Blood testing ‘untapped opportunity’ for detection of early-stage lung cancer

Geoffrey R. Oxnard

CHICAGO — Three prototype sequencing assays effectively detected early-stage lung cancer among a subset of patients included in the Circulating Cell-free Genome Atlas study, according to findings presented at the ASCO Annual Meeting.

Perspective from Jorge Nieva, MD

Lung cancer screening with low-dose CT improves survival; however, rate of clinical adoption remains below 2%.

“We know that lung cancer screening has the potential to improve survival outcomes,” Geoffrey R. Oxnard, MD, associate professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School, said during a press briefing. “In this analysis, we proposed to investigate an untapped opportunity for cancer detection using cell-free DNA. This is an area of cancer detection that requires a different approach and could address an unmet medical need.”

The prospective, longitudinal, multicenter, observational Circulating Cell-free Genome Atlas (CCGA) study has a target enrollment of 15,000 individuals. So far, 12,000 people have been enrolled from 141 sites in 24 states. Researchers aim to characterize the landscape of cell-free DNA profiles using a high-intensity sequencing approach.

For the current subanalysis, Oxnard and colleagues assessed the ability of three novel assays to detect lung cancer in 2,800 samples from 118 patients with cancer (median age, 67 years; 85% ever smokers; 46% men) and 561 individuals without cancer (median age, 60 years; 43% ever smokers; 22% men).

The three prototype assays included:

targeted sequencing to detect 507 somatic mutations, such as single nucleotide variants and small insertions and/or deletions, and 60,000X depth;
whole-genome sequencing to detect somatic gene copy number changes at 30X depth; and
whole-genome bisulfite sequencing of cell-free DNA to detect epigenetic changes at 30X depth.

Results of the subanalysis showed the biologic signal for lung cancer was comparable across all assays and increased as cancer stage increased.

At 98% specificity, the whole-genome bisulfite sequencing assay detected 41% of early-stage disease as well as 89% of late-stage disease.

Similarly, the whole-genome sequencing assay effectively detected 38% of early-stage disease and 87% of late-stage disease.

The targeted assay detected 51% of early-stage disease and 89% of late-stage disease.

All three prototype sequencing assays detected lung cancer with a low rate of false-positive findings, Oxnard said. Five control samples (< 1%) had cancer-like signals across all three assays. Two of these participants were subsequently diagnosed with cancer — stage III ovarian cancer and stage II endometrial cancer — suggesting the potential for these tests to identify early-stage cancers.

Of 3,055 nonsynonymous mutations detected across evaluable patients with lung cancer, more than 54% of somatic mutations detected in the blood samples were derived from white blood cells, not from tumors, and are likely due to clonal hematopoiesis of indeterminate potential, which will be an import fact to consider in the development of blood tests for early detection of cancer, Oxnard said.

Research also is currently underway to verify these results in an independent group of nearly 1,000 patients included in CCGA as part of the same substudy.

“This first interim analysis of the CCGA study demonstrates that confidence of sequencing of cell-free DNA can generate high-quality data across the entire genome and it permits noninvasive cancer detection. Assays can detect lung cancer stages across histologies and across populations,” Oxnard said. “Together, these results support the promise of using cell-free DNA assays to develop an early cancer detection test with high-specificity.” – by Jennifer Southall

Reference:

Oxnard GR, et al. Abstract LBA8501. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Disclosures: The study was funded by GRAIL, Inc. Oxnard reports consultant/advisory roles with AstraZeneca, Boehringer Ingelheim, Dropworks, Genentech/Roche, GRAIL, Inc., Ignyta, Inivata, LOXO, Novartis and Takeda, as well as patents, royalties or other intellectual property with Bio-Rad, Chugai Pharma, Guardant Health and Sysmex Corporation. Please see the abstract for all other authors’ relevant financial disclosures.

Perspective

Jorge Nieva, MD

This is a very interesting abstract. It was a very large study; any time we look at a screening study, we really want to have a good-sized population, and the researchers did a great job of doing that.

The very exciting finding of a nearly 50% sensitivity for finding lung cancer simply on the basis of a blood test is a significant finding. The fact that their specificity was better than 99.5% also is wonderful, because the big problem of most screening tests is specificity. It appears as though this study overcomes that challenge.

This study lays the groundwork for a future prospective study of a screened population.

Jorge Nieva, MD

Keck School of Medicine

University of Southern California

Disclosures: Nieva reports no relevant financial disclosures.