The future of lung cancer therapy: Striding beyond conventional EGFR and ALK treatments

Iyer,Sandhya; Prajapati,Rambaksh; Ramesh,Aarthi; Basavalingegowda,Madhura; Todur,Seema; Kavishvar,Shubham; Vijaykumar,Rajeev; Naik,Radhesyam; Kulkarni,Padmaj; Bhatt,Amit  D.; Maniar,Vashishth; Maka,Vinayak; Thungappa,Sateesh  Chiradoni; Singhal,Manish; Ranade,Anantbhushan; Shafi,Gowhar

doi:10.3892/mco.2019.1811

April-2019 Volume 10 Issue 4

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

April-2019 Volume 10 Issue 4

Full Size Image

Article

The future of lung cancer therapy: Striding beyond conventional EGFR and ALK treatments

Authors:
- Sandhya Iyer
- Rambaksh Prajapati
- Aarthi Ramesh
- Madhura Basavalingegowda
- Seema Todur
- Shubham Kavishvar
- Rajeev Vijaykumar
- Radhesyam Naik
- Padmaj Kulkarni
- Amit D. Bhatt
- Vashishth Maniar
- Vinayak Maka
- Sateesh Chiradoni Thungappa
- Manish Singhal
- Anantbhushan Ranade
- Gowhar Shafi
View Affiliations / Copyright

Affiliations: Department of Clinical Genomics and Bioinformatics, Positive Bioscience, Mumbai 400002, India, Department of Medical Oncology, HCG, Bangalore 560020, India, Deenanath Mangeshkar Hospital, Pune 411004, India, Avinash Cancer Clinic, Pune 411030, India, Indraprastha Apollo Hospital, New Delhi 110076, India
Pages: 469-475
|
Published online on: February 20, 2019

https://doi.org/10.3892/mco.2019.1811
Expand metrics +

Abstract

Lung cancer, one of the most frequently diagnosed cancers worldwide has long relied on testing for the molecular biomarkers EGFR/ALK. However, achieving superior clinical outcomes for patients with lung cancer requires developing comprehensive techniques beyond contemporary EGFR/ALK testing. Current technologies are on par with molecular testing for EGFR/ALK in terms of efficacy, most of them failing to offer improvements perhaps primarily due to skepticism among clinicians, despite being recommended in the NCCN guidelines. The present study endeavored to minimize chemotherapy‑dependence in EGFR/ALK‑negative patient cohorts, and use evidence‑based methods to identify ways to improve clinical outcomes. In total, 137 lung cancer cases obtained from ‘PositiveSelect NGS data’, comprising 91 males and 46 females, were investigated. EGFR‑ and ALK‑positivity was used for data dichotomization to understand the therapeutic utility of rare gene alterations beyond just EGFR/ALK. Statistics obtained from PositiveSelect were collated with data from international studies to construct a meta‑analysis intended to achieve better clinical outcomes. Upon dichotomization, 23% of cases harbored EGFR variants indicating that treating with EGFR TKIs would be beneficial; the remaining 77% exhibited no EGFR variants that would indicate favorable results using specific currently available chemotherapy practices. Similarly, 28% of cases had EGFR+ALK variants favoring EGFR/ALK‑based targeted therapeutics; the remaining 72% harbored no EGFR/ALK variants with known beneficial chemotherapy routes. The present study aimed to overcome current inadequacies of targeted therapies in patients with a conventional EGFR/ALK‑positive diagnosis and those in EGFR+ALK‑negative cohorts. Upon analysis of the negative cohorts, significant and clinically relevant single nucleotide variants were identified in KRAS, ERBB2, MET and RET, with frequencies of 7, 1, 2 and 3% in patients who were EGFR‑negative and 6, 1, 1, and 3% in patients who were EGFR and ALK‑negative, respectively, enabling the use of targeted therapeutics aside from EGFR/ALK TKIs. From the results of the current study only 35% of the two negative arms (EGFR negative and EGFR+ALK negative) would be recommended NCCN or off‑label chemotherapy; prior to the current study, the entire cohorts would have been recommended this treatment. The present study emphasizes the potential of comprehensive genomics in identifying hallmarks of lung cancer beyond EGFR/ALK, using broad‑spectrum genetic testing and data‑sharing among medical professionals to circumvent ineffective chemotherapy.

View Figures

View References

1	Bethune G, Bethune D, Ridgway N and Xu Z: Epidermal growth factor receptor (EGFR) in lung cancer: An overview and update. J Thorac Dis. 2:48–51. 2010.PubMed/NCBI
2	Siegelin MD and Borczuk AC: Epidermal growth factor receptor mutations in lung adenocarcinoma. Lab Invest. 94:129–137. 2014. View Article : Google Scholar : PubMed/NCBI
3	Shyr D and Liu Q: Next generation sequencing in cancer research and clinical application. Biol Proced Online. 15:42013. View Article : Google Scholar : PubMed/NCBI
4	Liu TC, Jin X, Wang Y and Wang K: Role of epidermal growth factor receptor in lung cancer and targeted therapies. Am J Cancer Res. 7:187–202. 2017.PubMed/NCBI
5	Zhang Z, Stiegler AL, Boggon TJ, Kobayashi S and Halmos B: EGFR-mutated lung cancer: A paradigm of molecular oncology. Oncotarget. 1:497–514. 2010.PubMed/NCBI
6	Noronha V, Pinninti R, Patil VM, Joshi A and Prabhash K: Lung cancer in the Indian subcontinent. South Asian J Cancer. 5:95–103. 2016. View Article : Google Scholar : PubMed/NCBI
7	Linardou H, Dahabreh IJ, Bafaloukos D, Kosmidis P and Murray S: Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC. Nat Rev Clin Oncol. 6:352–366. 2009. View Article : Google Scholar : PubMed/NCBI
8	Van Assche K, Ferdinande L, Lievens Y, Vandecasteele K and Surmont V: EGFR mutation positive stage IV non-small-cell lung cancer: Treatment beyond progression. Front Oncol. 4:350–358. 2014. View Article : Google Scholar : PubMed/NCBI
9	Capelozzi VL: Role of immunohistochemistry in the diagnosis of lung cancer. J Bras Pneumol. 35:375–382. 2009. View Article : Google Scholar : PubMed/NCBI
10	Mafficini A, Amato E, Fassan M, Simbolo M, Antonello D, Vicentini C, Scardoni M, Bersani S, Gottardi M, Rusev B, et al: Reporting tumor molecular heterogeneity in histopathological diagnosis. PLoS One. 9:e1049792014. View Article : Google Scholar : PubMed/NCBI
11	Janku F: Tumor heterogeneity in the clinic: Is it a real problem? Ther Adv Med Oncol. 6:43–51. 2014. View Article : Google Scholar : PubMed/NCBI
12	Han HS and Magliocco AM: Molecular testing and the pathologist's role in clinical trials of breast cancer. Clin Breast Cancer. 16:166–179. 2016. View Article : Google Scholar : PubMed/NCBI
13	McCoach CE and Doebele RC: The minority report: Targeting the rare oncogenes in NSCLC. Curr Treat Options Oncol. 15:644–657. 2014. View Article : Google Scholar : PubMed/NCBI
14	Levy MA, Lovly CM and Pao W: Translating genomic information into clinical medicine: Lung cancer as a paradigm. Genome Res. 22:2101–2108. 2012. View Article : Google Scholar : PubMed/NCBI
15	Meldrum C, Doyle MA and Tothill RW: Next-generation sequencing for cancer diagnostics: A practical perspective. Clin Biochem Rev. 32:177–195. 2011.PubMed/NCBI
16	Khoo C, Rogers TM, Fellowes A, Bell A and Fox S: Molecular methods for somatic mutation testing in lung adenocarcinoma: EGFR and beyond. Transl Lung Cancer Res. 4:126–141. 2015.PubMed/NCBI
17	Gagan J and Van Allen EM: Next-generation sequencing to guide cancer therapy. Genome Med. 7:802015. View Article : Google Scholar : PubMed/NCBI
18	Rothschild SI: Targeted therapies in non-small cell lung cancer - Beyond EGFR and ALK. Cancers (Basel). 7:930–949. 2015. View Article : Google Scholar : PubMed/NCBI
19	Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E, Cho J, Suh J, Capelletti M, Sivachenko A, et al: Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell. 150:1107–1120. 2012. View Article : Google Scholar : PubMed/NCBI
20	George J, Lim JS, Jang SJ, Cun Y, Ozretić L, Kong G, Leenders F, Lu X, Fernández-Cuesta L, Bosco G, et al: Comprehensive genomic profiles of small cell lung cancer. Nature. 524:47–53. 2015. View Article : Google Scholar : PubMed/NCBI
21	Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, et al: Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 348:124–128. 2015. View Article : Google Scholar : PubMed/NCBI
22	Zhang YL, Yuan JQ, Wang KF, Fu XH, Han XR, Threapleton D, Yang ZY, Mao C and Tang JL: The prevalence of EGFR mutation in patients with non-small cell lung cancer: A systematic review and meta-analysis. Oncotarget. 7:78985–78993. 2016.PubMed/NCBI
23	Choughule A, Noronha V, Joshi A, Desai S, Jambhekar N, Utture S, Thavamanni A, Prabhash K and Dutt A: Epidermal growth factor receptor mutation subtypes and geographical distribution among Indian non-small cell lung cancer patients. Indian J Cancer. 50:107–111. 2013. View Article : Google Scholar : PubMed/NCBI
24	Korpanty GJ, Graham DM, Vincent MD and Leighl NB: Biomarkers that currently affect clinical practice in lung cancer: EGFR, ALK, MET, ROS-1, and KRAS. Front Oncol. 4:2042014. View Article : Google Scholar : PubMed/NCBI
25	Cheng L, Lopez-Beltran A, Massari F, MacLennan GT and Montironi R: Molecular testing for BRAF mutations to inform melanoma treatment decisions: A move toward precision medicine. Mod Pathol. 31:24–38. 2018. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

The future of lung cancer therapy: Striding beyond conventional EGFR and ALK treatments

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Related Articles