The Use of Genetic Markers to Improve Outcomes in Non-Small Cell Lung Cancer

Anguiano, Arturo, MD
Vice Chairman, Genetics and Chief Director, Cytogenetics
Quest Diagnostics Nichols Institute
San Juan Capistrano, CA Also by this Author 

Despite advances in surgical technique and drug therapy, lung cancer remains as one of the leading causes of cancer-related deaths.1

While reductions in tobacco use provide the largest single opportunity for preventing deaths due to lung cancer­,2 recent developments in diagnosis and therapy are having some impact in improving survival for a subset of patients.

Dr. Arturo Anguiano, Chief Director, Cytogenetics, Quest Diagnostics Nichols Institute, discusses how genetic markers are providing a basis for more effective management of patients with adenocarcinoma, the most prevalent form of non-small cell lung cancer (NSCLC), and looks ahead to further developments in the field.

Early Diagnosis

Dr. Anguiano stresses the importance of early, precise diagnosis in improving survival for lung cancer patients. The overall five-year survival rate is about 16% but rises to 53% for cases detected when the disease is still localized. However, only 15% of lung cancer cases are diagnosed at an early stage and over half of people with lung cancer die within one year of being diagnosed.1

“Advances in diagnosis are shifting toward the earliest possible detection of adenocarcinoma tumors using imaging studies,” says Dr. Anguiano. “The focus is on identifying localized and minimally invasive adenocarcinoma (MIA), since these are associated with the most successful outcomes after complete resection.”3 It has been shown that if these tumors are identified, patients will have a 100% or near 100% survival following resection.3

Genetic Markers for Targeting Therapy

For patients with advanced adenocarcinoma disease, molecular profiling can identify individuals who may benefit from targeted therapies, explains Dr. Anguiano. “In these patients it is important to classify the tumors histologically, in particular, to identify those that are adenocarcinomas or NSCLC not otherwise specified,” says Dr. Anguiano. “These should then be tested for epidermal growth factor receptor (EGFR) mutations, as the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors (TKIs). Testing for ALK rearrangement is also important, since, if present, this leads to targeted therapy with crizotinib, with good response rates.”

Last year the National Comprehensive Cancer Network (NCCN) issued recommendations for gene mutation testing in patients with NSCLC. These guidelines recommend that both EGFR and ALK mutation tests are performed to guide therapy.4

Continuing Challenges

Only a subset of patients (often younger, female, never-smokers) has EGFR mutations that make them suitable for EGFR TKI treatment with very good response rates, notes Dr. Anguiano.  “While some patients with no EGFR mutations may derive clinical benefit from EGFR TKIs, these patients should be tested for other possible genetic markers that could be targeted by a specific TKI.”

He cautions that even patients showing excellent objective response to EGFRTKIs eventually develop resistance to this treatment. It is important therefore to identify secondary mutations in EGFR or MET amplification/over-expression that could explain the lack of response, in order to try other types of therapy.5

Lack of response can also be predicted by the presence of KRAS mutations that tend to impartresistance to gefitinib and erlotinib. EGFR, KRAS and ALK mutations are nearly always mutually exclusive and so there is a strong rationale for including all 3 tests in one panel.

Future Developments

Work continues to harness the potential of genetic markers to expand the number of patients who can benefit from targeted therapies, indicates Dr. Anguiano. “Researchers are working to identify new genetic markers that can lead to the development of new targeted therapies. Significant attention is being paid to the therapeutic potential of the following markers: MET amplification/over-expression, ROS1 rearrangements, and KIF5-RET fusions.“5-8

At the same time, developments are in progress to improve next generation treatments that irreversibly target tyrosine kinase of the EGFR family of receptors.

References

  1. Cancer Facts and Figures, 2012. American Cancer Society. Available at:
    www.cancer.org/Research/CancerFactsFigures/ACSPC-031941
    . Accessed August 30, 2012.
  2. Jemal A, Thun MJ, Ries LGA, et al. Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst. 2008;100:1672–1694.
  3. Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/ European Respiratory Society International multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6:244-285.
  4. NCCN Clinical Practice Guidelines in Oncology™. Non-small cell lung cancer. v3.2012. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed August 30, 2012.
  5. Kosaka T, Yamaki E, Mogi A, et al. Mechanisms of resistance to EGFR TKIs and development of a new generation of drugs in non-small cell lung cancer. J Biomed Biotechnol. 2011;2011:165214.
  6. Vincent MD, Kuruvilla MS, Leighl NB, et al. Biomarkers that currently affect clinical practice: EGFR, ALK, MET, KRAS. Curr Oncol. 2012;19(Supplement 1):S33–S44.
  7. Kohno T, Ichikawa H, Totoki Y, et al. KIF5B-RETfusions in lung adenocarcinoma.  Nat Med.2012;18:375-377.
  8. Bergethon K, Shaw AT, Ou SH, et al. ROS1rearrangements define a unique molecular class of lung cancers. J Clin Oncol.2012;30:863-370.