A novel, high-intensity sequencing approach identified mutations in both tumor tissue and circulating tumor DNA (ctDNA) at a high rate, bringing medicine closer to one day detecting cancer early with a blood test. The study evaluated this approach among metastatic breast cancer, non-small cell lung cancer (NSCLC), and castration-resistant prostate cancer (CRPC) patients, and results were presented at the 2017 ASCO Annual Meeting (Abstract LBA11516).
Current ctDNA tests, or liquid biopsies, detect a few actionable mutations to guide treatment decisions and monitor disease progression.
“There are a lot of people in the field that are really looking forward to the day where we can substitute tumor biopsies with liquid biopsies—that is, looking in the blood for the mutations,” said ASCO Expert John Heymach, MD, PhD. “A step beyond that is looking into the blood to actually detect cancer before we even know it's there.”
However, to detect cancer early, a different sequencing approach is needed, said lead study author Pedram Razavi, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York City.
Razavi explained that the test must fulfill three criteria: 1) It must detect cancer without prior knowledge of the tumor. 2) To overcome the challenge of tumor heterogeneity within each patient and across the patients in the population, the test must cover a large portion of the genome. 3) Because the amount of ctDNA in the bloodstream is often very low, particularly during the early stage of cancer, the assay must sequence the genome very deeply so that sensitivity is high.
The study researchers designed a high-intensity sequencing approach that scans a broad portion of the genome, 508 genes, and 2 million base pairs. To achieve high sensitivity, each position is sequenced 60,000 times on average. The outcome is this approach produces about 100 times more information than current sequencing methods.
In the study, patients were enrolled who had metastatic or advanced disease, so this high-intensity approach wasn't used for early detection in this study, Heymach said.
Tumor and blood samples from 161 participants with advanced disease were prospectively obtained and analyzed independent from one another; participants had metastatic breast cancer, NSCLC, or CRPC. To be eligible, participants could not have metastatic or progressive disease at the time of enrollment.
In total, 37 participants had to be excluded because sequencing results were not available for both tumor and blood samples, leaving 124 for study. Each cancer type in the study was represented in about the same proportion; 39 participants had breast cancer, 41 had NSCLC, and 44 had CRPC.
Cell-free DNA and white blood cell genomic DNA were extracted from the blood samples and sequenced using a 508-gene panel. Tissue samples were analyzed using a 410-gene panel.
At least one mutation was found in both the blood and tumor samples in 89 percent of participants (95% CI: 82-94). The highest rate was found among metastatic breast cancer patients, for which 38 of 39 participants (97%) had concordance between blood and tumor samples (95% CI: 87-100).
Genetic variants in the tumor tissue for the three tumor types totaled to 864, and 627 of those (73%) were also found in the blood sample. When sequenced without prior knowledge of tumor genetics, blood sample sequencing revealed 76 percent actionable mutations, which are alterations for which a targeted therapy can be recommended.
Future of Liquid Biopsies
“In conclusion, this novel high-intensity sequencing assay incorporates unprecedented combination of depth and breadth of coverage compared to previous assays,” Razavi noted.
Because study participants already had advanced disease, this high-intensity sequencing approach could not fulfill the criterion that the test must detect cancer without prior knowledge of the tumor. However, the study design did mimic this scenario as best possible by analyzing the blood samples independent from tumor samples, meaning tumor genetics were not known when detecting actionable mutations.
“The work by Dr. Razavi and colleagues is a clear advance in the field because it surveys for the first time a much broader panel of genes, 508 genes in this case, and it does it with much deeper sequencing, which means that it's much more sensitive—it can detect much rarer alterations,” Heymach said.
Although supportive of the findings, ASCO Expert Sumanta Kumar Pal, MD, cautioned, “I think we are a long way from utilizing liquid biopsy for detecting cancers.”
“[This study] helps illuminate a path towards the day when we could be using circulating tumor DNA assays for early detection of cancer and not just for selecting certain therapies,” Heymach concluded.
Christina Bennett is a contributing writer.