Every year, we lose approximately 600,000 loved ones to cancer.¹ We have been waging a war against cancer for 50 years, and despite remarkable advances, it often feels that cancer is winning.

One factor playing a significant role is how we approach screening for cancer. We currently screen for individual cancers rather than what cancer an individual may have, we use decades-old technology, and compliance is suboptimal. Simply adding more individual screening tests—either as independent tests or a string of single cancer markers in a single test—is clinically and economically untenable.

Simply put, the status quo in cancer detection is unacceptable.

But how can we change this paradigm? One tool in our arsenal lies in multi-cancer early detection (MCED), a new approach that identifies a common cancer signal shared by many different types of cancer, with the goal of detecting cancer in earlier stages when treatment is more likely to be successful and potentially curative.

The unmet medical need and potential benefits are clear. Today we have widely available screenings for just five types of cancer, yet most cancer deaths are from those without recommended screenings.¹, ² Decades of research demonstrates that when we find cancer earlier, we can save more lives. Cancer diagnosed in earlier stages is often easier to treat and cure, and screening is recommended by the U.S. Preventive Services Task Force and endorsed by the American Cancer Society, Centers for Disease Control and Prevention, and National Comprehensive Cancer Network for at-risk individuals for certain cancer types.

The impact of adding MCED tests to existing screenings could mean saving one in four lives otherwise expected to be lost to cancer within five years of diagnosis.³

All cancer screening tests must have a balance of potential harms and benefits, as no screening or diagnostic test is 100% accurate. That said, GRAIL’s MCED technology is designed to maximize the benefits of early detection by increasing cancer detection rates while minimizing potential harms—false positives, overdiagnosis, and potential healthcare system burden.

Limiting False Positives

When a test indicates that a disease is present, but the disease is not confirmed with diagnostic follow-up, this is a false positive. False positives can lead to unnecessary tests like biopsies and overdiagnosis of cancers for which treatment would not have had a benefit.

False positives are a common result of cancer screening, with tests like mammography and colorectal cancer screenings carrying significant risk of false positives. In fact, a Breast Cancer Surveillance Consortium study including mostly film mammography estimated that after 10 years of annual screening in women aged 40 to 59 years, including their baseline mammogram, 61% of individuals would experience at least one false positive and 7% to 9% at least one false-positive biopsy recommendation.⁴

Despite this risk, these screenings remain recommended gold standards due to the proven benefits of finding cancer earlier. However, looking forward to a population cancer screening test, a lower false-positive rate can reduce harms and serve as a critical screening test performance characteristic for managing the scope, cost, and complexity of evaluating asymptomatic patients.

GRAIL’s Galleri® MCED test was intentionally engineered to balance detecting a cancer signal across many types of cancer, while maintaining a low false-positive rate of less than 1%. The very low false-positive rate (also called “high specificity”) is achieved by balancing “specificity”—a test’s ability to correctly identify people without cancer—with “sensitivity”—a test’s ability to correctly identify people with cancer.

For the overwhelming majority of these cancer types, including pancreatic, head and neck, and stomach cancer, the status quo is zero sensitivity due to the lack of available screening tools for these cancers—until now.

Preferentially Detecting More Aggressive Cancers to Limit Overdiagnosis

Methylation is a process by which methyl groups are added to DNA. Through this process, methylation patterns on DNA that is shed into the bloodstream by both healthy and cancer cells (called cell-free DNA) can carry cancer-specific signals. GRAIL’s MCED technology uses next-generation sequencing and machine learning algorithms to analyze the methylation patterns of cell-free DNA to detect a cancer signal and determine its origin, or location, in the body. These methylation patterns are considered a hallmark of cancer.

Slow growing (or “indolent”) cancers shed less cell-free DNA, whereas fast growing or aggressive cancers shed larger amounts of cell-free DNA. The lower amount of cell-free DNA shed in more indolent cancers makes them inherently less detectable by the Galleri test, limiting overdiagnosis and overtreatment. Conversely, the higher cell-free DNA shed by more aggressive cancers makes them inherently more detectable.⁵

Galleri was designed to have lower sensitivity for indolent cancers, like thyroid and encapsulated prostate cancer, to improve specificity for more aggressive cancers. In studies, cancers not detected by Galleri were more likely to be associated with better outcomes (including survival) versus detected cancers, including those with higher mortality. Galleri is less likely to identify the indolent cancers that may never cause symptoms or become life-threatening.

MCED Tests Offer Potential Value for Patients and the Healthcare System

Cancers with widespread screening recommendations only account for about 15% of all cancers diagnoses.⁶ When cancer isn’t found through screening, it is typically identified after an individual becomes symptomatic in later stages, when treatment is more intensive and outcomes are poorer.

MCED tests can potentially triple the number of cancers found in the general population,⁷ maximizing efficiencies for diagnostic workups, and minimizing the harms associated with cancer screenings. Even if single screening tests were available for each aggressive, fast-growing cancer that can occur in adults over 50, such an approach would be impractical, inefficient, cost-prohibitive, and would overwhelm the healthcare system.

MCED tests identify cancer more efficiently when combined with existing screenings, minimizing the overall burden of the healthcare system while maximizing value. By detecting cancers earlier, we can significantly reduce the cost and complexity of cancer treatment.⁸ In fact, costs to treat late-stage cancer are often two to three times greater than those for earlier stage cancer and can be as much as seven times higher.⁹

Adding an MCED has the potential to reduce overall cancer resource utilization for cancer management by shifting cancer treatment to earlier stages where less resources are needed and costs of treatment are lower.¹⁰

To get an advantage over cancer through improved screening—leading to early diagnosis and treatment—without unnecessary harm, we must do things differently. MCED tests offer personalized, precision medicine at population scale. This is how we can start to really turn the tide against an epidemic of late-stage cancer diagnosis.

For more information about Galleri, including Important Safety Information, visit Galleri.com.

References

1. 1. American Cancer Society. Cancer Facts & Figures 2022. Published online 2022.  https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2022/2022-cancer-facts-and-figures.pdf.  
   2. GRAIL, LLC. Data on File
   3. Hawkes N. Cancer survival data emphasise importance of early diagnosis. BMJ. 2019 Jan 25;364:l408. 
   4. Ho TH, Bissell MCS, Kerlikowske K, et al. Cumulative Probability of False-Positive Results After 10 Years of Screening With Digital Breast Tomosynthesis vs Digital Mammography. JAMA Netw Open. 2022;5(3):e222440. doi:10.1001/jamanetworkopen.2022.2440
   5. Chen X, Dong Z, Hubbell E, et al. Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA. Clin Cancer Res. 2021 Aug 1;27(15):4221-4229. doi: 10.1158/1078-0432.CCR-21-0417. Epub 2021 Jun 4. 
   6. Hackshaw, A., Cohen, S.S., Reichert, H. et al. Estimating the population health impact of a multi-cancer early detection genomic blood test to complement existing screening in the US and UK. Br J Cancer 125, 1432–1442 (2021).
   7. ​​Based on Surveillance, Epidemiology, and End Results (SEER) incidence in individuals 50-79 years old who are screening eligible and have average risk of cancer. GRAIL Data on file GA_2021_012. Diagnostic work up based on National Comprehensive Cancer Network (NCCN) guidelines, with unit costs applied based on Medicare pricing and a commercial multiplier (2.3×). Assumes nationally-representative adherence to USPSTF A, B, or C recommended screening  (breast, colorectal, lung, cervical, and prostate  cancer) and 100% screening with MCED test in the USPSTF-screened group. Baseline population of 107M (men and women aged 50 – 79; US Census Bureau. Annual Estimates of the Resident Population by Single Year of Age and Sex for the United States. https://www.census.gov/data/tables/time-series/demo/popest/2010s-national-detail.html. Accessed May 29, 2020.
   8. U.S. Preventive Services Task Force (USPSTF). Rockville, MD: U.S. Dept. of Health & Human Services, Agency for Healthcare Research and Quality.
   9. Banegas MP, et al. Medical Care Costs Associated With Cancer in Integrated Delivery Systems. J Natl Compr Canc Netw. 2018;16(4):402-410. doi: 10.6004/jnccn.2017.7065.
   10. Reddy SR, Broder MS, Chang E, et al. Cost of cancer management by stage at diagnosis among Medicare beneficiaries. Curr Med Res Opin. 2022 Aug;38(8):1285-1294.