The effect of smoking and TP53 mutations on molecular-targeted therapy in lung adenocarcinoma patients

The treatment of non-small cell lung cancer (NSCLC) reached a major turning point with the discovery of gefitinib as an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and the identification of EGFR mutations in 2004 (1). Furthermore, the concept of individualized therapy (precision medicine) has become realistic, as therapeutic target oncogenic driver gene arrangements, such as anaplastic lymphoma kinase (ALK), ROS1, and RET, have been found, and targeted therapeutic drugs have developed (2-4). Developments in genetic analyses using next-generation sequencing and large databases of lung cancer patients have also facilitated the advent of precision medicine (5).

However, not all lung cancer patients benefit from molecular-targeted therapy (6,7), and the development of resistance to drugs that were initially effective remains a serious problem (8-10). A number of issues, such as obtaining detailed patient background information, performing gene mutation analyses, and clarifying the correlations among gene mutations, remain to be managed before true individualized therapy can be implemented. It is necessary to clarify the interaction between frequently occurring gene mutations and the influence of these on drug sensitivity or the prognosis.

The race and life history of patients are certain to be important factors to consider when predicting oncogenic gene mutations. When considering drug therapy for lung cancer patients, the smoking status should always be noted, as smoking is a major risk factor for lung cancer, and the carcinogenic mechanisms of smokers are believed to differ from those of never-smokers (5,11,12). EGFR mutations are known to be more frequent in women, adenocarcinoma patients, never-smokers, and Asians (7,13). Although lung adenocarcinoma patients who are eligible for molecular-targeted therapy tend to be non-smokers, it should be noted that some former or current smokers have genetic alterations that make them suitable candidates for molecular-targeted therapeutic drugs, as ALK translocation has been found in smoker patients (2). Indeed, approximately 10% of lung adenocarcinoma patients with a smoking history have oncogenic driver mutations (12,13), and the therapeutic response to molecular-targeted therapeutic agents is expected to be good when appropriate molecular-targeted drugs are used. In studies of adenocarcinoma patients with EGFR mutations, approximately 30% were smokers; thus, we should perform genetic testing, including testing for EGFR mutations, even for patients with a smoking history (11,14). In addition, it should be noted that even in cases with the same sensitizing mutations as those used to indicate EGFR-TKI therapy, the disease control rate and the period for which EGFR-TKIs are effective differ according to the patient’s background. Particularly with regard to the response duration, it has been reported that the cumulative smoking dose (CSD) was indirectly associated with the progression-free survival (PFS) and overall survival (OS) in patients with EGFR-mutated lung adenocarcinoma receiving EGFR-TKIs. Kim et al. (11) reported the effect of the CSD on the clinical outcomes, including PFS and OS, in patients with EGFR-mutated lung adenocarcinoma receiving EGFR-TKIs. Among the 142 patients, including 91 never-smokers, 12 light smokers (0–10 pack-years), 22 moderate smokers (11–30 pack-years), and 17 heavy smokers (>30 pack-years), the median PFS was significantly worse with an increased CSD, with values of 11.8, 11.0, 7.4, and 3.9 months (P<0.001), respectively, and similar results were obtained for the median OS [33.6, 26.3, 20, and 2.9 months (P<0.001), respectively]. The CSD is therefore an important predictive and prognostic factor in patients with EGFR-mutated lung adenocarcinoma. When treating smoker patients with EGFR-TKIs, it is necessary to pay attention to the timing at which the drug is changed.

Another thing to consider when conducting molecular-targeted therapy, is interactions with oncogenic driver mutations and other gene mutations. In particular, we should also check for TP53 mutations. A loss-of-function of the p53 protein, caused by the mutation of the TP53 tumor suppressor gene leads to alterations in DNA repair, apoptosis cell-cycle control and consequently, to genome instability (15). Although there is no targeted therapy for TP53 mutations, it is necessary to confirm the influence of TP53 mutations on the efficacy of targeted therapy for other gene mutations. The frequency of TP53 mutations was reported to be approximately 40% in lung adenocarcinoma patients. As this frequency is relatively high and TP53 mutations are reported to influence the prognosis of lung cancer patients and anti-cancer drug resistance (13,14,16,17), TP53 mutations should be confirmed before selecting the method of treatment and drugs. Furthermore, when considering the effects of a TP53 mutation on carcinogenesis and treatment, we should bear in mind that among the various TP53 mutations, there are germline mutations associated with Li-Fraumeni syndrome (LFS) and somatic mutations associated with smoking exposure. In a study of 1,730 French patients with symptoms suggestive of LFS, Bougeard et al. (18) reported that it might be appropriate to stratify the clinical management of LFS according to the class of the mutation. Ricordel et al. (19) reported on two LFS patients diagnosed with EGFR-mutated lung adenocarcinoma treated with EGFR-TKIs, and the response to the EGFR-TKIs seemed to be similar to that in individuals with EGFR mutations in the general population. They also reported a case of acquired resistance with a T790M second mutation, and noted that this was the same resistance mechanism as observed in the general population without LFS.

The effect of somatic TP53 mutations on lung adenocarcinoma with molecular-targeted gene mutations has been investigated by several groups (20,21). Aisner et al. (21) reported that a concurrent TP53 mutation, especially a distractive mutation, was associated with poor survival among lung adenocarcinoma patients with drug-sensitive EGFR mutations. They also demonstrated that a concurrent TP53 mutation was associated with poor survival among lung adenocarcinoma patients with EGFR, ALK, or ROS1 alterations. Furthermore, Molina-Vila et al. (20) reported that a nondisruptive mutation in the TP53 gene was an independent prognostic factor for reduced survival in cases of advanced NSCLC with EGFR wild-type or EGFR mutations. Further investigations will be necessary to clarify the interactions between EGFR mutations and TP53 mutations with regard to the prognosis and drug sensitivity of lung adenocarcinoma.

In order to establish individualized therapy and improve the prognosis of lung cancer patients, it is necessary to clarify the interaction between tumor suppressor gene mutations, especially TP53 mutations, and the mechanism of drug resistance. The smoking status and TP53 mutation status are associated with the efficacy of not only molecular-targeted drug but also novel immunotherapeutic agents (22). To construct individualized therapeutic regimens and improve the prognosis of lung adenocarcinoma, we must efficiently and accurately identify the oncogenic driver mutations and suppressor gene mutations in each patient. In the field of cancer therapy, immune checkpoint therapy has become widespread as a novel treatment for lung cancer. At present, since there are no drugs that are effective for all patients, research is ongoing to link gene analyses with patient background information. In Japan, the nationwide SCRUM-Japan cancer genome screening project is trying to construct a system that delivers the most effective therapeutic agents to each patient, which can play a key role in the development of multiplex diagnostic products and novel indications for targeted therapy for precision cancer screening and treatments (23).

With the worldwide development of next-generation sequencing and information technology, many genetic mutations can now be retrieved from a small specimen in a relatively short period of time. To facilitate the selection of effective therapeutic agents and improve the prognosis of each lung cancer patient, it is necessary to clarify the influence of the interaction of gene mutations on different treatment. To achieve ideal individualized therapy for lung cancer patients, it is necessary to clarify the interaction of various environmental factors and gene mutations. Ideally, anyone should be able to easily use the accumulated data and determine the most appropriate treatment for each lung cancer patient.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-500. [Crossref] [PubMed]
2. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561-6. [Crossref] [PubMed]
3. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30:863-70. [Crossref] [PubMed]
4. Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012;18:378-81. [Crossref] [PubMed]
5. Imielinski M, Berger AH, Hammerman PS, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 2012;150:1107-20. [Crossref] [PubMed]
6. Kawaguchi T, Koh Y, Ando M, et al. Prospective analysis of oncogenic driver mutations and environmental factors: Japan Molecular Epidemiology for Lung Cancer Study. J Clin Oncol 2016;34:2247-57. [Crossref] [PubMed]
7. Zhang YL, Yuan JQ, Wang KF, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget 2016;7:78985-93. [PubMed]
8. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of no-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786-92. [Crossref] [PubMed]
9. Sasaki T, Okuda K, Zheng W, et al. The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. Cancer Res 2010;70:10038-43. [Crossref] [PubMed]
10. Sasaki T, Koivunen J, Ogino A, et al. A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res 2011;71:6051-60. [Crossref] [PubMed]
11. Kim IA, Lee JS, Kim HJ, et al. Cumulative smoking dose affects the clinical outcomes of EGFR-mutated lung adenocarcinoma patients treated with EGFR-TKIs: a retrospective study. BMC Cancer 2018;18:768. [Crossref] [PubMed]
12. Mounawar M, Mukeria A, Le Calvez F, et al. Patterns of EGFR, HER2, TP53, and KRAS mutations of p14arf expression in non-small cell lung cancers in relation to smoking history. Cancer Res 2007;67:5667-72. [Crossref] [PubMed]
13. Kosaka T, Yatabe Y, Endoh H, et al. Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res 2004;64:8919-23. [Crossref] [PubMed]
14. VanderLaan PA, Rangachari D, Mockus SM, et al. Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: Correlation with clinical outcomes. Lung Cancer 2017;106:17-21. [Crossref] [PubMed]
15. Toledo F, Wahl GM. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer 2006;6:909-23. [Crossref] [PubMed]
16. Jao K, Tomasini P, Kamel-Reid S, et al. The prognostic effect of single and multiple cancer-related somatic mutations in resected non-small-cell lung cancer. Lung Cancer 2018;123:22-9. [Crossref] [PubMed]
17. Labbé C, Cabanero M, Korpanty GJ, et al. Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Lung Cancer 2017;111:23-9. [Crossref] [PubMed]
18. Bougeard G, Renaux-Petel M, Flaman JM, et al. Revisiting Li-Fraumeni syndrome form TP53 mutation carriers. J Clin Oncol 2015;33:2345-52. [Crossref] [PubMed]
19. Ricordel C, Labalette-Tiercin M, Lespagnol A, et al. EGFR-mutant lung adenocarcinoma and Li-Fraumeni syndrome: report of two cases and review of the literature. Lung Cancer 2015;87:80-4. [Crossref] [PubMed]
20. Molina-Vila MA, Bertran-Alamillo J, Gasco A, et al. Nondisruptive p53 mutations are associated with shorter survival in patients with advanced non-small cell lung cancer. Clin Cancer Res 2014;20:4647-59. [Crossref] [PubMed]
21. Aisner DL, Sholl LM, Berry LD, et al. The impact of smoking and TP mutations in lung adenocarcinoma patients with targetable mutations – The Lung Cancer Mutation Consortium (LCMC2). Clin Cancer Res 2018;24:1038-47. [Crossref] [PubMed]
22. Kadara H, Choi M, Zhang J, et al. Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up. Ann Oncol 2018;29:1072. [Crossref] [PubMed]
23. Bando H. The current status and problems confronted in delivering precision medicine in Japan and Europe. Curr Probl Cancer 2017;41:166-75. [Crossref] [PubMed]