Next-Gen Blood Tests

Theranos made a hasty exit, but blood-based diagnostics for cancer detection are beginning to settle in.


May 2022 – The Journal of Healthcare Contracting


By Mark Thill

How’s this for a worthy goal: To quickly, conveniently and inexpensively conduct dozens of tests with one drop of blood! At home!

We all know the rest of the story.

Well, Theranos may have fallen victim to haste and deceit, but blood-based diagnostics for cancer detection through genomic profiling is no empty promise. Questions remain about its impact on outcomes and cost, and it’s way too early to say if it will enter the physician’s office, or be used for routine screening, or yield results at the point of care. But some experts believe these things may someday be possible.

Genomic profiling is a laboratory method used to learn about the genes in a person or in a specific cell type, including cancer biomarkers. (Genes are pieces of DNA that hold the codes for making proteins – the instructions that make the body run.) The genes in our cells – about 30,000 of them in total – make up the genome. Changes to genes called mutations can make a person more likely to get cancer.

Biomarkers (sometimes called tumor markers) are genes, proteins and other substances that can provide information about cancer. Each person’s cancer has a unique pattern of biomarkers. The promise of genomic profiling is to spot cancer biomarkers early, target the cancer with specific therapeutics matched to those biomarkers, and gauge the progress of treatment. That is the essence of what is called precision, or personalized, medicine. For example, people with cancer that has genetic changes in the EGFR (epidermal growth factor receptor) gene may be treated successfully with EGFR inhibitors.

Tissue or blood biopsy?

“Next generation sequencing” of a tumor – a technology that can sequence an entire human genome within a single day – is the gold standard for molecular profiling, according to the American Society of Clinical Oncology. (To “sequence” DNA means to determine the order of the four chemical building blocks, or bases, of the DNA molecule – adenine, thymine, cytosine and guanine. The sequence tells scientists the kind of genetic information that is carried in a particular DNA segment.)

As applied in traditional tissue biopsies, next-generation sequencing allows the clinician to compare tumor DNA with normal tissue DNA. But not all patients can get a tissue biopsy, either because the tumor is inaccessible or lacks adequate tissue, or the patient is too sick for such a procedure. In such cases, a noninvasive approach, which can identify circulating tumor DNA, or ctDNA, in blood, is an appealing alternative. Circulating tumor DNA is extracellular DNA from cancer cells that have undergone cell death.

The Food and Drug Administration approved the first liquid biopsy test – the cobas® EGFR Mutation Test v2 (Roche Molecular Systems Inc.) – in June 2016. The test uses plasma specimens for the detection of epidermal growth factor receptor (EGFR) gene mutations in ctDNA of patients with non-small-cell lung cancer. The test identifies patients who may be candidates for treatment with erlotinib (Tarceva®A) and osimeritinib (Tagrisso®), targeted therapies that attack cancer cells with EGFR mutations.

“In my opinion, tissue biopsies and liquid will be complementary,” Daniel Hayes, M.D., FASCO, FACP, Stuart B. Padnos Professor of Breast Cancer Research, University of Michigan Rogel Cancer Center, told Repertoire. A tissue biopsy yields more cells, which improves accuracy, he says. “But the downside is, it demands a biopsy. If it’s on your skin, that’s one thing; but if it’s in your liver or lung, that’s a very big deal. The other problem is, you only get results of the tissue that is biopsied. We’ve known that within a breast – even within the same tissue – cancer can be heterogeneous, meaning some cells are cancerous, some are not.

“Finally it’s difficult to do serial tissue biopsies, because, by definition, there’s nothing to biopsy in a person who is free of disease. So they are not helpful for monitoring the progress of treatment.”

Liquid biopsies, on the other hand, are convenient to administer, facilitate serial monitoring, and offer a snapshot of the patient’s entire tumor burden, he says.

Sandip Patel, M.D., associate professor, University of San Diego Moores Cancer Center, says that today, some biopsies can only be performed reliably with tissue. Liquid biopsy offers advantages in instances where detection of biomarkers isn’t feasible based on the distribution of disease, e.g., in bone or the brain. Both tissue and plasma biopsy methods continue to progress, he adds. “There’s a rising tide for both boats. I foresee complementary usage of both.”

Where do we go from here?

Since that first FDA approval in 2016, researchers continue to develop applications for liquid biopsy. FoundationOne Liquid CDx from Cambridge, Massachusetts-based Foundation Medicine is said to be capable of analyzing over 300 genes from two tubes of blood, plus MSI and blood tumor mutational burden (bTMB), both of which are genomic signatures that can help predict whether a patient might respond to immunotherapy. In addition, the company’s genomic profiling test was FDA-approved to identify prostate cancer patients likely to respond to Lynparza® (olaparib) or Rubraca® (rucaparib).

In January 2022, researchers at the University of Sussex in the United Kingdom reported identifying distinctive biomarkers in patient blood samples that may signal the presence of glioblastoma, the most common high-grade primary brain tumor in adults. The team identified biomarkers within extracellular vesicles, which are small particles secreted by all cells carrying different information, such as proteins or DNA.

Meanwhile, South San Francisco, California-based Freenome and Redwood City, California-based Guardant Health are undertaking clinical studies on the effectiveness of liquid biopsies in detecting early-stage colorectal cancer.

Early cancer detection

The National Cancer Institute is supporting an initiative to advance the development and validation of liquid biopsy technologies that can detect early-stage cancers, distinguish cancer from benign conditions, and identify fast- and slow-growing cancers. Such tests could screen for early-stage cancer in high-risk individuals, such as those with hereditary cancer syndromes.

Meanwhile, The University of Texas MD Anderson Cancer Center reported in January that a blood test using a four-protein marker panel, combined with a risk model based on an individual’s history, more accurately determined who is likely to benefit from lung cancer screening than current U.S. recommendations.

“We recognize that a small percentage of people who are eligible for lung cancer screening through an annual low-dose CT scan are actually getting screening,” Sam Hanash, M.D., Ph.D., leader of the McCombs Institute for the early Detection and Treatment of Cancer, was quoted as saying. “Moreover, CT screening is not readily available in most countries. So, our goal, for many years, has been to develop a simple blood test that can be used first to determine need for screening and make screening for lung cancer that much more effective.”

In February, Menlo Park, California-based GRAIL announced an agreement with Point32Health, the combined organization of Harvard Pilgrim Health Care and Tufts Health Plan, to collaborate on a two-phased pilot of Galleri®, GRAIL’s multicancer early detection blood test. GRAIL has reported that in a clinical study, the Galleri test detected more than 50 types of cancer, over 45 of which lack recommended screening tests today, with a false-positive rate of less than 1%. When cancer is detected, Galleri can determine the cancer signal origin with high accuracy, according to the company.

Monitoring cancer treatment response

Another potential application for blood-based diagnostics is monitoring progress – or lack thereof – of cancer treatment.

Because they are noninvasive and easily repeated, ctDNA-based liquid biopsies may be useful for monitoring patients’ responses to therapy both during treatment and after it is completed, says NCI. Clinicians are hopeful that tracking a patient’s response to treatment may allow adjustments to be made in real time. In other words, the treatment could be stopped or adjusted if the test indicates it is not working.

Imaging techniques such as CT scans are currently used to track treatment response for patients with certain cancer types, but they are not sensitive enough to detect small changes in tumor size and they tend to be costly, according to Mark Roschewski, M.D., of NCI’s Center for Cancer Research.

As a potential alternative, Dr. Roschewski and colleagues have tested the ability of a liquid biopsy test to track treatment responses in patients with lymphoma. They showed that changes in ctDNA correlated with positive responses to chemotherapy. Furthermore, they were able to use ctDNA patterns to detect when some patients’ disease was coming back—months before it was possible to do so via CT scan.

NCI researchers have also correlated changes in ctDNA levels with patients’ responses to immunotherapy treatment – a type of therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection, and other diseases. They found that they could detect these changes within two weeks of the start of treatment. Having an early indicator of the treatment’s efficacy could be helpful because only a small proportion of patients typically respond to immunotherapy treatment.

Last year, GRAIL announced collaborations with biopharmaceutical companies Amgen, AstraZeneca and Bristol Myers Squibb to evaluate the company’s technology for the detection of minimal residual disease, or MRD (referring to cancer cells remaining after treatment that can’t be detected by other scans or tests). Currently, many MRD tests for solid tumors require tissue samples and development of patient-specific assays. GRAIL says its methylation platform could enable a blood-based MRD detection assay for solid tumors that perform comparably to tissue-based assays, while reducing complexity and processing times.

Another firm, Italy-based Menarini Silicon Biosystems, reports that its CELLSEARCH® Circulating Tumor Cell Kit provides in vitro diagnostic applications that are FDA-cleared for predicting overall and progression-free survival in metastatic breast, prostate, and colorectal cancers. Evaluation of circulating tumor cells at any time during the course of disease allows assessment of patient prognosis and predictions of progression-free survival and overall survival.

Questions

Early-detection tests have potential, and some day may be incorporated into clinical guidelines, according to the American Society of Clinical Oncology. In fact, a bill (The Medicare Multi-Cancer Early Detection Screening Coverage Act of 2021) was introduced into the U.S. Senate in May 2021 that would provide Medicare coverage and payment for multicancer early detection screening tests that are approved by the Food and Drug Administration.

But questions remain: How often should these tests be performed? Who will pay for them? Can the cost be justified by the number of lives saved? Would such testing lead to overdiagnosis, leading to more tests and even treatment of cancers that might pose little threat to the patient?

Dr. Patel believes routine screening for cancer with blood-based diagnostics is a possibility. “Two years ago, mRNA vaccines were science fiction. Now millions of people accept it as fact. The pace of biomedical engineering and discovery is fast. But we’re at the ground floor. None of us know what the real performance of these tests will be.”

As for rapid turnaround of blood-based biopsies, Dr. Hayes foresees bioengineers working on it, but he questions its clinical utility. A great deal more clinical research will be necessary to demonstrate that the benefits of screening with so-called Multi-Cancer Early Detection (MCED) assays outweigh the harms, he says. “Screening is catching everyone’s attention, and intuitively it is perceived to be good no matter what. But early detection, which has been proven to be beneficial in some cancers – breast, cervical, lung, colon, and probably prostate – is not necessarily better for all cancers, and the benefits in regard to mortality reduction need to be rigorously demonstrated. The odds of hurting people by overdiagnosing them are almost the same as helping them. So the stakes are very high.”

Even more promising than screening is the progress being made to match biomarkers with drugs specifically designed to treat the patient’s cancer, he says. He looks forward to cancers being treated based on their molecular profile rather than their origin (e.g., lung, prostate, breast). “We may find opportunities to treat people based on their molecular findings, which is different from what we ever imagined.”