Prognostic value of EGFR 19‑del and 21‑L858R mutations in patients with non‑small cell lung cancer

Hong,Weiwei; Wu,Qiuji; Zhang,Junhong; Zhou,Yunfeng

doi:10.3892/ol.2019.10715

Prognostic value of EGFR 19‑del and 21‑L858R mutations in patients with non‑small cell lung cancer

Authors:
- Weiwei Hong
- Qiuji Wu
- Junhong Zhang
- Yunfeng Zhou
View Affiliations

Affiliations: Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
Published online on: August 6, 2019 https://doi.org/10.3892/ol.2019.10715
Pages: 3887-3895

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Previous studies have demonstrated a significant difference in clinical characteristics between patients with non‑small cell lung cancer (NSCLC) harboring exon 19 deletion (19‑del) and an exon point mutation (21‑L858R) in EGFR. The present retrospective study aimed to investigate the differential prognosis in patients with NSCLC harboring exon 19‑del and 21‑L858R mutations. The clinical and follow‑up data of 137 patients treated at the Zhongnan Hospital of Wuhan University (Wuhan, Hubei, China) between August 2012 and August 2016, who were diagnosed with stage IIIB‑IV NSCLC harboring either exon 19‑del or 21‑L858R mutations, were analyzed. The patients were divided into the first‑line tyrosine kinase inhibitor (TKI), first‑line chemotherapy and second‑line TKI treatment groups. The median progression‑free survival (PFS) time of patients harboring the exon 19‑del mutation was significantly improved compared with that in patients harboring the 21‑L858R mutation (11.3 vs. 8.8 months, respectively; P=0.017) following first‑line TKI treatments. However, no significant difference in the median PFS time was observed between the exon 19‑del and 21‑L858R groups following the first‑line chemotherapy or second‑line TKI treatment. In patients with the exon 19‑del, first‑line TKI treatment achieved an increased objective response rate (ORR; 51.9 vs. 18.5%; P=0.004) and disease control rate (96.2 vs. 77.8%; P=0.030), and a longer PFS time (11.3 vs. 8.0 months; P=0.034) compared with that in the patients following first‑line chemotherapy. First‑ and second‑line TKI treatment achieved a similar PFS time (11.3 vs. 11.0 months, respectively; P=0.140). However, in patients with the 21‑L858R mutation, the first‑line TKI therapy and first‑line chemotherapy groups exhibited a similar PFS time (8.8 vs. 3.5 months, respectively; P=0.063), while the second‑line TKI treatment group exhibited a significantly longer PFS time compared with the first‑line TKI treatment group (13.6 vs. 8.8 months, respectively; P=0.030). There was a differential sensitivity to treatment between patients harboring the exon 19‑del and 21‑L858R mutations. Therefore, chemotherapy may increase the sensitivity to TKIs in patients harboring the 21‑L858R mutation.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
2	Jiang H: Overview of gefitinib in non-small cell lung cancer: An Asian perspective. Jpn J Clin Oncol. 39:137–150. 2009. View Article : Google Scholar : PubMed/NCBI
3	NSCLC Meta-Analyses Collaborative Group, : Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: A systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol. 26:4617–4625. 2008. View Article : Google Scholar : PubMed/NCBI
4	Lara-Guerra H, Waddell TK, Salvarrey MA, Joshua AM, Chung CT, Paul N, Boerner S, Sakurada A, Ludkovski O, Ma C, et al: Phase II study of preoperative gefitinib in clinical stage I non-small-cell lung cancer. J Clin Oncol. 27:6229–6236. 2009. View Article : Google Scholar : PubMed/NCBI
5	Roberts PJ, Stinchcombe TE, Der CJ and Socinski MA: Personalized medicine in non-small-cell lung cancer: Is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy? J Clin Oncol. 28:4769–4777. 2010. View Article : Google Scholar : PubMed/NCBI
6	Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Isobe H, Gemma A, Harada M, Yoshizawa H, et al: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 362:2380–2388. 2010. View Article : Google Scholar : PubMed/NCBI
7	Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG and Varmus H: Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2:e732015. View Article : Google Scholar
8	Ciardicllo F and Tortora G: EGFR antagonists in cancer treatment. N Engl J Med. 358:1160–1174. 2008. View Article : Google Scholar : PubMed/NCBI
9	Coorper WA, Lam DC, O'Toole SA and Minna JD: Molecular biology of lung cancer. J Thorac Dis. 5 (Suppl 5):S479–S490. 2013.PubMed/NCBI
10	Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 350:2129–2139. 2004. View Article : Google Scholar : PubMed/NCBI
11	Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science. 304:1497–1500. 2004. View Article : Google Scholar : PubMed/NCBI
12	Gazdar AF: Activating and resistance mutations of EGFR in non-small-cell lung cancer: Role in clinical response to EGFR tyrosine kinase inhibitors. Oncology. 28 (Suppl 1):S24–S31. 2009.
13	Sharma SV, Bell DW, Settleman J and Haber DA: Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 7:169–181. 2007. View Article : Google Scholar : PubMed/NCBI
14	Chintala L and Kurzrock R: Epidermal growth factor receptor mutation and diverse tumors: Case report and concise literature review. Mol Oncol. 4:306–308. 2010. View Article : Google Scholar : PubMed/NCBI
15	Riely GJ, Pao W, Pham DK, Li AR, Rizvi N, Venkatraman ES, Zakowski MF, Kris MG, Ladanyi M and Miller VA: Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res. 12:839–844. 2006. View Article : Google Scholar : PubMed/NCBI
16	Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL and Trotti A: AJCC cancer staging manual. 7th. Chicago: Springer; pp. 129–143. 2010
17	Taron M, Ichinose Y, Rosell R, Mok T, Massuti B, Zamora L, Mate JL, Manegold C, Ono M, Queralt C, et al: Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. Clin Cancer Res. 11:5878–5885. 2005. View Article : Google Scholar : PubMed/NCBI
18	Eisenhauer EA, Therasse P, Bogearts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al: New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 45:228–247. 2009. View Article : Google Scholar : PubMed/NCBI
19	Sugio K, Uramoto H, Onitsuka T, Mizukami M, Ichiki Y, Sugaya M, Yasuda M, Takenoyama M, Oyama T, Hanagiri T and Yasumoto K: Prospective phase II study of gefitinib in non-small cell lung cancer with epidermal growth factor receptor gene mutations. Lung Cancer. 64:314–318. 2009. View Article : Google Scholar : PubMed/NCBI
20	Schuler M, Yang JCH, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Massey D, Zazulina V, Shahidi M and Sequist L: LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations (Subgroup Analysis). Lung Cancer. 77 (Suppl 1):S25–S26. 2012. View Article : Google Scholar
21	Mok TS, Wu Y, Thongprasert S, Yang C, Chu D, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 361:947–957. 2009. View Article : Google Scholar : PubMed/NCBI
22	Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, 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. 11:121–128. 2010. View Article : Google Scholar : PubMed/NCBI
23	Zhou C, Wu Y, Chen G, Feng J, Liu X, Wang C, Zhang S, Wang J, Zhou S, Ren S, 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. 12:735–742. 2011. View Article : Google Scholar : PubMed/NCBI
24	Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, 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. 13:239–246. 2012. View Article : Google Scholar : PubMed/NCBI
25	Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee KY, et al: Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): An open-label, randomised phase 3 trial. Lancet Oncol. 15:213–222. 2014. View Article : Google Scholar : PubMed/NCBI
26	Wu JY, Yu CJ, Yang CH, Wu SG, Chiu YH, Gow CH, Chang YC, Hsu YC, Wei PF, Shih JY and Yang PC: First- or second-line therapy with gefitinib produces equal survival in non-small cell lung cancer. Am J Respir Crit Care Med. 178:847–853. 2008. View Article : Google Scholar : PubMed/NCBI
27	Massuti B, Morán T, Porta R, Queralt C, Cardenal F, Mayo C, Camps C, Majem M, Tarón M and Rosell R: Multicenter prospective trial of customized erlotinib for advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: Final results of the Spanish lung cancer group (SLCG) trial. J Clin Oncol. 27:80232009.
28	Wang H, Huang J, Yu X, Han S, Yan X, Sun S and Zhu X: Different efficacy of EGFR tyrosine kinase inhibitors and prognosis in patients with subtypes of EGFR-mutated advanced non-small cell lung cancer: A meta-analysis. J Cancer Res Clin Oncol. 140:1901–1909. 2014. View Article : Google Scholar : PubMed/NCBI
29	Jackman DM, Yeap BY, Sequist LV, Lindeman N, Holmes AJ, Joshi VA, Bell DW, Huberman MS, Halmos B, Rabin MS, et al: Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res. 12:3908–3914. 2006. View Article : Google Scholar : PubMed/NCBI
30	Zhu JQ, Zhong WZ, Zhang GC, Li R, Zhang XC, Guo AL, Zhang YF, An SJ, Mok TS and Wu YL: Better survival with EGFR exon 19 than exon 21 mutations in gefitinib-treated non-small cell lung cancer patients is due to differential inhibition of downstream signals. Cancer Lett. 265:307–317. 2008. View Article : Google Scholar : PubMed/NCBI
31	Sordella R, Bell DW, Haber DA and Settleman J: Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science. 305:1163–1167. 2004. View Article : Google Scholar : PubMed/NCBI
32	Hata A, Yoshioka H, Fujita S, Kunimasa K, Kaji R, Imai Y, Tomii K, Iwasaku M, Nishiyama A, Ishida T and Katakami N: Complex mutations in the epidermal growth factor receptor gene in non-small cell lung cancer. J Thorac Oncol. 5:1524–1528. 2010. View Article : Google Scholar : PubMed/NCBI
33	Wang Y, Li RQ, Ai YQ, Zhang J, Zhao PZ, Li YF, He WJ, Xia YX and Li WH: Exon 19 deletion was associated with better survival outcomes in advanced lung adenocarcinoma with mutant EGFR treated with EGFR-TKIs as second-line therapy after first-line chemotherapy: A retrospective analysis of 128 patients. Clin Transl Oncol. 17:727–736. 2015. View Article : Google Scholar : PubMed/NCBI
34	Risbud MV, Fertala J, Vresilovic EJ, Albert TJ and Shapiro IM: Nucleus pulposus cells upregulate PI3K/Akt and MEK/ERK signaling pathways under hypoxic conditions and resist apoptosis induced by serum withdrawal. Spine (Phila Pa 1976). 30:882–889. 2005. View Article : Google Scholar : PubMed/NCBI
35	Bai H, Wang Z, Wang Y, Zhuo M, Zhou Q, Duan J, Yang L, Wu M, An T, Zhao J and Wang J: Detection and clinical significance of intratumoral EGFR mutational heterogeneity in Chinese patients with advanced non-small cell lung cancer. PLoS One. 8:e541702013. View Article : Google Scholar : PubMed/NCBI
36	Ke EE, Zhou Q, Zhang QY, Su J, Chen ZH, Zhang XC, Xu CR, Yang JJ, Tu HY, Yan HH, et al: A higher proportion of the EGFR T790M mutation may contribute to the better survival of patients with exon 19 deletions compared with those with L858R. J Thorac Oncol. 12:1368–1375. 2017. View Article : Google Scholar : PubMed/NCBI
37	Tomonaga N, Nakamura Y, Yamaguchi H, Ikeda T, Mizoguchi K, Motoshima K, Doi S, Nakatomi K, Iida T, Hayashi T, et al: Analysis of intratumor heterogeneity of EGFR mutations in mixed type lung adenocarcinoma. Clin Lung Cancer. 14:521–526. 2013. View Article : Google Scholar : PubMed/NCBI