An initial report from the large, ongoing Circulating Cell-Free Genome Atlas (CCGA) study provides preliminary evidence that a blood test may be able to detect early-stage lung cancer.

This is one of the first studies to explore blood tests analysing free-floating or cell-free DNA as a tool for early detection of cancer.

The findings will be featured in a press briefing today and presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting.

“We’re excited that initial results from the CCGA study show it is possible to detect early-stage lung cancer from blood samples using genome sequencing,” said lead study author Geoffrey R. Oxnard, MD, Associate Professor of Medicine at Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA.

“There is an unmet need globally for early detection tests for lung cancer that can be easily implemented by health care systems.”

Survival rates are significantly higher when lung cancer is diagnosed early.

In the United States, annual lung cancer screening with low-dose computed tomography (LDCT) is recommended by the U.S. Preventive Services Task Force (USPSTF) for people with significant smoking history, but screening is vastly under-utilised.

Globally, LDCT is not widely adopted due to cost and lack of health infrastructure.

Having a blood test that can be done through a simple blood draw at the doctor’s office may improve lung cancer screening rates, but before such a test could be widely used, additional validation in larger data sets and in studies with people who have not been diagnosed with cancer would be needed.

Analysis of cell-free DNA from blood is already used to help choose targeted therapies (e.g., the cobas EGFR mutation test), but such “liquid biopsies” are used only for people with advanced lung cancer.

Until recently there has been limited evidence to show cell-free DNA analysis may be feasible for early detection of lung cancer.

About the study

The CCGA study has enrolled more than 12,000 of the planned 15,000 participants (70% with cancer, 30% without cancer), across 141 sites in the United States and Canada.

This report is from the first pre-planned sub-study from the CCGA, in which three prototype sequencing assays were performed on blood samples from approximately 1,700 participants.

Twenty different cancer types across all stages were included in the sub-study.

In this initial sub-analysis, researchers explored the ability of three different assays to detect cancer in 127 people with stage I-IV lung cancer.

The three assays that were designed to detect cancer-defining signals (mutations and other genomic changes) that could be used in the development of an early cancer detection test are:

• Targeted sequencing to detect non-inherited (somatic) mutations, such as single nucleotide variants and small insertions and/or deletions
• Whole-genome sequencing (WGS) to detect somatic gene copy number changes
• Whole-genome bisulfite sequencing (WGBS) of cfDNA to detect abnormal cfDNA methylation patterns (epigenetic changes)

Key findings

Among the 127 participants with lung cancer, the biologic signal for lung cancer was comparable across the assays, and the signal increased with cancer stage.

At 98% specificity, the WGBS assay detected 41% of early stage (stage I-IIIA) lung cancers and 89% of late-stage (stage IIIB-IV) cancers.

The WGS assay was similarly effective, detecting 38% of early-stage cancers and 87% of late-stage cancers, whereas the targeted assay detected 51% of early-stage cancers and 89% of late- stage cancers.

Initial results showed that all three prototype assays could detect lung cancer with a low rate of false positive findings (a false positive occurs when the test suggests a person has cancer when there is no cancer).

Of the 580 control samples (from people without cancer at study enrolment) in the sub-study, five (<1%) had a cancer-like signal across all three assays.

Of those five participants, two were subsequently diagnosed with cancer (one with stage III ovarian cancer, and one with stage II endometrial cancer), highlighting the potential for such a test to identify early stage cancers.

The study also found that in the participants with lung cancer, more than 54% of somatic (non-inherited) mutations detected in the blood samples were derived from white blood cells and not from tumours.

These mutations are likely due to natural ageing processes (so-called clonal hematopoiesis of indeterminate potential, or CHIP) and will be important to consider when developing blood tests for early detection of cancer, noted Dr. Oxnard.

Next steps

The researchers are verifying these results in an independent group of approximately 1,000 participants from CCGA as part of the same sub-study.

“These are promising early results, and next steps are to further optimise the assays and validate results in a larger group of people,” said Dr. Oxnard.

With increased sample sizes, machine learning approaches are expected to improve assay performance, he noted.

Source: ASCO 2018