Research ArticleClinical Studies

Factors Associated With Distant Metastasis in EGFR-mutated Non-small Cell Lung Cancer Patients: Logistic Analysis

HIROKO WATANABE, SHINICHIRO OKAUCHI, KUNIHIKO MIYAZAKI, HIROAKI SATOH and NOBUYUKI HIZAWA
In Vivo July 2019, 33 (4) 1369-1372; DOI: https://doi.org/10.21873/invivo.11613

Abstract

Background/Aim: The aim of this retrospective study was to identify, using logistic analysis, the factors associated with distant metastasis in non-small cell lung cancer patients carrying mutations in epidermal growth factor receptor. Patients and Methods: Patients who were diagnosed with distant metastasis at the time of diagnosis up to their death and during the period from April 2009 to March 2019, were included in this study. Clinical charts and imaging studies were reviewed. Results: A total of 64 patients during the research period. The factors associated with pleural metastasis were “female” and “no bone metastasis”. The factor associated with brain metastasis was “lung metastasis”. The factors associated with liver metastasis were “age under 70” and “Exon 19 deletion”. Conclusion: Knowing the factors associated with distant metastasis will provide useful information to conduct targeted and efficient imaging studies.

In epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients, therapy with EGFR-tyrosine kinase inhibitor (TKI) has increased the number of long-term survivors (1, 2). However, with current medical technology, it is difficult to expect cure (3, 4). In most patients, regrowth of the primary tumor and metastasis occur. In addition, many patients with critical metastasis are difficult to treat. Particularly, patients with brain metastasis may become dysfunctional and develop paralysis, even if TKI or radiation results in shrinkage of the metastatic lesion (5-7). Thus, brain metastases can lead to a deterioration of quality of life. Some patients with liver metastasis, especially those with liver relapse after a good response to TKI, have a poor response to TKI therapy (8). Therefore, it is important to identify the factors that are related to metastasis to a specific organ by use of multivariate analysis.

In this study, we evaluated distant organ metastasis detected throughout the entire clinical course of NSCLC. Therefore, not only “metastasis at diagnosis” but also “metastasis appearing in the clinical course” was taken into consideration. In order to identify the factors associated with distant metastasis in EGFR mutated non-small cell lung cancer patients, we used Logistic analysis.

Patients and Methods

Patients, who were presented at three tertiary hospitals from April 2009 to March 2019, and were diagnosed with distant metastasis at the time of diagnosis and during the clinical course of the disease up to their death, were included in this study. Clinical charts and imaging studies were retrospectively reviewed. Distant metastasis sites included lung, bone, brain, liver, lymph nodes other than regional nodes, and pleura. Logistic regression analysis was used for statistical analysis. One organ was selected as the objective variable and the other organ metastases were considered as independent variables. By selecting several objective variables, the same analyses were performed. p-Values less than 0.05 were considered as statistically significant. Comprehensive informed consent was obtained from each patient at the time of admission for lung cancer diagnosis. This study was approved by Institutional Review Board.

Results

A total of 64 patients matching the above conditions during the research period were identified. The background of patients is shown in Table I. The median age of them was 73, and 43 were female patients. Exon 19 deletion and Exon 21 L858R mutation were found in 37 and 27 patients, respectively. The number of patients with distant metastases to lungs, bones, brain, liver, adrenals, lymph nodes other than regional lymph nodes, and other sites were 28, 29, 26, 19, 19, 8, and 9, respectively. Therefore, the metastatic sites that could be analyzed as objective variables were pleura, brain and liver. We defined each of the three metastases as “target variables” and examined their relationship with metastases to other organs. Table II shows the analysis results when treating “pleural metastasis” as the objective variable. The factors associated with pleural metastasis were “female” and “no bone metastasis”. As shown in Table III, the factor associated with brain metastasis was “lung metastasis” The factors associated with liver metastasis were “age under 70” and “Ex 19 deletion” (Table IV).

Discussion

Regarding distant organ metastasis in lung cancer, there are many studies mainly examining metastasis frequency to each organ (9-12). We have also published several studies on this subject (10-12). In particular, EGFR mutated NSCLC patients is of interest because some of them develop metastasis to lungs and brain (13, 14). These lung cancer patients are treated with EGFR-TKI as the ‘standard therapy’ and the number of long-term survivors has increased (1, 2). However, at present, cure has not been achieved (3, 4), and there is a risk of recurrence of primary and distant metastatic lesions. Long-term survivors must repeat imaging studies for metastatic lesions for longer periods, even though their frequency becomes low. If factors related to specific organ metastasis, especially factors that predict metastasis to other organs become clear, targeted and efficient imaging studies may be performed and effectively use limited medical resources.

The analysis of the results of this study revealed that the factors associated with pleural metastasis were “female” and “no bone metastasis”, when treating “pleural metastasis” as the objective variable. The factor associated with brain metastasis was “lung metastasis”, when treating “brain metastasis” as the objective variable. The factors associated with liver metastasis were “age under 70” and “Ex 19 deletion”, when treating “liver metastasis” as the objective variable. The standard treatment for meningeal recurrence after EGFR-TKI treatment has not been established and is one of the metastatic sites of interest. In the same logistic analysis when using “meninges” as the objective variable, Exon21 L858R gene mutation was identified as a significant factor (data not shown).

Although the above results are remarkable, there were certain limitations in this study. First, this study included patients from three tertiary hospitals, but included a small number of patients. One of the reasons was prolongation of survival time in EGFR mutated NSCLC patients due to effective treatment with EGFR-TKI. Second, the frequency of imaging studies and selection of EGFR-TKI were dependent on treatment plan of each chest physician. Therefore, it is necessary to confirm our results in prospective registration studies with regularly repeated imaging examination in a large number of patients. However, it is hypothesized that the implementation of uniform treatment for patients with prolonged survival may limit patient treatment, as progress in TKI treatment is remarkable. That is, prospective registration with fixed therapy, such as administration of old generation TKI, may not be practical because patients may suffer disadvantages. Third, the validity of this research method of changing objective variables and repeating logistic analysis is questionable. Such limitations must be overcome in future studies.

View this table:
Table I.

Characteristics of 64 NSCLC patients with EGFR mutation.

In summary, identification of specific factors related to specific organ metastasis is very important. It will allow targeted and efficient imaging studies and effective use of limited medical resources.

View this table:
Table II.

Factors associated with pleural metastasis in 64 EGFR mutated NSCLC patients.

View this table:
Table III.

Factors associated with brain metastasis in 64 EGFR mutated NSCLC patients.

View this table:
Table IV.

Factors associated with liver metastasis in 64 EGFR mutated NSCLC patients.

Footnotes

  • Authors' Contributions

    Hiroko Watanabe, Hiroaki Satoh, Nobuyuki Hizawa designed the study; Hiroko Watanabe, Shinichiro Okauchi and Kunihiko Miyazaki collected the data; Hiroko Watanabe and Hiroaki Satoh analyzed the data; Hiroko Watanabe and Hiroaki Satoh prepared the manuscript. All Authors approved the final version for submission.

  • This article is freely accessible online.

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare.

  • Received May 6, 2019.
  • Revision received June 10, 2019.
  • Accepted June 11, 2019.

References

  1. ↵
    1. Lin JJ,
    2. Cardarella S,
    3. Lydon CA,
    4. Dahlberg SE,
    5. Jackman DM,
    6. Jänne PA,
    7. Johnson BE
    : Five-year survival in EGFR-mutant metastatic lung adenocarcinoma treated with EGFR-TKIs. J Thorac Oncol 11(4): 556-565, 2016. PMID: 26724471. DOI: 10.1016/j.jtho.2015.12.103
    OpenUrlCrossRefPubMed
  2. ↵
    1. Huang CY,
    2. Chen BH,
    3. Chou WC,
    4. Yang CT,
    5. Chang JW
    : Factors associated with the prognosis and long-term survival of patients with metastatic lung adenocarcinoma: a retrospective analysis. J Thorac Dis 10(4): 2070-2078, 2018. PMID: 29850110. DOI: 10.21037/jtd.2018.03.143
    OpenUrl
  3. ↵
    1. Hrustanovic G,
    2. Lee BJ,
    3. Bivona TG
    : Mechanisms of resistance to EGFR targeted therapies. Cancer Biol Ther 14(4): 304-314, 2013. PMID: 23358468. DOI: 10.4161/cbt.23627
    OpenUrl
  4. ↵
    1. Kuwata T,
    2. Yoneda K,
    3. Kobayashi K,
    4. Oyama R,
    5. Matumiya H,
    6. Shinohara S,
    7. Takenaka M,
    8. Oka S,
    9. Chikaishi Y,
    10. Imanishi N,
    11. Kuroda K,
    12. Tanaka F
    : achievement of cure with gefitinib in advanced lung adenocarcinoma harboring an activating EGFR mutation: A case report. Case Rep Oncol 9(3): 565-567, 2016. PMID: 27790122. DOI: 10.1159/000449371
    OpenUrl
  5. ↵
    1. Sekine A,
    2. Satoh H
    : Paradigm shift of therapeutic management of brain metastases in EGFR-mutant non-small cell lung cancer in the era of targeted therapy. Med Oncol 34(7): 121, 2017. PMID: 28555261. DOI: 10.1007/s12032-017-0978-2
    OpenUrl
    1. Dempke WC,
    2. Edvardsen K,
    3. Lu S,
    4. Reinmuth N,
    5. Reck M,
    6. Inoue A
    : Brain metastases in NSCLC - are TKIs changing the treatment strategy? Anticancer Res 35(11): 5797-5806, 2015. PMID: 26504000.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Burel-Vandenbos F,
    2. Ambrosetti D,
    3. Coutts M,
    4. Pedeutour F
    : EGFR mutation status in brain metastases of non-small cell lung carcinoma. J Neurooncol 111(1): 1-10, 2013. PMID: 23086434. DOI: 10.1007/s11060-012-0990-5
    OpenUrl
  8. ↵
    1. He Y,
    2. Wang Y,
    3. Boyle T,
    4. Ren S,
    5. Chan D,
    6. Rivard C,
    7. Li X,
    8. Li J,
    9. Zhou C,
    10. Hirsch FR
    : hepatic metastasis is associated with poor efficacy of erlotinib as 2nd/3rd line therapy in patients with lung adenocarcinoma. Med Sci Monit 22: 276-283, 2016. PMID: 26811313. DOI: 10.12659/msm.896607
    OpenUrl
  9. ↵
    1. Inamura K,
    2. Ishikawa Y
    : Lung cancer progression and metastasis from the prognostic point of view. Clin Exp Metastasis 27(6): 389-397, 2010. PMID: 20225084. DOI: 10.1007/s10585-010-9313-4.
    OpenUrlCrossRefPubMed
  10. ↵
    1. Tamura T,
    2. Kurishima K,
    3. Nakazawa K,
    4. Kagohashi K,
    5. Ishikawa H,
    6. Satoh H,
    7. Hizawa N
    : Specific organ metastases and survival in metastatic non-small-cell lung cancer. Mol Clin Oncol 3(1): 217-221, 2015. PMID: 25469298. DOI: 10.3892/mco.2014.410
    OpenUrl
    1. Nakazawa K,
    2. Kurishima K,
    3. Tamura T,
    4. Kagohashi K,
    5. Ishikawa H,
    6. Satoh H,
    7. Hizawa N
    : Specific organ metastases and survival in small cell lung cancer. Oncol Lett 4(4): 617-620, 2012. PMID: 23205072. DOI: 10.3892/ol.2012.792
    OpenUrlPubMed
  12. ↵
    1. Oikawa A,
    2. Takahashi H,
    3. Ishikawa H,
    4. Kurishima K,
    5. Kagohashi K,
    6. Satoh H
    : Application of conditional probability analysis to distant metastases from lung cancer. Oncol Lett 3(3): 629-634, 2012. PMID: 22740965. DOI: 10.3892/ol.2011.535
    OpenUrlPubMed
  13. ↵
    1. Togashi Y,
    2. Masago K,
    3. Kubo T,
    4. Sakamori Y,
    5. Kim YH,
    6. Hatachi Y,
    7. Fukuhara A,
    8. Mio T,
    9. Togashi K,
    10. Mishima M
    : Association of diffuse, random pulmonary metastases, including miliary metastases, with epidermal growth factor receptor mutations in lung adenocarcinoma. Cancer 117(4): 819-825, 2011. PMID: 20886633. DOI: 10.1002/cncr.25618
    OpenUrlPubMed
  14. ↵
    1. Sekine A,
    2. Kato T,
    3. Hagiwara E,
    4. Shinohara T,
    5. Komagata T,
    6. Iwasawa T,
    7. Satoh H,
    8. Tamura K,
    9. Kasamatsu T,
    10. Hayashihara K,
    11. Saito T,
    12. Takahashi H,
    13. Ogura T
    : Metastatic brain tumors from non-small cell lung cancer with EGFR mutations: distinguishing influence of exon 19 deletion on radiographic features. Lung Cancer 77(1): 64-69, 2012. PMID: 22335887. DOI: 10.1016/j.lungcan.2011.12.017
    OpenUrlCrossRefPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Factors Associated With Distant Metastasis in EGFR-mutated Non-small Cell Lung Cancer Patients: Logistic Analysis
HIROKO WATANABE, SHINICHIRO OKAUCHI, KUNIHIKO MIYAZAKI, HIROAKI SATOH, NOBUYUKI HIZAWA
In Vivo Jul 2019, 33 (4) 1369-1372; DOI: 10.21873/invivo.11613
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords