Tumor Biol. (2015) 36:861–869 DOI 10.1007/s13277-014-2692-4
RESEARCH ARTICLE
Pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR genotypes Xiangli Jiang & Bo Yang & Jiuqin Lu & Zhongli Zhan & Kai Li & Xiubao Ren
Received: 22 May 2014 / Accepted: 30 September 2014 / Published online: 10 October 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract Advanced lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) activating mutations usually are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs), but whether EGFR-mutant lung adenocarcinoma is also responsive to pemetrexed-based chemotherapy remains controversial. We conducted a retrospective study to evaluate the efficacy and outcome of pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR mutation statuses. Sixty-nine EGFR-mutant and 89 wild-type patients with advanced lung adenocarcinoma were enrolled. They all had received pemetrexed-based treatments. Chemotherapy objective response rate (ORR), median progression-free survival (mPFS), and thymidylate synthase (TS) expression levels of EGFR-mutant patients were compared with those of EGFR-wild-type patients. For the EGFRmutant patients treated with first-line platinum/pemetrexed combinations, the ORR was significantly higher than that of
Xiangli Jiang and Bo Yang contribute equally to this paper. X. Jiang : J. Lu : K. Li (*) Department of Thoracic Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China e-mail: [email protected] B. Yang : Z. Zhan Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China X. Ren (*) Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin 300060, China e-mail: [email protected] X. Jiang : X. Ren Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin 300060, China
the wild-type patients treated with similar regimens (43 vs. 21 %, p=0.039). Nonetheless, for the patients treated with pemetrexed monotherapy, the difference in ORR was not significant between patients with EGFR mutations and those with wild-type EGFR in any line of treatments (in the first-line setting 20 vs. 13 %, p=0.715; in the second-/third-line setting 13 vs. 8 %, p=0.655). On the other hand, the mPFS for the EGFR-mutant patients treated with first-line combinations was also obviously prolonged (8.3 vs. 6.7 months, p = 0.004). However, among the patients receiving second-line platinum/pemetrexed combinations or any line of single-agent pemetrexed, there was no difference in PFS between EGFRmutant and wild-type patients. Our results indicated that the efficacies and outcomes of pemetrexed treatment in advanced lung adenocarcinoma patients with EGFR activating mutations were similar to those in patients with EGFR-wild-type genotype, except in the setting of first-line platinum/ pemetrexed combination chemotherapy. Keywords Lung adenocarcinoma . Epidermal growth factor receptor . Activating mutation . Pemetrexed . Thymidylate synthase
Introduction Since 2004, the mutations of epidermal growth factor receptor (EGFR) have drawn much attention in lung cancer research [1, 2]. EGFR activating mutations, including exon 19 deletion and exon 21 L858R mutation, consist of 10–44 % of lung adenocarcinoma patients, and are associated with high sensitivity to EGFR tyrosine kinase inhibitors (TKIs) [3–5]. Based on a number of randomized phase III trials, EGFR TKIs have been confirmed superior to conventional chemotherapy and are now established as a standard first-line treatment for advanced patients with activating EGFR mutations [6–11].
862
However, most patients will develop to disease progression due to acquired resistance to TKIs and systemic chemotherapy is an important option for post-progression therapy. Given the varied functional expression between patients harboring EGFR mutations and those harboring wild-type EGFR, understanding the potential differences of the efficacies and outcomes of systemic chemotherapy between different EGFR mutation statuses is therefore of important clinical value. Pemetrexed, a multitargeted antifolate, has been demonstrated as an effective agent for lung adenocarcinoma. Pemetrexed/platinum combination chemotherapy is now a standard regimen for advanced non-small cell lung cancer (NSCLC) patients [12], and single-agent pemetrexed is also a common practice in second-/third-line treatment or a firstline alternative for patients with performance status 2 or for the elderly [13, 14]. Two recent studies revealed inconsistent conclusions on how EGFR mutation statuses may impact the efficacy of pemetrexed-based chemotherapy for advanced NSCLC. In one retrospective study, Wu et al. [15] suggested that pemetrexed monotherapy for advanced adenocarcinoma patients with EGFR mutation had a longer progression-free survival (PFS) than those with wild-type EGFR. EGFR mutation may serve as a predictive biomarker for pemetrexed chemotherapy response. In contrast, a phase II study by Kawano et al. [16] reported no obvious differences in the efficacies of first-line pemetrexed/cisplatin combination chemotherapy between the EGFR-mutant patients and the wildtype EGFR patients. In the former study, over half of the patients had been treated with single-agent pemetrexed as fourth-line or beyond therapy, while the latter study had a relatively small trial population (n
RESEARCH ARTICLE
Pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR genotypes Xiangli Jiang & Bo Yang & Jiuqin Lu & Zhongli Zhan & Kai Li & Xiubao Ren
Received: 22 May 2014 / Accepted: 30 September 2014 / Published online: 10 October 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract Advanced lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) activating mutations usually are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs), but whether EGFR-mutant lung adenocarcinoma is also responsive to pemetrexed-based chemotherapy remains controversial. We conducted a retrospective study to evaluate the efficacy and outcome of pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR mutation statuses. Sixty-nine EGFR-mutant and 89 wild-type patients with advanced lung adenocarcinoma were enrolled. They all had received pemetrexed-based treatments. Chemotherapy objective response rate (ORR), median progression-free survival (mPFS), and thymidylate synthase (TS) expression levels of EGFR-mutant patients were compared with those of EGFR-wild-type patients. For the EGFRmutant patients treated with first-line platinum/pemetrexed combinations, the ORR was significantly higher than that of
Xiangli Jiang and Bo Yang contribute equally to this paper. X. Jiang : J. Lu : K. Li (*) Department of Thoracic Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China e-mail: [email protected] B. Yang : Z. Zhan Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China X. Ren (*) Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin 300060, China e-mail: [email protected] X. Jiang : X. Ren Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin 300060, China
the wild-type patients treated with similar regimens (43 vs. 21 %, p=0.039). Nonetheless, for the patients treated with pemetrexed monotherapy, the difference in ORR was not significant between patients with EGFR mutations and those with wild-type EGFR in any line of treatments (in the first-line setting 20 vs. 13 %, p=0.715; in the second-/third-line setting 13 vs. 8 %, p=0.655). On the other hand, the mPFS for the EGFR-mutant patients treated with first-line combinations was also obviously prolonged (8.3 vs. 6.7 months, p = 0.004). However, among the patients receiving second-line platinum/pemetrexed combinations or any line of single-agent pemetrexed, there was no difference in PFS between EGFRmutant and wild-type patients. Our results indicated that the efficacies and outcomes of pemetrexed treatment in advanced lung adenocarcinoma patients with EGFR activating mutations were similar to those in patients with EGFR-wild-type genotype, except in the setting of first-line platinum/ pemetrexed combination chemotherapy. Keywords Lung adenocarcinoma . Epidermal growth factor receptor . Activating mutation . Pemetrexed . Thymidylate synthase
Introduction Since 2004, the mutations of epidermal growth factor receptor (EGFR) have drawn much attention in lung cancer research [1, 2]. EGFR activating mutations, including exon 19 deletion and exon 21 L858R mutation, consist of 10–44 % of lung adenocarcinoma patients, and are associated with high sensitivity to EGFR tyrosine kinase inhibitors (TKIs) [3–5]. Based on a number of randomized phase III trials, EGFR TKIs have been confirmed superior to conventional chemotherapy and are now established as a standard first-line treatment for advanced patients with activating EGFR mutations [6–11].
862
However, most patients will develop to disease progression due to acquired resistance to TKIs and systemic chemotherapy is an important option for post-progression therapy. Given the varied functional expression between patients harboring EGFR mutations and those harboring wild-type EGFR, understanding the potential differences of the efficacies and outcomes of systemic chemotherapy between different EGFR mutation statuses is therefore of important clinical value. Pemetrexed, a multitargeted antifolate, has been demonstrated as an effective agent for lung adenocarcinoma. Pemetrexed/platinum combination chemotherapy is now a standard regimen for advanced non-small cell lung cancer (NSCLC) patients [12], and single-agent pemetrexed is also a common practice in second-/third-line treatment or a firstline alternative for patients with performance status 2 or for the elderly [13, 14]. Two recent studies revealed inconsistent conclusions on how EGFR mutation statuses may impact the efficacy of pemetrexed-based chemotherapy for advanced NSCLC. In one retrospective study, Wu et al. [15] suggested that pemetrexed monotherapy for advanced adenocarcinoma patients with EGFR mutation had a longer progression-free survival (PFS) than those with wild-type EGFR. EGFR mutation may serve as a predictive biomarker for pemetrexed chemotherapy response. In contrast, a phase II study by Kawano et al. [16] reported no obvious differences in the efficacies of first-line pemetrexed/cisplatin combination chemotherapy between the EGFR-mutant patients and the wildtype EGFR patients. In the former study, over half of the patients had been treated with single-agent pemetrexed as fourth-line or beyond therapy, while the latter study had a relatively small trial population (n
