BY Peter S. Hammerman, MD, PhD
The management of lung adenocarcinoma, the most common type of non-small cell lung cancer (NSCLC) has evolved dramatically over the last decade due to the ability to identify subsets of patients who are likely to benefit from targeted therapies. The best examples of this modern approach are the use of erlotinib for patients with Epidermal Growth Factor Receptor (EGFR) mutations and crizotinib for individuals with fusions of the Anaplastic Lymphoma Kinase (ALK) gene. These targeted therapies, when used to treat individuals with these specific genetic alterations, lead to dramatically improved response rates as compared with conventional chemotherapy with far less associated toxicity. Tumor genotyping studies for EGFR, ALK and a number of other important genes have now become the standard of care for patients with lung adenocarcinoma, and new targeted therapeutic strategies continue to be identified in this disease.
In contrast to lung adenocarcinoma, targeted agents have not yet been shown to be successful in the treatment of squamous cell lung cancer, the second most common type of NSCLC. This has been largely due to a lack of knowledge of the genomic alterations that drive these tumors, leading to an inability to devise targeted therapeutic approaches for this disease. However, recent work by The Cancer Genome Atlas (TCGA) Network has greatly added to our knowledge of this disease.
TCGA is a joint NCI/NHGRI-funded initiative that has taken on the challenge of deeply studying over 20 tumor types using cutting-edge genomic technology. Squamous cell lung cancer was selected as a priority project, along with glioblastoma multiforme and serous ovarian cancer given the morbidity and mortality associated with these diseases.
In a recent publication, TCGA reports DNA and RNA sequencing, gene expression, copy number, methylation, and micro-RNA analysis of 178 squamous cell lung cancers. This is the largest study undertaken to date of squamous cell lung carcinomas by several orders of magnitude and the first to analyze tumors using this number of analysis platforms.
One of the major findings from the TCGA Network is that the majority of squamous cell lung cancers harbor a genomic alteration in a gene that is a likely therapeutic target. The most promising of these are alterations of Fibroblast Growth Factor (FGFR) and Phosphatidyl-inositol-3 (PI3K) kinase families. Clinical activity of FGFR inhibitors has already been reported in this disease for patients with amplification of FGFR1. Other important observations were the overall complexity of squamous cell lung cancers which harbor nearly 400 mutations per tumor. Almost all tumors have disruptions in two key tumor suppressor genes (TP53 and CDKN2A) and many demonstrated dysregulation of genes controlling squamous cell differentiation or cellular responses to oxidative damage. A surprising result was the identification of inactivating mutations in the HLA-A gene, suggesting that lung cancers may undergo mutations which make them less immunogenic.
The data from the study have been made publically available to the scientific community via the TCGA website. This will undoubtedly be a useful resource for investigators wishing to examine other genes and pathways in detail.
This work is one of several large genomic studies of lung cancer published recently which demonstrate the power of next-generation sequencing technologies. Further pre-clinical and clinical evaluation of altered genes in lung cancer will be essential to realize the full potential of these datasets and to continue to improve targeted treatment approaches.
Peter S. Hammerman, MD, PhD, a member of The Cancer Genome Atlas Research Network, is a medical oncologist at Dana-Farber Cancer Institute and an Instructor in Medicine at Harvard Medical School. He was on the Writing Committee of the TCGA lung cancer report.
Additional Comments from Ramaswamy Govindan, MD, OT Clinical Advisory Editor for Oncology and Co-chair of The Cancer Genome Atlas Project’s Lung Cancer Disease Working Group:
As Dr. Hammerman points out, tools and technologies that have evolved over the past decades now enable us to look at the complex genomic landscape of cancer cells as never before. Over the next several months, we plan to complete comprehensive genomic analyses of 1,000 patients with lung adenocarcinoma and squamous cell carcinoma. This research will hopefully unearth not only some new targets for therapy but also yield new information about cancer biology. The major take-home point from the TCGA study is that targeted therapies may soon be available for patients with squamous NSCLC.