Top

Clinical and Translational Oncology

Published in:

01-02-2019 | Research Article

Differential molecular markers of primary lung tumors and metastatic sites indicate different possible treatment selections in patients with metastatic lung adenocarcinoma

Authors: L.-L. Deng, H.-B. Deng, C.-L. Lu, G. Gao, F. Wang, Y. Yang

Published in: Clinical and Translational Oncology | Issue 2/2019

Abstract

Purpose

Detecting different molecular markers in primary tumors and metastases may provide therapeutic information. Here we investigated differences between primary tumors and four metastatic sites of lung adenocarcinoma in the biomarkers’ features and discussed potential therapeutic implications.

Methods

A total of 228 patients with metastatic lung adenocarcinoma were analyzed for EGFR, KRAS, BRAF and PIK3CA mutations detected by xTAG liquidchip technology (xTAG-LCT), as well as ERCC1, TYMS, RRM1, TUBB3, STMN1, TOP2A and VEGFR1-3 mRNA expression detected by branched DNA-liquidchip technology (bDNA-LCT).

Results

Higher rates of low ERCC1 (35.6 vs. 20.3%, P = 0.0105), RRM1 (23.3 vs. 13.0%, P = 0.0437), STMN1 (72.2 vs. 42.8%, P = 0.0000) and high VEGFR2 (34.4 vs. 18.8%, P = 0.0078) mRNA expression were found in EGFR-mutated tumors, suggesting possible benefit from platinum, gemcitabine, taxanes or VEGFR2 inhibitors. Primary lesions showed low ERCC1 (31.6 vs. 18.5%, P = 0.0271), TYMS (17.6 vs. 7.6%, P = 0.0300), TUBB3 (16.9 vs. 7.6%, P = 0.0415), STMN1 (62.1 vs. 42.9%, P = 0.0065) and high TOP2A (48.7 vs. 33.1%, P = 0.0262) mRNA expression and higher KRAS mutations (25.7 vs. 14.1%, P = 0.0350), suggesting platinum, taxanes, pemetrexed, anti-TOP2A agents and resistant to anti-EGFR therapies. Liver metastases showed absence of low TYMS expression, indicating insensitivity to pemetrexed-based regimen. Pleura metastases harbored higher rates of high VEGFR2 expression (50.0 vs. 19.1%, P = 0.0127). Lymph node metastases presented higher rates of high VEGFR2 expression (37.5 vs. 19.1%, P = 0.0253) and EGFR mutations (59.4 vs. 34.4%, P = 0.0011), suggesting use of anti-VEGFR2 and anti-EGFR therapies.

Conclusion

Molecular profiling of 228 lung adenocarcinomas determined a significant difference between biomarkers such as EGFR and KRAS subtypes at primary and metastatic sites. Our results serve as a reference for individual treatment based on different potential targets in metastatic lung adenocarcinoma directed by molecular profiling.

Available only for authorised users

An N, Yang X. Identification of prognostic genes through expression differentiation during metastatic process in lung adenocarcinoma. Sci Rep. 2017;7(1):11119. https://doi.org/10.1038/s41598-017-11520-6.CrossRefPubMedPubMedCentral

Song Z, Yu X, Zhang Y. Clinicopathological characteristics and survival of ALK, ROS1 and RET rearrangements in non-adenocarcinoma non-small cell lung cancer patients. Cancer Biol Ther. 2017;18(11):883–7. https://doi.org/10.1080/15384047.2016.1235660.CrossRefPubMed

Ko R, Kenmotsu H, Serizawa M, Koh Y, Wakuda K, Ono A, et al. Frequency of EGFR T790M mutation and multimutational profiles of rebiopsy samples from non-small cell lung cancer developing acquired resistance to EGFR tyrosine kinase inhibitors in Japanese patients. BMC Cancer. 2016;16(1):864. https://doi.org/10.1186/s12885-016-2902-0.CrossRefPubMedPubMedCentral

Wu YL, Saijo N, Thongprasert S, Yang JC, Han B, Margono B, et al. Efficacy according to blind independent central review: post-hoc analyses from the phase III, randomized, multicenter, IPASS study of first-line gefitinib versus carboplatin/paclitaxel in Asian patients with EGFR mutation-positive advanced NSCLC. Lung Cancer. 2017;104:119–25. https://doi.org/10.1016/j.lungcan.2016.11.022.CrossRefPubMed

Douillard JY, Shepherd FA, Hirsh V, Mok T, Socinski MA, Gervais R, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol. 2010;28(5):744–52. https://doi.org/10.1200/JCO.2009.24.3030.CrossRefPubMed

Litvak AM, Paik PK, Woo KM, Sima CS, Hellmann MD, Arcila ME, et al. Clinical characteristics and course of 63 patients with BRAF mutant lung cancers. J Thorac Oncol. 2014;9(11):1669–74. https://doi.org/10.1097/JTO.0000000000000344.CrossRefPubMedPubMedCentral

Brcic L, Jakopovic M, Misic M, Seiwerth F, Kern I, Smojver-Jezek S, et al. Analysis of the frequency of EGFR, KRAS and ALK mutations in patients with lung adenocarcinoma in Croatia. Diagn Pathol. 2016;11(1):90. https://doi.org/10.1186/s13000-016-0544-9.CrossRefPubMedPubMedCentral

Lohinai Z, Klikovits T, Moldvay J, Ostoros G, Raso E, Timar J, et al. KRAS-mutation incidence and prognostic value are metastatic site-specific in lung adenocarcinoma: poor prognosis in patients with KRAS mutation and bone metastasis. Sci Rep. 2017;7:39721. https://doi.org/10.1038/srep39721.CrossRefPubMedPubMedCentral

Zhu CQ, da Cunha Santos G, Ding K, Sakurada A, Cutz JC, Liu N, et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol. 2008;26(26):4268–75. https://doi.org/10.1200/jco.2007.14.8924.CrossRefPubMed

10.

Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med. 2005;352(25):2589–97. https://doi.org/10.1056/NEJMoa043623.CrossRefPubMed

11.

Song Z, Yu X, Zhang Y. Mutation and prognostic analyses of PIK3CA in patients with completely resected lung adenocarcinoma. Cancer Med. 2016;5(10):2694–700. https://doi.org/10.1002/cam4.852.CrossRefPubMedPubMedCentral

12.

Sad LM, Younis SG, Elity MM. Prognostic and predictive role of ERCC1 protein expression in locally advanced stage III non-small cell lung cancer. Med Oncol. 2014;31(7):58. https://doi.org/10.1007/s12032-014-0058-9.CrossRefPubMed

13.

Zhao H, Zhang H, Du Y, Gu X. Prognostic significance of BRCA1, ERCC1, RRM1, and RRM2 in patients with advanced non-small cell lung cancer receiving chemotherapy. Tumour Biol. 2014;35(12):12679–88. https://doi.org/10.1007/s13277-014-2592-7.CrossRefPubMed

14.

Jiang H, Wang H, Wang S, Pei Z, Fu Z, Fang C, et al. Expression of ERCC1, TYMS, RRM1, TUBB3, non-muscle myosin II, myoglobin and MyoD1 in lung adenocarcinoma pleural effusions predicts survival in patients receiving platinum-based chemotherapy. Mol Med Rep. 2015;11(5):3523–32. https://doi.org/10.3892/mmr.2014.3141.CrossRefPubMed

15.

Kang CH, Jang BG, Kim DW, Chung DH, Kim YT, Jheon S, et al. The prognostic significance of ERCC1, BRCA1, XRCC1, and betaIII-tubulin expression in patients with non-small cell lung cancer treated by platinum- and taxane-based neoadjuvant chemotherapy and surgical resection. Lung Cancer. 2010;68(3):478–83. https://doi.org/10.1016/j.lungcan.2009.07.004.CrossRefPubMed

16.

Nikolinakos PG, Altorki N, Yankelevitz D, Tran HT, Yan S, Rajagopalan D, et al. Plasma cytokine and angiogenic factor profiling identifies markers associated with tumor shrinkage in early-stage non-small cell lung cancer patients treated with pazopanib. Cancer Res. 2010;70(6):2171–9. https://doi.org/10.1158/0008-5472.CAN-09-2533.CrossRefPubMedPubMedCentral

17.

Bao P, Yokobori T, Altan B, Iijima M, Azuma Y, Onozato R, et al. High STMN1 expression is associated with cancer progression and chemo-resistance in lung squamous cell carcinoma. Ann Surg Oncol. 2017;24(13):4017–24. https://doi.org/10.1245/s10434-017-6083-0.CrossRefPubMed

18.

Wang TL, Song YQ, Ren YW, Zhou BS, Wang HT, Gao Y, et al. Dual-specificity phosphatase 6 genetic variants associated with risk of lung squamous cell carcinoma in Han Chinese. J Cancer Res Ther. 2018;14(Supplement):S72–8. https://doi.org/10.4103/0973-1482.172108.CrossRefPubMed

19.

Deng LL, Deng HB, Lu CL, Guo Y, Wang D, Yan CH, et al. Mutations of EGFR or KRAS and expression of chemotherapy-related genes based on small biopsy samples in stage IIIB and IV inoperable non-small cell lung cancer. J Cancer Res Clin Oncol. 2014;140(12):2097–105. https://doi.org/10.1007/s00432-014-1751-y.CrossRefPubMed

20.

Caswell DR, Swanton C. The role of tumour heterogeneity and clonal cooperativity in metastasis, immune evasion and clinical outcome. BMC Med. 2017;15(1):133. https://doi.org/10.1186/s12916-017-0900-y.CrossRefPubMedPubMedCentral

21.

Hallou A, Jennings J, Kabla AJ. Tumour heterogeneity promotes collective invasion and cancer metastatic dissemination. R Soc Open Sci. 2017;4(8):161007. https://doi.org/10.1098/rsos.161007.CrossRefPubMedPubMedCentral

22.

Detterbeck FC, Franklin WA, Nicholson AG, Girard N, Arenberg DA, Travis WD, et al. The IASLC lung cancer staging project: background data and proposed criteria to distinguish separate primary lung cancers from metastatic foci in patients with two lung tumors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11(5):651–65. https://doi.org/10.1016/j.jtho.2016.01.025.CrossRefPubMed

23.

Quere G, Descourt R, Robinet G, Autret S, Raguenes O, Fercot B, et al. Mutational status of synchronous and metachronous tumor samples in patients with metastatic non-small-cell lung cancer. BMC Cancer. 2016;16:210. https://doi.org/10.1186/s12885-016-2249-6.CrossRefPubMedPubMedCentral

24.

Chansky K, Detterbeck FC, Nicholson AG, Rusch VW, Vallieres E, Groome P, et al. The IASLC lung cancer staging project: external validation of the revision of the TNM stage groupings in the eighth edition of the TNM classification of lung cancer. J Thorac Oncol. 2017;12(7):1109–21. https://doi.org/10.1016/j.jtho.2017.04.011.CrossRefPubMed

25.

Niu X, Ai X, Chen Z, Chuai S, Yang Y, Lu S. Tumor heterogeneity in lesion specific response creates ROS1 fusion mediating resistance to gefitinib in EGFR 19 deletion lung adenocarcinoma: topic—medical oncology. J Thorac Oncol. 2016;11(11S):S273. https://doi.org/10.1016/j.jtho.2016.09.042.CrossRef

26.

Tan LM, Qiu CF, Zhu T, Jin YX, Li X, Yin JY, et al. Genetic polymorphisms and platinum-based chemotherapy treatment outcomes in patients with non-small cell lung cancer: a genetic epidemiology study based meta-analysis. Sci Rep. 2017;7(1):5593. https://doi.org/10.1038/s41598-017-05642-0.CrossRefPubMedPubMedCentral

27.

Lee SM, Falzon M, Blackhall F, Spicer J, Nicolson M, Chaudhuri A, et al. Randomized prospective biomarker trial of ERCC1 for comparing platinum and nonplatinum therapy in advanced non-small-cell lung cancer: ERCC1 trial (ET). J Clin Oncol. 2017;35(4):402–11. https://doi.org/10.1200/JCO.2016.68.1841.CrossRefPubMed

28.

Pierceall WE, Sprott KM, Heikkinen T, Heikkila P, Alaparthi L, Aittomaki K, et al. Utilization of fluorescence in situ hybridization with cytokeratin discriminators in TOP2A assessment of chemotherapy-treated patients with breast cancer. Hum Pathol. 2012;43(9):1363–75. https://doi.org/10.1016/j.humpath.2011.08.018.CrossRefPubMed

29.

Marchetti A, Felicioni L, Malatesta S, Grazia Sciarrotta M, Guetti L, Chella A, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol. 2011;29(26):3574–9. https://doi.org/10.1200/JCO.2011.35.9638.CrossRefPubMed

30.

An N, Zhang Y, Niu H, Li Z, Cai J, Zhao Q, et al. EGFR-TKIs versus taxanes agents in therapy for non-small-cell lung cancer patients: a PRISMA-compliant systematic review with meta-analysis and meta-regression. Medicine (Baltimore). 2016;95(50):e5601. https://doi.org/10.1097/MD.0000000000005601.CrossRef

31.

Hirano S, Naka G, Takeda Y, Iikura M, Hayama N, Yanagisawa A, et al. A prospective, multicenter phase II trial of low-dose erlotinib as maintenance treatment after platinum doublet chemotherapy for advanced non-small cell lung cancer harboring EGFR mutation. Chin Clin Oncol. 2016;5(6):77. https://doi.org/10.21037/cco.2016.11.02.CrossRefPubMed

32.

Campos-Parra AD, Zuloaga C, Manriquez ME, Aviles A, Borbolla-Escoboza J, Cardona A, et al. KRAS mutation as the biomarker of response to chemotherapy and EGFR-TKIs in patients with advanced non-small cell lung cancer: clues for its potential use in second-line therapy decision making. Am J Clin Oncol. 2015;38(1):33–40. https://doi.org/10.1097/COC.0b013e318287bb23.CrossRefPubMed

33.

Hou GX, Liu P, Yang J, Wen S. Mining expression and prognosis of topoisomerase isoforms in non-small-cell lung cancer by using Oncomine and Kaplan–Meier plotter. PLoS One. 2017;12(3):e0174515. https://doi.org/10.1371/journal.pone.0174515.CrossRefPubMedPubMedCentral

34.

Kaczmarczyk G, Lewandowski R, Trautsolt W, Ziolkowski A, Kozielski J. Cytological examination of pleural cavity lavage accompanied by the study of gene promoter hypermethylation of p16 and O6-methylguanine-DNA-methyltransferase genes in diagnostics of non-small cell lung cancer metastatic changes into pleura. Contemp Oncol (Pozn). 2012;16(4):322–7. https://doi.org/10.5114/wo.2012.30061.CrossRef

35.

Zhang J, Fu J, Pan Y, Zhang X, Shen L. Silencing of miR-1247 by DNA methylation promoted non-small-cell lung cancer cell invasion and migration by effects of STMN1. Oncol Targets Ther. 2016;9:7297–307. https://doi.org/10.2147/OTT.S111291.CrossRef

Title: Differential molecular markers of primary lung tumors and metastatic sites indicate different possible treatment selections in patients with metastatic lung adenocarcinoma
Authors: L.-L. Deng
H.-B. Deng
C.-L. Lu
G. Gao
F. Wang
Y. Yang
Publication date: 01-02-2019
Publisher: Springer International Publishing
Published in: Clinical and Translational Oncology / Issue 2/2019
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI: https://doi.org/10.1007/s12094-018-1906-4

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 2/2019

Outcomes of early-stage breast cancer patients treated with sequential anthracyclines–taxanes in relationship to relative dosing intensity: a secondary analysis of a randomized controlled trial

iTRAQ-based proteomic analysis of DMH-induced colorectal cancer in mice reveals the expressions of β-catenin, decorin, septin-7, and S100A10 expression in 53 cases of human hereditary polyposis colorectal cancer

Prognostic analysis of stage III gastric cancer after curative surgery according to the newest TNM classification

Controversies in the management of stage I seminoma: adjuvant carboplatin revisited

Molecular biomarkers for prognosis of gastrointestinal stromal tumor

New horizons in breast cancer: the promise of immunotherapy

Keynote webinar | Spotlight on antibody–drug conjugates in cancer