clamp PCR method or Cobas method) by commercial laboratories.
Data collection. We collected the following data from medical records: age, sex, smoking history, Eastern Cooperative Oncology Group performance status (PS), histologic type, and overall survival duration (OS).
Statistical analysis. Clinical characteristics were compared between any two groups using either Chi-square tests. Univariate and multivariate analyses based on a Cox regression model were used to identify significant prognostic factors. Parameters with p-values of <0.05 in the univariate analysis were selected for inclusion in the multivariable analysis. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test to examine the significance of differences between groups. To reduce the effects of treatment selection bias and potential confounding factors, we used propensity score matching to rigorously adjust for significant differences in the baseline characteristics of patients. The propensity score for each patient was calculated as a probability from a logistic regression model that included age, sex, smoking status, histologic type, Eastern Cooperative Oncology Group performance status and clinical stage. Generally, results with p-values of <0.05 were considered to be statistically significant for all analyses. All statistical analyses were performed using JMP®14 software (SAS Institute Inc., Cary, NC, USA).
Results
Patient characteristics. A total of 1,197 patients diagnosed with unresectable NSCLC were included in this analysis. Among them, 950 patients underwent initial treatment for NSCLC. Additionally, 247 patients did not undergo treatment for NSCLC (Figure 1). The clinical characteristics of the patients who received initial treatment or BSC are shown in Table I. Note that the proportions of patients with high age, poor PS and clinical stage IV were significantly higher in BSC group than treated group.
Flow chart of participants. BSC: Best supportive care, EGFR: epidermal growth factor receptor, TKI: tyrosine kinase inhibitor, NSCLC: non-small cell lung cancer, PD-1: programmed cell death-1.
Comparison of patient characteristics between treatment and best supportive care group.
Comparison of survival time in patients with or without EGFR gene mutation who underwent only BSC. Among 247 BSC patients, 226 patients underwent EGFR mutation analysis, and 35 and 191 did and did not harbor an EGFR mutation, respectively (Figure 1). The proportions of patients with brinkman index <800 and adenocarcinoma cases were significantly higher among patients with EGFR-mutated NSCLC, compared to patients without the mutation (Table II). To determine the significance of EGFR gene mutation on survival in the patients who underwent only BSC, we compared the median survival times (MST) between untreated patients with EGFR-mutated and unmutated disease. The MST did not differ significantly between these groups (107 vs. 83 days, p=0.715; Figure 2). Moreover, the univariate and multivariate Cox regression analyses identified the clinical stage, PS, and clinical stage as significant independent prognostic factors among untreated patients (Table III). Consistent with the survival analysis, EGFR mutation was not identified as an independent prognostic factor.
Comparison of patient characteristics who underwent only BSC between EGFR mutation positive and negative group.
Kaplan–Meier analysis of overall survival in patients with epidermal growth factor receptor gene (EGFR) mutation-positive or -negative non-small-cell lung cancer. OS: Overall survival, CI: confidence interval.
Univariate and multivariate Cox analyses of overall survival in the patients underwent only BSC.
Anti-tumor effects of EGFR-TKI on the patients with EGFR-mutated NSCLC in comparison with the patients who received BSC alone. The number of EGFR-mutated patients who underwent EGFR-TKI treatment alone was 77 cases in the 695 patients who underwent chemotherapy for NSCLC (Figure 1). To compare the survival time between EGFR-mutated patients who received BSC alone and EGFR-TKI treatment alone, we used propensity score matching to adjust for differences in the characteristics between the patients who received BSC alone (n=35) and EGFR-TKI monotherapy alone (n=77) (Figure 1). After propensity score matching (matched patient background shown in Table IV), we investigated the MST between the EGFR mutated patients treated with only EGFR-TKI (n=30) or BSC (n=30). Notably, the MST of patients treated with EGFR-TKI was three times longer than that of untreated patients (272 vs. 99, p<0.001) (Figure 3).
Comparison of patient characteristics with EGFR mutation between EGFR-TKI treated and BSC group.
Kaplan–Meier analysis of overall survival in patients with epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer who received EGFR-tyrosine kinase inhibitor (TKI) therapy or best supportive care (BSC). OS: overall survival, CI: confidence interval.
Discussion
In this study, we did not observe any significant difference in MST between patients with and without the EGFR mutation who received BSC alone. Moreover, EGFR mutation was not identified as a significant prognostic factor in patients with untreated NSCLC. To the best of our knowledge, this is the first study to report these findings. EGFR mutation is a known oncogene in lung cancer. The corresponding mutant protein can activate multiple signaling pathways, including those mediated by mitogen-activated protein kinase, phosphatidyl-inositol 3-kinase/AKT, and signal transducer and activator of transcription, leading to cancer cell proliferation, migration, and metastasis (13). Accordingly, patients harboring an EGFR mutation would be expected to have a shorter survival duration than those without this mutation if BSC alone was administered. In contrast to our expectations, however, we demonstrated that patients with untreated NSCLC had similar survival durations, regardless of the EGFR mutation status. This finding is reason why lung cancer tends to be more proliferative and metastatic than other types of cancer and more likely to yield multi-organ metastases to the brain, bone, and liver, regardless of EGFR gene mutation (18-21). Moreover, some patients with lung cancer harbor another driver oncogene such as ALK, the ROS1 fusion gene, and/or BRAF mutation. Actually, ALK, ROS1 rearrangement or BRAF mutation was reported to be detected in approximately 3-5%, 1-2% or 1-3% of patients with NSCLC (6, 22, 23). We note that we did not fully explore these oncogenes in our study, although they certainly could have influenced the prognoses of the included patients.
Among patients with EGFR-mutation, we observed MSTs of 272 and 99 days among patients treated with EGFR-TKIs and BSC, respectively (p<0.001). Although several clinical trials have demonstrated the superiority of EGFR-TKI vs. chemotherapy in terms of prolonged PFS among EGFR mutation-positive lung cancer patients (9, 10), no study has clarified the effect of EGFR-TKI vs. BSC on prognosis. Therefore, our study is unique in analysing the significant effect of EGFR-TKI specifically in patients with EGFR mutation-positive NSCLC. Our results may help explain the benefit of EGFR-TKI, particularly for patients who would otherwise be directed towards treatment with BSC alone.
We note that our study was a retrospective analysis and is subjected to the limitations inherent to the study design. A prospective multicenter study is warranted to verify our findings.
In conclusion, we demonstrated that the MST of untreated patients with NSCLC did not differ significantly according to the EGFR mutation status. Consistent with this analysis, EGFR mutation was not identified as an independent prognostic factor. These results may help to explain the prognosis for the EGFR-mutated patients who would be directed towards treatment with BSC. Moreover, patients with EGFR mutation-positive disease who received EGFR-TKI therapy had a significantly longer MST than their untreated counterparts. We hope that our results can elucidate the benefit of EGFR-TKI therapy for patients with EGFR-mutated lung cancer.
Acknowledgements
The Authors acknowledge Isao Murakami (Department of Respiratory Internal Medicine, Higashihiroshima Medical Center,) for collecting clinical date. In addition, we thank Akiko Miyake (Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan) for support in this study.
Footnotes
Authors’ Contributions
Study conception and design: Takeshi Masuda, Taku Nakashima, Kazunori Fujitaka, Noboru Hattori. Acquisition of data: Takeshi Masuda, Yu Wakabayashi, Taku Nakashima, Yoshifumi Nishimura, Kiyofumi Shimoji, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Yasushi Horimasu, Shintaro Miyamoto, Tadashi Senoo, Hiroshi Iwamoto, Shinichiro Ohshimo, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori. Analysis and interpretation of data: Takeshi Masuda, Yu Wakabayashi, Taku Nakashima. Drafting of manuscript: Takeshi Masuda, Yu Wakabayashi, Taku Nakashima, Kazunori Fujitaka, Noboru Hattori. All Authors read and approved the final manuscript.
Conflicts of Interest
N. Hattori has received fund from Pfizer, MSD, Taiho Pharmaceutical, ONO Pharmaceutical, and lecture fees, honoraria from Bristol-Myers Squibb, AstraZeneca, Pfizer, Chugai Pharmaceutical, Boehringer Ingelheim. H. Iwamoto has received lecture fees, honoraria from AstraZeneca.
- Received March 8, 2021.
- Revision received March 25, 2021.
- Accepted March 29, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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