The Cancer Genome Atlas Plays Role in Future Therapies for NSCLC

The Cancer Genome Atlas (TCGA) began in 2006, with a total investment of $100 million from the National Cancer Institute and the National Human Genome Research Institute for a 3-year pilot period.

Its remarkable success ensured substantial subsequent investment from the National Institutes of Health. The aim of TCGA is to generate detailed genomic characterization and analysis of more than 20 tumor types, through the cooperation of a national network of clinicians and scientists. “TCGA is a multi-institutional consortium,” said James Suh, MD, clinical assistant professor in the department of pathology at the New York University Langone Medical Center. Data from these analyses are freely available to support and facilitate worldwide advances in oncology.¹

The Cancer Genome Atlas has recently characterized the 2 most common subtypes of non-small cell lung carcinoma (NSCLC), namely squamous cell lung carcinoma (which comprises 25%-30% of NSCLC) and lung adenocarcinoma (which accounts for approximately 40% of NSCLC).^2-4“As a pathologist involved in the lung cancer project, I reviewed tumor samples to make sure that they contained enough viable tumor cells for the proposed analyses,” explained Suh. Tumors from previously untreated patients with disease ranging from stage 1 to stage 4 were used for analysis.

“What we know about lung adenocarcinoma (and [this] may also be true of lung squamous cell carcinoma) is that chemotherapy or other therapies may induce dynamic molecular changes in which the genetic profile that you started with may be different after treatment,” said Benjamin Levy, MD, director of thoracic medical oncology at the Mount Sinai Beth Israel Hospital and assistant professor at the Icahn School of Medicine, both in New York. “I think that we are fairly sure at this point that the genetic underpinnings of a tumor are not static and may change over time, with or without treatment.”

Squamous Cell Lung Carcinoma

Researchers from TCGA published the results of a genomic and epigenomic study of squamous cell lung carcinoma, along with an assessment of possible opportunities for therapy; in 2012.³The researchers utilized tumors from 178 patients, 96% of whom had a history of tobacco use. Squamous cell lung carcinoma was found to have a high somatic mutation rate of 8.1 mutations per megabase. This study revealed that somatic alterations appeared to drive molecular pathways necessary for the initial development and ongoing growth of cancer. Of importance, mutation or somatic copy number alterations were found in genes participating in the differentiation of squamous cells and oxidative stress response. Indeed, 44% of the samples contained alterations in genes involved in squamous cell differentiation.SOX2andTP63were amplified and overexpressed, and there were mutations leading to loss of function inNOTCH1, NOTCH2,andASCL4. The researchers also identified the inactivation of a confirmed tumor suppressor gene,CDKN2A,in 72% of cases of squamous cell lung carcinoma.Overall, the authors reported statistically recurrent mutations in 11 genes, and mutation ofTP53was found in the majority of samples.

KRASandEGFRare commonly mutated in lung adenocarcinoma, but they were not found to be common among the squamous cell lung carcinoma tumors studied. Instead, 96% of the tumors had mutations in tyrosine kinases, serine/threonine kinases, nuclear hormone receptors, and others, and the authors predicted that 50% to 77% of these mutations were likely to have functional impact. The presence of an inactivating mutation of theHLA-Agene suggests use of genotyping to select patients for immunotherapies in NSCLC.

Lung Adenocarcinoma

In July 2014, TCGA published a comprehensive molecular profiling of lung adenocarcinoma.⁴Researchers took tumor specimens from 230 patients, 81% of whom either had a history of tobacco use or were current smokers. Analysis revealed that the tumors had 8.9 mutations per megabase.

Vassiliki Papadimitrakopoulou, MD, on Implementing Personalized Medicine in Lung Cancer

Papadimitrakopoulou is a Professor at the University of Texas, MD Anderson Cancer Center

Among the samples studied, 76% had somatic evidence ofRTK/RAS/RAFactivation. Although it has been established that this pathway is frequently activated in lung adenocarcinoma by mutations in known driver oncogenes, the present study revealed the existence of hitherto unknown mechanisms also capable of activating the pathway. The authors recommended investigating inhibition of other possible target alterations, including MET and ERB2/HER2, and stressed the importance of their discovery of inactivating mutations ofMGA, highlighting a role for the MYC pathway. “This study has broadened our knowledge by revealing additional molecular findings (NF1, loss of function MGA mutations) yet to be this extensively reported on,” said Levy. The analysis encountered abnormalities in the PI3K-mTOR pathway (25% of cases), the P53 pathway (63% of cases), and alteration of cell cycle regulators and oxidative stress pathways (64% and 22% of cases, respectively).

“This massive undertaking by TCGA was able to identify additional molecular alterations that have potential therapeutic implications, specifically in oncogene negative tumors,” stated Levy. “This includes identification of aberrations in genes, such asNFI,RIT1,andKEAP1, that may be actionable and thus have future clinical relevance. The hope is that these new findings will provide further insight that will translate into the development of additional targeted therapies in attempts to improve outcomes.”

Clinical Pearls

• The aim of TCGA is to generate detailed genomic characterization and analysis of more than 20 tumor types, through the cooperation of a national network of clinicians and scientists.
• TCGA has recently characterized the 2 most common subtypes of NSCLC, namely squamous cell lung carcinoma and lung adenocarcinoma.
• In a study on squamous cell carcinoma, authors reported statistically recurrent mutations in 11 genes, and mutation of TP53 was found in the majority of samples.
  • 96% of the tumors had mutations in tyrosine kinases, serine/threonine kinases, nuclear hormone receptors, and others.
• In July 2014, TCGA published a comprehensive molecular profiling of lung adenocarcinoma
  • Authors recommended investigating inhibition of target alterations, such as MET and ERB2/HER2, and stressed importance of their discovery of inactivating mutations of MGA, highlighting a role for the MYC pathway.

References

1. The Cancer Genome Atlas. Program overview. http://cancergenome.nih.gov/abouttcga/overview. Accessed September 9, 2014.
2. American Cancer Society. Lung cancer (non-small cell). http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed September 11, 2014.
3. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers.Nature. 2012;489:519-525.
4. The Cancer Genome Research Atlas. Comprehensive molecular profiling of lung adenocarcinoma.Nature.2014;511;543-550.

Considering the overall impact of this multi-institutional endeavor by TCGA on future drug development in NSCLC, Suh commented, “TCGA identifies smaller subsets of patients with actionable targets, enabling clinical research to develop an agent and subsequently obtain FDA approval in a shorter time frame than in the past.”