Impact Factor 4.416

Frontiers journals are at the top of citation and impact metrics

Editorial ARTICLE

Front. Oncol., 03 February 2015 | https://doi.org/10.3389/fonc.2015.00020

The treatment of metastatic non-small cell lung cancer in a new era of personalized medicine

  • Department of Medical Oncology, McGill University Health Centre, Montreal, QC, Canada

Lung cancer is the leading cause of cancer-related mortality in Canada (1) and around the world. Non-small cell lung cancer (NSCLC) is the most frequent form of lung cancer, accounting for approximately 87% of cases and the majority of these are metastatic at the time of presentation (2, 3).

We have reached a plateau (4, 5) with different systemic chemotherapies, specifically platinum-based, which have been used to treat metastatic NSCLC for several decades; median survival improved to 8–10 months (from 4-6 months without treatment). Significant toxicities limited the number of cycles that could be administered (6).

Current recommendations for first-line treatment of advanced NSCLC use both histologic and molecular diagnostics in designing the course of treatment (7, 8). We have learned the importance of distinguishing between squamous and non-squamous histologies (9) in order to choose an appropriate chemotherapy regimen. The algorithms for first-line treatment of advanced NSCLC recommend using both histologic and molecular diagnostics in designing the treatment (7, 10, 11). This in turn requires an adequate amount of biopsied tumor tissue in order to be able to perform all the necessary testing, which is needed for right decisions (12). Tumor aspirations for the diagnosis are not acceptable anymore.

Recent advances in understanding signaling pathways for malignant cells, interconnections in those pathways, the importance of various receptors (1315), and biomarkers, and also the interplay between various oncogenes have led to the development of targeted treatments that are improving not only the efficacy of the treatments, but also safety benefits, less toxicity (16) with improvement of patient’s quality of life (17) in this palliative setting.

These treatments are aimed at specific (especially genetic) alterations in the malignant cells. Various NSCLC subtypes are associated with potentially targetable biomarkers such as mutation of the epidermal growth factor receptors (EGFR) (1822), KRAS (23), or the presence of echinoderm microtubule-associated protein-like 4 (EML-4) and anaplastic lymphoma kinase (ALK) fusion genes, ALK rearrangements (13, 15). C-Met over-expression or amplification (2427), are playing a role in the development of resistance to the therapies (28), i.e., with EGFR-TKIs. T790M mutation on Exon 20 in the EGFR domain is the most frequent cause of the development of this resistance (29).

Knowledge about the advantages of treatments with targeted agents in advanced NSCLC is rapidly growing, but the hope is to eventually apply this knowledge to earlier stages of NSCLC and thus to increase the cure rate of these patients. Combining various targeted agents or sequencing them properly will be of the utmost importance in the new era of personalized targeted therapy (30). Many clinical trials are ongoing to help us make the appropriate decisions how to optimally treat advanced NSCLC in future (31, 32). Immunotherapy of advanced NSCLC (33) is one of the exciting areas of research and results of phase III trials are eagerly awaited.

Contributors in this issue of Frontiers in Thoracic Oncology describe the importance of team work (34) from diagnosis through various treatments to supportive care. They explain and emphasize the importance of the treatments of brain metastases (35) and bone metastases with new bone targeted agents (36). Management of adverse events when the new targeted agents are used (16) and analysis of patients’ health-related quality of life (HR QOL) (17) and the impact on patients’ performance status (PS) are also discussed in this issue. It is very important to preserve a good PS of patients in order to make it possible for them to receive multiple lines of the treatments now available for advanced NSCLC.

Our review will cover the description starting with the interventional procedures (12), to treatments delivered by radiation oncologists (37), medical oncologists (10, 11, 34), including descriptions of ongoing trials to provide a glimpse of the future (31, 32). The importance of early supportive care (38), which should be an integral part of active care from the start of treatment of advanced NSCLC, will also be discussed.

We hope to provide a complete review of present and future approaches to personalized medicine in advanced NSCLC, reflecting the present views, and practices in Canada.

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We would like to thank the following sponsors for their support: Major sponsors: Boehringer-Ingelheim, Eli Lilly, and Roche, other sponsors: MERCK, Astra Zeneca, and Pfizer. We would also like to thank Stavroula Kalantzis for her kind secretarial support with this Research Topic, who not only helped both myself and Dr. Melosky but also many other authors in this issue.

References

1. Canadian Cancer Society’s Steering Committee. Canadian Cancer Statistics 2010. Toronto, ON: Canadian Cancer Society (2010).

Google Scholar

2. United States, National Institutes of Health, National Cancer Institute (NCI). Non-Small Cell Lung Cancer Treatment (PDQ). Bethesda, MD: Health professional version (2010). Available from: http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/healthprofessional

Google Scholar

3. Pisters KM, Evans WK, Azzoli CG, Kris MG, Smith CA, Desch CE, et al. Cancer care Ontario and American society of clinical oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I – IIIA resectable non-small cell lung cancer guideline. J Clin Oncol (2007) 25:5506–18. doi: 10.1200/JCO.2007.14.1226

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

4. Cagle PT, Allen TC, Dacic S, Beasley MB, Borczuk AC, Chirieac LR, et al. Revolution in lung cancer: new challenges for the surgical pathologist. Arch Pathol Lab Med (2011) 135:110–6. doi:10.1043/2010-0567-RA.1

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

5. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med (2002) 346:92–8. doi:10.1056/NEJMoa011954

CrossRef Full Text | Google Scholar

6. Cagle PT, Dacic S. Lung cancer and the future of pathology. Arch Pathol Lab Med (2011) 135:293–5. doi:10.1043/2011.0037-ED.1

CrossRef Full Text | Google Scholar

7. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol (2008) 26:3543–51. doi:10.1200/JCO.2007.15.0375

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

8. Brega E, Brandao G. Non-small cell lung carcinoma biomarker testing: the pathologist’s perspective. Front Oncol (2014) 4:182. doi:10.3389/fonc.2014.00182

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

9. Blais N, Hirsh V. Chemotherapy in metastatic NSCLC – new regimens (pemetrexed, nab-paclitaxel). Front Oncol (2014) 4:177. doi:10.3389/fonc.2014.00177

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

10. Al-Farsi A, Ellis PM. Treatment paradigms for patients with metastatic non-small cell lung cancer, squamous lung cancer: first, second, and third-line. Front Oncol (2014) 4:157. doi:10.3389/fonc.2014.00157

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

11. Melosky B. Treatment algorithms for patients with metastatic non-small cell, non-squamous lung cancer. Front Oncol (2014) 4:256. doi:10.3389/fonc.2014.00256

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

12. Ofiara LM, Navasakulpong A, Beaudoin S, Gonzalez AV. Optimizing tissue sampling for the diagnosis, subtyping, and molecular analysis of lung cancer. Front Oncol (2014) 4:253. doi:10.3389/fonc.2014.00253

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

13. Korpanty GJ, Graham DM, Vincent MD, Leighl NB. Biomarkers that currently affect clinical practice in lung cancer: EGFR, ALK, MET, ROS-1, and KRAS. Front Oncol (2014) 4:204. doi:10.3389/fonc.2014.00204

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

14. Melosky B. Review of EGFR TKIs in metastatic NSCLC, including ongoing trials. Front Oncol (2014) 4:244. doi:10.3389/fonc.2014.00244

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

15. Esfahani K, Agulnik JS, Cohen V. A systemic review of resistance mechanisms and ongoing clinical trials in ALK-rearranged non-small cell lung cancer. Front Oncol (2014) 4:174. doi:10.3389/fonc.2014.00174

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

16. Melosky B, Hirsh V. Management of common toxicities in metastatic NSCLC related to anti-lung cancer therapies with EGFR-TKIs. Front Oncol (2014) 4:238. doi:10.3389/fonc.2014.00238

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

17. Hirsh V. Is the evaluation of quality of life in NSCLC trials important? Are the results to be trusted? Front Oncol (2014) 4:173. doi:10.3389/fonc.2014.00173

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

18. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med (2004) 350:2129–39. doi:10.1056/NEJMoa040938

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

19. Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science (2004) 304:1497–500. doi:10.1126/science.1099314

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

20. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA (2004) 101:13306–11. doi:10.1073/pnas.0405220101

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

21. Li AR, Chitale D, Riely GJ, Pao W, Miller VA, Zakowski MF, et al. EGFR mutations in lung adenocarcinomas: clinical testing experience and relationship to EGFR gene copy number and immunohistochemical expression. J Mol Diagn (2008) 10:242–8. doi:10.2353/jmoldx.2008.070178

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

22. Uramoto H, Mitsudomi T. Which biomarker predicts benefit from EGFR – TKI treatment for patients with lung cancer? Br J Cancer (2007) 96:857–63. doi:10.1038/sj.bjc.6603665

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

23. Sartori G, Cavazza A, Sgambato A, Marchioni A, Barbieri F, Longo L, et al. EGFR and K- ras mutations along the spectrum of pulmonary epithelial tumors of the lung and elaboration of a combined clinicopathologic and molecular scoring system to predict clinical responsiveness to EGFR inhibitors. Am J Clin Pathol (2009) 131:478–89. doi:10.1309/AJCPH0TRMPXVZW2F

CrossRef Full Text | Google Scholar

24. Ma PC, Tretiakova MS, MacKinnon AC, Ramnath N, Johnson C, Dietrich S, et al. Expression and mutational analysis of MET in human solid cancers. Genes Chromosomes Cancer (2008) 47:1025–37. doi:10.1002/gcc.20604

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

25. Okuda K, Sasaki H, Yukiue H, Yano M, Fujii Y. MET gene copy number predicts the prognosis for completely resected non-small cell lung cancer. Cancer Sci (2008) 99:2280–5. doi:10.1111/j.1349-7006.2008.00916.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

26. Lutterbach B, Zeng Q, Davis LJ, Hatch H, Hang G, Kohl NE, et al. Lung cancer cell lines harboring MET gene amplification are dependent on Met for growth and survival. Cancer Res (2007) 67:2081–8. doi:10.1158/0008-5472.CAN-06-3495

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

27. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ErbB3 signaling. Science (2007) 316:1039–43. doi:10.1126/science.1141478

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

28. Spaans JN, Goss GD. Trials to overcome drug resistance to EGFR and ALK targeted therapies – past, present, and future. Front Oncol (2014) 4:233. doi:10.3389/fonc.2014.00233

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

29. Spaans JN, Goss GD. Drug resistance to molecular targeted therapy and its consequences for treatment decisions in non-small-cell lung cancer. Front Oncol (2014) 4:190. doi:10.3389/fonc.2014.00190

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

30. Blais N, Kassouf E. Maintenance therapies for non-small cell lung cancer. Front Oncol (2014) 4:213. doi:10.3389/fonc.2014.00213

CrossRef Full Text | Google Scholar

31. Zer A, Leighl N. Promising targets and current clinical trials in metastatic non-squamous NSCLC. Front Oncol (2014) 4:329. doi:10.3389/fonc.2014.00329

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

32. Vincent MD. Promising targets and current clinical trials in metastatic squamous cell lung cancer. Front Oncol (2014) 4:320. doi:10.3389/fonc.2014.00320

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

33. Mostafa AA, Morris DG. Immunotherapy for lung cancer: has it finally arrived? Front Oncol (2014) 4:288. doi:10.3389/fonc.2014.00288

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

34. Dawe DE, Ellis PM. The treatment of metastatic non-small cell lung cancer in the elderly: an evidence-based approach. Front Oncol (2014) 4:178. doi:10.3389/fonc.2014.00178

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

35. Owen S, Souhami L. The management of brain metastases in non-small cell lung cancer. Front Oncol (2014) 4:248. doi:10.3389/fonc.2014.00248

CrossRef Full Text | Google Scholar

36. Hirsh V. Targeted treatments of bone metastases in patients with lung cancer. Front Oncol (2014) 4:146. doi:10.3389/fonc.2014.00146

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

37. Faria SL. Role of radiotherapy in metastatic non-small cell lung cancer. Front Oncol (2014) 4:229. doi:10.3389/fonc.2014.00229

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

38. Howe M, Burkes RL. Collaborative care in NSCLC: the role of early palliative care. Front Oncol (2014) 4:192. doi:10.3389/fonc.2014.00192

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar

Keywords: NSCLC, personalized medicine, lung cancer, NSCLC treatment, supportive care

Citation: Hirsh V (2015) The treatment of metastatic non-small cell lung cancer in a new era of personalized medicine. Front. Oncol. 5:20. doi: 10.3389/fonc.2015.00020

Received: 02 December 2014; Accepted: 16 January 2015;
Published online: 03 February 2015.

Edited and reviewed by: Stephen V. Liu, Georgetown University, USA

Copyright: © 2015 Hirsh. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: vera.hirsh@muhc.mcgill.ca