Medical Hypotheses 94 (2016) 20–22
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Hepatic metastasis is a poor predictive marker for erlotinib in lung adenocarcinoma Yayi He a,1, Yan Wang a,1, Shijia Zhang a, Shengxiang Ren a, Jiayu Li b, Caicun Zhou a,⇑ a b
Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, PR China Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, PR China
a r t i c l e
i n f o
Article history: Received 23 August 2015 Accepted 8 June 2016
a b s t r a c t Lung cancer is the leading cause of cancer related death worldwide and most of lung cancer patients have had metastases when they are diagnosed. With respect to chemotherapy, target therapy is a more effective and less toxic treatments. The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib or erlotinib, are one of the representatives of targeted therapy which have been widely used in first line, maintenance and 2nd/3rd line therapy among advanced non-small cell lung cancer (NSCLC). But those with hepatic metastases may insensitive to EGFR-TKIs due to MET activation by hepatocyte growth factor (HGF). In our retrospective analysis, 164 lung adenocarcinoma patients with known epidermal growth factor receptor (EGFR) mutation status who received the treatment of erlotinib as 2nd/3rd line setting were reviewed. The disease control rate (DCR) in patients without hepatic metastases group was higher than that in patients with hepatic metastases (66.1% vs 54.5%, p < 0.001). In EGFR mutation-positive patients, median PFS was significantly longer in patients without hepatic metastases than that in those with hepatic metastases (9.9 months 95% CI 7.74–12.06 months vs. 7.9 months 95% CI 5.88–9.92 months; p = 0.017). Therefore, we assume that hepatic metastasis may be a poor predictive marker for erlotinib in lung adenocarcinoma. Ó 2016 Elsevier Ltd. All rights reserved.
Introduction Lung cancer is the leading cause of cancer related death worldwide [1–3]. Non-small cell lung cancer (NSCLC) accounts for about 80% of primary lung cancer cases and approximately two thirds of them are diagnosed at an advanced stage [2]. Platinum-based doublet chemotherapy has been standard first-line therapy for advanced NSCLC [4,5]. Single-agent chemotherapy is used in the treatment of advanced NSCLC after failure of first line therapy, while the response rate (RR) is low and all of these agents have different toxicity profiles [6,7]. More effective and less toxic treatments are urgently needed for advanced NSCLC. The emerging of the molecular treatments provides a new choice for the treatment of advanced NSCLC. A good sample here is the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib or erlotinib, which have been widely used in first line, ⇑ Corresponding author at: Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No. 507 Zheng Min Road, Shanghai 200433, PR China. E-mail address:
[email protected] (C. Zhou). 1 The two authors contribute equally to this article. http://dx.doi.org/10.1016/j.mehy.2016.06.009 0306-9877/Ó 2016 Elsevier Ltd. All rights reserved.
maintenance and 2nd/3rd line therapy among advanced NSCLC [8–11]. The liver is one of the most frequent sites for blood borne metastases. The incidence of hepatic metastases in lung cancer patients has been reported to be 37–51% [12,13]. Studies showed that MET amplification activated by hepatocyte growth factor (HGF) activates ERBB3/PI3K/AKT signaling in EGFR mutant lung cancers, and causes resistance to EGFR kinase inhibitors [14,15]. Few studies have reported the therapeutic effect of erlotinib in the treatment of lung cancer hepatic metastases. Therefore, how to choose treatment of these patients seems to present a difficult clinical problem [16,17]. So we put forward the corresponding hypothesis. Hypothesis In our retrospective analysis, 164 patients histologically confirmed stage IV lung adenocarcinoma (Union for International Cancer Control classification version 7) with known EGFR mutation status who received the treatment of erlotinib as 2nd/3rd line setting were reviewed in Shanghai Pulmonary Hospital, Tongji University from Jan 2011 to May 2013. Erlotinib 150 mg tablets
Y. He et al. / Medical Hypotheses 94 (2016) 20–22
were given orally daily, and tumor measurements were assessed every 6 weeks as clinically indicated afterwards [18–20]. EGFR mutational analyses were performed in Tongji University Medical School Cancer Institute (Shanghai, China). The QIAamp DNA FFPE tissue kit (Qiagen, Hilden, Germany) was used for DNA extraction of FFPE tissue according to the user manual. The details were described in our previous articles [21,22]. Survival analysis curves were constructed using the Kaplan-Meier method, and survival was compared using the log-rank test. The SPSS statistical package for Windows version 19.0 was used. All p values were two-sided. The results were as follows. The disease control rate (DCR) in patients without hepatic metastases group was higher than that in patients with hepatic metastases (66.1% vs 54.5%, p < 0.001). In EGFR-positive patients with a known mutation type of EGFR—ie, an exon 19 deletion or an exon 21 L858R point mutation, median PFS was significantly longer in patients without hepatic metastases than that in those with hepatic metastases (9.9 months 95% CI 7.74–12.06 months vs. 7.9 months 95% CI 5.88–9.92 months; p = 0.017). Therefore, we assume that hepatic metastasis may be a poor predictive marker for erlotinib as 2nd/3rd line treatment in patients with lung adenocarcinoma.
Evaluation of the hypothesis In advanced NSCLC, chemotherapy offers symptomatic relief and modest improvement in survival [21]. Second-line chemotherapy with docetaxel or pemetrexed can prolong survival after platinum-based chemotherapy for NSCLC [6,7]. Shepherd et al. [6] showed that among patients treated with docetaxel after the failure of two or more chemotherapy regimens, survival was longer than those treated with supportive care. Erlotinib and gefitinib, which can inhibit the tyrosine kinase activity of EGFR, have been extensively studied [23–35]. In randomized phase II trials of gefitinib (Iressa Dose Evaluation in Advanced Lung Cancer [IDEAL] 1 and 2), 10–20% patients who were previously treated with platinum-based regimens responded to gefitinib [34,35]. After that, clinical trials also demonstrated erlotinib can prolong survival in previously treated NSCLC patients [11]. A phase II trial reported that erlotinib among previously treated patients with NSCLC cancer in which 10% or more of the cells expressed EGFR, the response rate was 12.3% [32]. These promising rates are perhaps higher than chemotherapy [6,7]. In our study, the DCR is 62.2%, which was similar to previous report [11]. The DCR in patients without hepatic metastases group was higher than that in patients with hepatic metastases. When we further divided EGFR mutation status into mutation-positive and mutation-negative, we found the same result. Patients without hepatic metastases had a higher DCR and longer PFS than patients with hepatic metastases. EGFR-TKIs are widely used in advanced NSCLC [8–10]. However, not all patients respond to the EGFR-TKIs. The response rate is about 10% in the unselected Caucasian population and 30–40% in the unselected Asian population [23,25]. ISEL study first found that patients of female, never-smoker, adenocarcinoma or East Asian ethnicity will benefit more from the treatment of EGFR-TKIs [25]. After that, several phase III prospective trials confirmed that EGFR mutation is the main predictive factor for EGFR-TKIs [8,9]. Subsequent studies found that it was smoking status and histology but not gender which affect the incidence of EGFR mutation and EGFR mutation is a unique entity for its predictive role for EGFR-TKIs [9,22,24,26–32]. Our study showed response to erlotinib was more common in non-smoke patients, which was in accordance with other studies [11,32]. Lung cancer with EGFR–activating mutations responds favorably to the EGFR-TKIs, gefitinib and erlotinib. However, 25–30%
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of patients with EGFR-activating mutations show intrinsic resistance, and the responders would invariably acquire resistance to EGFR-TKIs. HGF, a ligand of MET oncoprotein, induces EGFR-TKI resistance of lung adenocarcinoma cells with EGFR-activating mutations by restoring the phosphatidylinositol 3-kinase/AKT (PI3K/AKT) signaling pathway via phosphorylation of MET [14]. MET amplification activates ERBB3/PI3K/AKT signaling in EGFR mutant lung cancers, and causes resistance to EGFR kinase inhibitors. MET activation by its ligand, HGF, also induces drug resistance [15]. At the same time, we should consider the possibility that the actual status of EGFR genes in hepatic metastases, it could be different from the status of the sample analyzed. The samples used for EGFR gene analysis in this study were derived from lung tumors before initiation of chemotherapy, not from liver tumors. And all the patients had received one or two prior chemotherapy regimens. Previous research suggested that the EGFR mutation status would change after chemotherapy [36]. All the mentioned above may influence the efficacy of erlotinib and may cause poor curative effect of erlotinib in liver. Discussion and perspectives At present, most of lung cancer patients have had metastases when they are diagnosed. EGFR-TKIs, such as gefitinib or erlotinib, are more effective and less toxic than chemotherapy in EGFR mutation-positive patients. But those with hepatic metastases may insensitive to EGFR-TKIs due to MET activation by HGF. In our study, we found that the curative effect of erlotinib was not good in the hepatic metastases lesion in lung adenocarcinoma. Patients without hepatic metastases had a higher DCR and longer PFS than those with hepatic metastases, which suggested that Hepatic metastasis might be a poor predictive marker for erlotinib as 2nd/3rd line treatment in patients with lung adenocarcinoma. But our study has some limitations. First, our study was retrospective study. Second, the sample size was small. Further study is needed to explore the overall survival between patients with hepatic metastases and patients without hepatic metastases in more patients. More drugs should be investigated in the treatment of lung cancer patients with hepatic metastases. Conflict of interest statement The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. Acknowledgements This study was supported in part by a grant from the Young Program of Shanghai National Health and Family Planning Commission and grant of the Chronic Disease Comprehensive Prevention and Control Project by Shanghai Shen Kang Hospital Development Center (No. SHDC12012313). References [1] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893–917. [2] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69–90. [3] Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, et al. Cancer statistics 2005. CA Cancer J Clin 2005;55:10–30. [4] Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker Jr S, et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 2004;22:330–53. [5] D’Addario G, Pintilie M, Leighl NB, Feld R, Cerny T, Shepherd FA. Platinumbased versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature. J Clin Oncol 2005;23:2926–36.
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