SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Survival rates however are significantly higher when lung cancer is diagnosed early. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas, and 10% are Large cell carcinomas.
Although the U.S. Preventive Services Task Force (USPSTF) has recommended annual screening for lung cancer with Low-Dose Computed Tomography (LDCT) for individuals with significant smoking history, screening is vastly underutilized, with a screening rate of less than 2% among smokers eligible for screening. Screening for lung cancer using a peripheral blood sample may improve lung cancer screening rates. Analysis of cell-free DNA (cfDNA) from peripheral blood (Liquid Biopsy), is presently approved to select EGFR targeted therapies (cobas EGFR mutation test), in patients with advanced Non Small Cell Lung Cancer. However, the role of cell-free DNA analysis for early detection of lung cancer is not well established.
The Circulating Cell-Free Genome Atlas (CCGA) is a prospective, multi-center, observational study and is the largest study ever initiated, to develop a noninvasive, liquid biopsy assay for early cancer detection, based on cell-free DNA (cfDNA). This study has currently enrolled 10,012 of a planned 15,000 participants, including people with a recent cancer diagnosis and also a control group of individuals with no known malignancy (70% with cancer, 30% without cancer), across 141 sites in the United States and Canada. This report is one of the first pre-planned sub-studies from the CCGA, involving investigation of blood samples from 1,627 participants (878 patients with newly diagnosed untreated cancer including 127 patients with lung cancer and 749 controls – 580 controls and 169 technical assay controls ), across 20 tumor types and all clinical stages.
The cell-free DNA was isolated from the peripheral blood and analyzed using the following three sequencing methods that were designed to detect cancer-defining signals (mutations and other genomic changes), that could be utilized for early cancer detection.
Targeted sequencing to detect somatic (non-inherited) mutations, such as Single Nucleotide Variants and small insertions and/or deletions, in specific sections of the genome.
Whole-Genome Sequencing (WGS) to detect somatic gene copy number changes across the genome.
Whole-Genome Bisulfite Sequencing (WGBS) of cfDNA to detect abnormal patterns of cfDNA methylation (epigenetic changes)
In this initial sub-study, the authors explored the ability of the above three different assays to detect cancer in 127 people with stage I-IV lung cancer. It was noted that biologic signals suggesting lung cancer were detected and comparable across all assays, and the signal increased with cancer stage. At 98% specificity, the Targeted sequencing detected 51% of early-stage (stage I-IIIA) lung cancers and 89% of late-stage (stage IIIB-IV) lung cancers. Whole-Genome Sequencing detected 38% of early-stage cancers and 87% of late-stage cancers. Whole-Genome Bisulfite Sequencing had similar efficacy, detecting 41% of early stage lung cancers and 89% of late-stage cancers. Similar sensitivities were noted across all assays for adenocarcinoma, squamous cell and small cell lung cancer. False positive rates were low. Of the 580 control participants without cancer at study enrollment, less than 1% (five participants) had cancer-like signal across all three assays, of whom two were subsequently diagnosed with cancer. This highlights the potential for these assays to detect early stage cancers. The authors caution that a large proportion of cell-free DNA is derived from White Blood Cells (WBCs) and DNA mutations in the WBC population can also be generated by processes other than cancer such as clonal hematopoiesis during human aging. In this study, signal generated from the WBCs was subtracted resulting in a cleaner signal, only from tumor related variants.
It was concluded that based on the initial results from the CCGA study, it is possible to detect early-stage lung cancer, with a high degree of specificity, from a simple blood test, using genome sequencing. The authors plan to further optimize the assays and validate results in a larger group of people. Genome-wide sequencing for early stage lung cancer detection from plasma cell-free DNA (cfDNA): The Circulating Cancer Genome Atlas (CCGA) study. Oxnard GR, Maddala T, Hubbell E, et al. J Clin Oncol. 2018;36(suppl; abstr LBA8501)
