On April 15, 2003, the Human Genome Project was officially declared “complete” after generating a reference sequence for approximately 92.1% of the more than 3.1 billion base pairs that comprise the human genome1. By meticulously cataloging the 20,000 to 25,000 genes and regulatory regions that encode for all of the diverse tissues and organs found in the human body, biomedical researchers hoped to more concretely elucidate the genetic basis of disease in a way that improves patient outcomes. Given that cancer is a class of diseases that are fundamentally driven by the accumulation of genetic defects, it is uniquely amenable to characterization and detection by sequencing. Various companies have leveraged next generation sequencing (NGS) technologies to build cancer diagnosis platforms that are intended to better inform patient care. Two types of sequencing-based cancer diagnostics will be covered here: (1) those intended to guide clinical care for patients who have already been diagnosed with cancer and (2) those intended to detect early-stage cancer in seemingly healthy people.

Guiding Clinical Care for Patients Diagnosed with Cancer

These types of sequencing-based cancer diagnostics facilitate what is often referred to as “personalized medicine,” a treatment paradigm that uses data-driven approaches to sort patients into groups with optimized treatment regimens. Leaders in this cancer diagnostic space are developing technologies that examine cell free DNA (cfDNA) present in blood samples, sometimes referred to as “liquid biopsies”15. Liquid biopsies are attractive inputs for tools that are intended to be used among broader patient populations because they can be obtained with procedures that are less invasive than surgical techniques used to procure tissue biopsies. In patients with metastatic cancer, a significant amount of cfDNA is derived from cancer cells and is referred to as circulating tumor DNA (ctDNA), which can be analyzed and assessed for the presence of specific mutations. This is particularly useful to physicians because cancers with certain mutations are more amenable to treatment with targeted therapies. Therefore, these diagnostic tools have the potential to “personalize” patient care.

On Aug. 10, 2020, the Guardant360 CDx test became the first Federal Drug Administration (FDA)-approved diagnostic to screen patients with multiple kinds of solid tumors — such as in the lung, breast or prostate — for the presence of genetic mutations through a single blood draw2. The platform screens for mutations in a panel of 55 genes that are known to be associated with cancer. How might this information be used in practice? Suppose the Guardant360 CDx indicates that a metastatic non-small-cell lung cancer (NSCLC) harbors a mutation in the epidermal growth factor receptor (EGFR) gene. The FDA has determined that such information could be used to recommend treatment with AstraZeneca’s EGFR inhibitor osimertinib (Tagrisso), which has been demonstrated to cut the risk of disease progression or death by 54% relative to the standard-of-care for patients with EGFR-mutated NSCLC3.

Guardant Health isn’t the only company in this space. A couple of weeks after Guardant360 CDx obtained FDA approval, Foundation Medicine picked up a similar approval for its FoundationOne Liquid CDx platform, which screens for mutations across more than 300 genes4. Furthermore, the FDA appears to have embraced these data-driven approaches to patient care. In 2018, then FDA commissioner Scott Gottlieb issued two guidance documents that outline how sequencing-based diagnostic companies can use both FDA-recognized publicly available databases and orthogonal analytical tests to justify treatment recommendations based on readouts from their diagnostic platforms5.

While sequencing-based offerings by Guardant Health and Foundation Medicine may serve as one -stop shops for guiding treatment of late-stage metastatic cancer, their technical limitations make them unlikely to completely replace more traditional diagnostics. Early-stage cancers that are nonmetastatic and localized to a few areas in the body may not shed enough DNA into the bloodstream, and many still require sequencing of tissue biopsies or other chemical tests that determine whether targeted therapies are warranted. However, the unprecedented versatility offered by the ability to detect mutations for multiple cancer types with a single test provides meaningful advantages over traditional tests that are specialized for a single disease or condition.

Early Detection of Cancer in Seemingly Healthy People

These types of sequencing-based cancer diagnostics aim to fill a wide gap for which few or no alternatives currently exist: the lack of early detection of multiple types of cancer with a single test. Epidemiologic studies that have analyzed decades worth of patient records conclude that early-stage cancers are far more treatable than late-stage cancers, yielding a five- to ten-fold improvement in survival rates6. Therefore, two companies — GRAIL and Thrive Earlier Detection — have worked to develop highly sensitive sequencing-based platforms that aim to assess if seemingly healthy individuals harbor early-stage cancers by detecting the presence of ctDNA in blood samples. Furthermore, these platforms aim to apply a multiomics approach to those same blood samples to ascertain the cancer’s tissue of origin.

Why is this useful? Otherwise healthy people are typically subjected to a few early detection tests that are severely limited in their scope, which include prostate exams (prostate cancer, male only), mammograms (breast cancer, female only), Pap tests (cervical cancer, female only) and colonoscopies (colorectal cancer). However, virtually all other forms of cancer are often caught and diagnosed when patients present with symptoms, at which point the cancer may have already progressed from a more treatable early stage to a more aggressive late stage form of disease. Sequencing-based cancer diagnostics developed by GRAIL and Thrive aim to offer a single, minimally invasive test that asymptomatic people can take to find out if they have cancer. These analytical platforms also combine multiomics data with machine learning algorithms to suggest which organ a cancer is derived from (lung, breast, prostate, etc.) so that physicians can focus their efforts ion recommending follow-up tests and considering treatment options. In the long run, early detection and treatment of cancer that would have otherwise gone undiagnosed could significantly decrease the incidence of cancer-related morbidity and mortality.

At the annual American Association for Cancer Research (AACR) conference, held virtually in early 2020, Thrive provided interim data for a large-scale clinical trial assessing outcomes for otherwise healthy people, some of whom were ultimately found to harbor early-stage cancer. In collaboration with Geisinger health system and The Johns Hopkins University, Thrive’s sequencing-based early detection platform more than “doubled the number of cases detected by traditional diagnostics, from 25% to 52% when added to a routine work-up”8. The technology accurately indicated that various pre-metastatic tumors were derived from one of 10 organs of origin (lung, breast, prostate, etc.). Importantly, many of the cancer types that were identified currently lack a routine early detection test and might have otherwise gone undetected until they advanced to symptomatic, late-stage disease. About half of the identified cancers were later-stage cancers found in asymptomatic patients, which highlights how even advanced disease can go undetected if not for better screening methods10. The full results were published in Science by the scientific co-founders of Thrive — Bert Vogelstein, Kenneth Kinzler and Nickolas Papadopoulos — along with their associated labs at the Johns Hopkins University School of Medicine and partners9. The data presented at the AACR conference is part of an ongoing clinical trial that involves more than 10,000 women between age 65 and 75.

Data from the clinical assessment of GRAIL’s flagship sequencing-based early detection test, Galleri, also turned heads (virtually) at the AACR 2020 meeting. A subanalysis of its Circulating Cell-free Genome Atlas Study involving approximately 9,500 participants (the full study includes approximately 115,000 participants across four trials) found that Galleri was able to “detect more than 50 different cancer types across all stages (stage I–III sensitivity: 43.9%, stage I–IV sensitivity: 54.9%) at a specificity of more than 99% and with a single false positive rate of less than 1%”11. In other words, Galleri performed with high fidelity and frequently identified the presence of tumors in patients who did have tumors while reporting the absence of tumors in those without them. This is important because it could enable clinicians to accurately judge which patients require follow-up and which ones don’t. Additionally, a proprietary analysis of DNA methylation, facilitated by a machine learning algorithm integral to the Galleri platform, was able to trace identified tumors to their tissue of origin with 93% accuracy. The data was presented alongside a publication in the Annals of Oncology that provides a more comprehensive look at the findings11. Regulatory documents filed on behalf of GRAIL outline the intent to launch Galleri in 2021 as a “laboratory-developed test, which doesn’t require FDA approval as a medical device12. The company would expand its use after FDA approval. Of particular note, Illumina, the market leader in commercial next generation sequencing technologies, formally announced its decision to acquire GRAIL on Sept. 21, 2020. Illumina had spun GRAIL out in 201614.

Next generation sequencing-based cancer diagnostics that either guide cancer treatment or detect cancer early exemplify the innovative applications of our newfound understanding of the human genome. They have enabled data-driven approaches that could have profound implications for clinical oncology. Personalized medicine approaches developed by Guardant Health and Foundation Medicine are FDA approved and well positioned to become dominant methodologies used to guide patient care. Early detection approaches developed by Thrive and GRAIL are still in clinical-stage development (they were not FDA approved as of mid-2020), but they address massive gaps in our ability to diagnose and treat cancer at earlier stages. Taken together, these technologies represent the sum of the fruits of the “genomic revolution” that scientists at the National Institutes of Health hoped to usher in as they first embarked on the Human Genome Project back in 1990.


  1. genome.gov/human-genome-project/Timeline-of-Events
  2. fiercebiotech.com/medtech/fda-approves-guardant-s-next-gen-tumor-sequencing-blood-test
  3. astrazeneca.com/content/astraz/media-centre/press-releases/2018/us-fda-approves-tagrisso-as-1st-line-treatment-for-EGFR-mutated-non-small-cell-lung-cancer.html
  4. foundationmedicine.com/press-releases/445c1f9e-6cbb-488b-84ad-5f133612b721
  5. fda.gov/news-events/press-announcements/fda-finalizes-guidances-accelerate-development-reliable-beneficial-next-generation-sequencing-based
  6. doi.org/10.1016/j.cell.2017.01.030
  7. biomedicalodyssey.blogs.hopkinsmedicine.org/2019/09/cancer-diagnosis-its-in-your-blood/
  8. fiercebiotech.com/medtech/aacr-thrive-s-early-blood-test-doubles-real-world-cancer-screening-rates
  9. doi.org/10.1126/science.abb9601
  10. statnews.com/2020/04/28/thrive-aacr-results-blood-test-heathy-people/
  11. doi.org/10.1016/j.annonc.2020.02.011
  12. sec.gov/Archives/edgar/data/1699031/000162827920000227/grails-1.htm
  13. ncbi.nlm.nih.gov/pmc/articles/PMC5101928/
  14. investor.illumina.com/news/press-release-details/2020/Illumina-to-Acquire-GRAIL-to-Launch-New-Era-of-Cancer-Detection/default.aspx
  15. cancer.org/latest-news/liquid-biopsies-past-present-future.html

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