Ultrasensitive blood test spots minute levels of biomarker highly specific to multiple common cancers. The cost? $3 ! It’s now a reality!
By Dona Suri
California has led the way to bring biomarker testing within the reach of all patients, rich or poor. On Governor October 7, Governor Gavin Newsom signed Senate Bill 496. This law requires Medi-Cal and private insurers to cover medically necessary biomarker testing – allowing more people to access effective, individualized cancer treatments. The bill was co-sponsored by American Cancer Society Cancer Action Network and the University of California, with expert insight from the University of California Cancer Consortium.
This measure is highly significant because biomarker testing has become essential for determining the most appropriate targeted therapy for cancer patients. But even with this new law, it’s not all smooth sailing: just about everywhere you look, the incorporation of biomarker testing into clinical practice lags behind recommendations in National Comprehensive Cancer Network guidelines. Moreover, insurance companies are taking their time to rejig their coverage policies. Obviously, private insurers are highly conservative when it comes to paying for any procedure. And, even when insurance coverage exists for recommended biomarker testing, patients may still be paying heavy out-of-pocket costs.
Prior authorization for biomarker testing for some patients can add an administrative burden and may delay testing and thus treatment if it is not done in a timely manner. Louisiana and Illinois have also recently passed laws designed to improve access to biomarker testing at the state level. The laws of the three states are very different in terms of the population affected, the stage of cancer, and whether the coverage of testing is mandated, or the legislation addresses only prior authorization.
The cost of a biomarker test can run into thousands of dollars. No wonder that the insurance companies are tip-toeing around the new legislation. People who are insured by private companies should not be surprised to see premiums go up.
Companies that sell and conduct biomarker tests are well aware of the impact of cost on their business. They know that if they can bring down the cost of biomarker testing, they will gain in client base. More doctors will prescribe the tests, more patients will be tested and the procedure will gain wider acceptance among insurance companies. Last year, a Menlo Park, CA-based biotech company named Grail came out with a test it calls Galleri. Per test cost is $949. Much cheaper than most other biomarker tests and a bargain given the fact that it picks up markers for more than 50 kinds of cancers.
Suppose you could get the same cancer-sniffing accuracy from a blood test that would set you back by $3 only?
Here’s the news out of Mass General Brigham. (MGB is America’s largest hospital-based research program and the oldest and largest teaching affiliate of Harvard Medical School.) Last month – October 6, to be precise –
Investigators from MGB (plus Harvard University’s Wyss Institute for Biologically Inspired Engineering at, and Dana-Farber Cancer Institute) announced that they had created a low-cost, ultrasensitive blood test to detect minute levels of a cancer biomarker that is highly specific to multiple common cancers.
Each test can be performed with merely half a drop of blood (25 microliters). The tool showed promise for early cancer detection and disease monitoring, and could potentially be used in conjunction with other tools for detection, risk stratification and treatment. Results are published in Cancer Discovery.
It’s all about a protein called LINE-1 ORF1. Since the 1980s, cancer researchers have known that transposable elements are active in some cancers. Around 2010 it was observed that the LINE-1 ORF1 protein was a pervasive cancer biomarker.
Here comes the technical part:
Genomics is the study of an organism’s genome – its genetic material – and how that information is applied. When a genomics researcher looks at a portion of a DNA sequence that does not include a stop codon (which functions as a stop signal) he calls it an Open Reading Frame (ORF).
This LINE-1 ORF1 protein is a transposable element protein, which means that it is a mobile DNA sequence capable of replicating itself within the genome independently of the host cell DNA. These ORF-1 proteins are really big – up to 10,000 base pairs or larger. Geneticists refer to transposable elements as “selfish”. This means that they can enhance their own transmission at the expense of other genes in the genome, even if this has no effect or a negative effect on organismal fitness. A chunk of transposable element is every bit as selfish as a virus. Transposable Elements are present in every human cell; they replicate through a copy-and-paste mechanism, resulting in new copies in new positions in the genome.
Most of the time, the body keeps LINE-1 in check. There are layers of mechanisms that prevent it from being expressed. ORF1p is a protein that LINE-1 produces a lot of when there is cancer. It is not a very nice part of your genome, but, on the plus-side, it cannot tell a lie. The presence of the ORF! protein is a sure sign of an unhealthy cell that no longer has control over its transcriptome. (Transcriptome means the sum total of all the messenger RNA molecules expressed from the genes of an organism.) Around 2010 it was observed that ORF1 protein was a pervasive cancer biomarker. ORF1 protein does not show up in normal tissue. Carcinoma cells make ORF1p from Day 1, so the ability to spot it quick, before the cancer can spread, means lives saved.
So, what is new here and what is not new? Since the 1980s cancer researchers have known that transposable elements are active in some cancers. But how to quickly, accurately spot that ORF1 protein?
That is the breakthrough. A multi-disciplinary team of 58 scientists led by pathologist David Walt of Brigham and Women’s Hospital, worked for more than ten years to devise an ultrasensitive blood test that detects minute levels of a cancer-specific protein across a range of cancer types.
The researchers used the single-molecule–based detection technology Simoa—developed by Dr Walt —and contributed custom nanobodies derived and developed from llamas to act as capture reagents that ensnare the ORF1p protein and as sensitive probes to detect it. In their report, the researchers described their investigation as a pilot experiment that wound up working better than they had imagined. They followed up with a series of engineering improvements and iterations in patient samples.
With this technology, the researchers engineered a fast-working assay capable of detecting the ORF1p protein in the plasma. The researchers found that the assay was highly accurate at detecting ORF1p in the blood samples of patients with a variety of cancer types—including ovarian cancer, gastroesophageal cancer, and colorectal cancer.
Unlike many cancer tests that are limited in scope, expensive, or reliant on invasive tissue sampling, the researchers highlighted that the novel blood test is a low-cost multicancer detector that can pick up the presence of the protein in a tiny amount of blood in less than 2 hours. Notably, the test costed less than $3 to produce and returned results fast.
The test worked well enough for them to declare ORF1p expression is a ‘hallmark of cancer’ and one that shows up early in the disease process. Pervasive expression of ORF1p in carcinomas and the lack of expression in normal tissues makes ORF1p unlike other protein biomarkers, which have normal expression levels. This unique biology makes it highly specific.