Molecular Residual Disease Detected Up to Two Years Prior to Clinical Relapse, with Zero False Positives

SAN CARLOS, California, April 16, 2019 /PRNewswire/ -- Natera, Inc. (NASDAQ: NTRA), Cancer Research UK, Imperial College London and the University of Leicester, today announced the publication of results of a clinical study demonstrating that the Signatera™ research-use-only (RUO) molecular residual disease (MRD) assay detected disease relapse up to two years earlier than imaging in patients with early-stage breast cancer.¹ The new publication validates clinical performance of Signatera for recurrence monitoring and MRD assessment in breast cancer. The results were published online today in the latest issue of Clinical Cancer Research.

The prospective national study funded by Cancer Research UK evaluated 49 patients with early-stage breast cancer from three National Health Service (NHS) trusts in the UK (Imperial College Healthcare, the Christie Foundation, and University Hospitals of Leicester), who had recently completed treatment with surgery and adjuvant chemotherapy. The study included a cross section of breast cancer subtypes including HER2-positive, hormone receptor-positive, and triple-negative. Plasma samples were collected every six months for up to four years from each patient. A total of 208 plasma samples were then analyzed using Signatera (RUO), and results were correlated with radiographic imaging and clinical outcomes.

In the study, Signatera (RUO) detected 16 of 18 (89 percent) relapses, with a median lead time 8.9 months earlier than the current standard of care. Among 31 patients that did not relapse, Signatera reported zero false positives across 156 plasma samples tested, with an overall specificity of 100 percent. In the study, this translates to a positive predictive value of 100 percent.

The study concludes that early recurrence detection with Signatera (RUO) may provide a critical window of opportunity for additional therapeutic intervention. Furthermore, tumor analysis showed that one third (33 percent) of all patients had no actionable hotspot mutations, indicating the validity of Signatera's personalized, tumor-informed approach to circulating tumor DNA (ctDNA) monitoring.

"The study showed that Signatera is an effective tool for the early detection of breast cancer recurrence, which occurs in up to 30 percent of certain patient groups," said Alexey Aleshin, M.D., M.B.A., Natera's Oncology Medical Director. "With imaging and serum-based biomarkers alone, recurrence is often caught late after patients become symptomatic. We now have an accurate tool for detecting molecular recurrence and hope this will accelerate future research into evaluating whether treatment can be delivered earlier."

"Standard technologies for the detection of cancer recurrence have always been imprecise," said R Charles Coombes, Professor of Medical Oncology at Imperial College. "With this innovative method of detecting minimal residual breast cancer, we now have the opportunity to conduct trials of treatments to prevent patients relapsing with symptomatic metastatic breast cancer."

Breast cancer is the second leading cause of cancer death in women.² Approximately 250,000 women are diagnosed with invasive breast cancer every year in the United States,² and it is estimated that 2 million cases are diagnosed worldwide.³ While the overall survival rate for breast cancer has improved, recurrence is an ongoing problem with five-year recurrence rates estimated to be as high as 30 percent.^4,5

The study, titled Personalized Detection of Circulating Tumor DNA Antedates Breast Cancer Metastatic Recurrence, can be found here.

About Signatera™
Signatera is the first circulating tumor DNA (ctDNA) test custom-built for molecular treatment monitoring and molecular residual disease (MRD) assessment. The test is available for research use only (RUO) until its clinical launch planned for Q2 2019. The Signatera methodology differs from currently available liquid biopsy tests, which test for a fixed panel of therapeutically relevant genes. Signatera provides each individual with a customized blood test tailored to match the clonal mutations found in that individual's tumor tissue. This maximizes accuracy for detecting the presence or absence of MRD in a blood sample, even at levels down to a single mutant molecule in a tube of blood. Signatera also allows researchers to track additional mutations of interest, up to several hundred mutations, for clinical studies.

The body of evidence on the utility of Signatera is growing.

• A 2017 study demonstrated the Signatera (RUO) method's ability to detect MRD, measure treatment response, and identify recurrence up to 11 months earlier than the standard of care for early stage non-small-cell lung cancer with 93 percent sensitivity and zero false positives.⁶
• I-SPY 2 study results presented at the 2018 San Antonio Breast Conference demonstrated Signatera (RUO) as able to predict neoadjuvant treatment response and clinical outcomes (p<0.001) based on ctDNA positive/negative status in a cross-section of breast cancer patients, including those who were HER-2 positive, hormone receptor-positive, and triple negative. Failure to clear ctDNA after neoadjuvant treatment correlated with poor clinical outcomes. ctDNA levels were also associated with tumor burden as determined by imaging (p<0.01).⁷
• Data presented at the European Society for Medical Oncology 2018 Congress showed successful results from bladder and colorectal cancer studies, including median detection points of MRD that were 3.3 and 7.9 months, respectively, ahead of clinical relapse detection.^8,9

Based on numerous studies across multiple cancer types, a positive Signatera (RUO) result without further treatment has predicted clinical relapse over 98 percent of the time.^1,6-9

Natera will also offer a research-use-only service for plasma-based whole exome sequencing, to create a personalized assay when tissue is not available, or reflexively for Signatera ctDNA positive cases, to characterize resistance mutations, actionable mutations, neoantigens, and tumor evolution. The service will interrogate approximately 20,000 genes from ctDNA to detect somatic mutations, representing a significant increase in coverage over most commercially available fixed liquid biopsy panels. If ordered as a combined service, researchers can first use Signatera to monitor patients for the presence or absence of ctDNA, and for positive patients they can reflex to a plasma exome to characterize tumor evolution using the same exact DNA library sample. Natera expects the service to become available in the second half of 2019.

About Natera
Natera is a global leader in cell-free DNA testing. The mission of the company is to change the management of disease worldwide. Natera operates an ISO 13485-certified and CAP-accredited laboratory certified under the Clinical Laboratory Improvement Amendments (CLIA) in San Carlos, Calif. It offers a host of proprietary genetic testing services to inform physicians who care for pregnant women, researchers in cancer including bio pharmaceutical companies, and genetic laboratories through its cloud-based software platform. For more information, visit natera.com. Follow Natera on LinkedIn.

About Cancer Research UK

• Cancer Research UK is the world's leading cancer charity dedicated to saving lives through research.
• Cancer Research UK's pioneering work into the prevention, diagnosis and treatment of cancer has helped save millions of lives.
• Cancer Research UK receives no government funding for its life-saving research. Every step it makes towards beating cancer relies on vital donations from the public.
• Cancer Research UK has been at the heart of the progress that has already seen survival in the UK double in the last forty years.
• Today, 2 in 4 people survive their cancer for at least 10 years. Cancer Research UK's ambition is to accelerate progress so that by 2034, 3 in 4 people will survive their cancer for at least 10 years.
• Cancer Research UK supports research into all aspects of cancer through the work of over 4,000 scientists, doctors and nurses.
• Together with its partners and supporters, Cancer Research UK's vision is to bring forward the day when all cancers are cured.
• Cancer Research UK has extensive expertise in drug discovery and development as established through the charity's Therapeutic Discovery Laboratories and Centre for Drug Development. The organisation also has access to large scale clinical trial capabilities through the Experimental Cancer Medicine Centre (ECMC) network.

About Imperial College London
Imperial College London is one of the world's leading universities. The College's 16,000 students and 8,000 staff are expanding the frontiers of knowledge in science, medicine, engineering and business, and translating their discoveries into benefits for society. Founded in 1907, Imperial builds on a distinguished past—having pioneered penicillin, holography and fibre optics—to shape the future. Imperial researchers work across disciplines to improve health and wellbeing, understand the natural world, engineer novel solutions and lead the data revolution. This blend of academic excellence and its real-world application feeds into Imperial's exceptional learning environment, where students participate in research to push the limits of their degrees. Imperial collaborates widely to achieve greater impact. It works with the NHS to improve healthcare in West London, is a leading partner in research and education within the European Union and is the UK's number one research collaborator with China. Imperial has nine London campuses. Learn more at www.imperial.ac.uk.   

About the University of Leicester
The University of Leicester is led by discovery and innovation—an international centre for excellence renowned for research, teaching, and broadening access to higher education. It is among the top 25 universities in the Times Higher Education REF Research Power rankings with, 75 percent of research adjudged to be internationally excellent with wide-ranging impacts on society, health, culture, and the environment. Learn more at https://le.ac.uk/about.

Forward-Looking Statements
All statements other than statements of historical facts contained in this press release are forward-looking statements and are not a representation that Natera's plans, estimates, or expectations will be achieved. These forward-looking statements represent Natera's expectations as of the date of this press release, and Natera disclaims any obligation to update the forward-looking statements. These forward-looking statements are subject to known and unknown risks and uncertainties that may cause actual results to differ materially, including with respect to our efforts to develop and commercialize new product offerings, our ability to successfully increase demand for and grow revenues for our product offerings, our collaborations with commercial partners such as medical institutions, contract laboratories, laboratory partners, and other third parties, whether the results of clinical studies will support the use of our product offerings, including our Signatera offering for breast cancer, our expectations of the reliability, accuracy and performance of our screening tests, which may be different in research and clinical practice as compared to in the results of studies – such as the ability of Signatera to detect disease relapse earlier than current standards in patients with early-stage breast cancer, as described in this study, or of the benefits of our screening tests and product offerings to patients, providers and payers. Additional risks and uncertainties are discussed in greater detail in "Risk Factors" in Natera's recent filings on Forms 10-K and 10-Q and in other filings Natera makes with the SEC from time to time. These documents are available at www.natera.com/investors and www.sec.gov.

This test was developed by Natera, Inc. a laboratory certified under the Clinical Laboratory Improvement Amendments (CLIA). This test has not been cleared or approved by the U.S. Food and Drug Administration (FDA). Although FDA does not currently clear or approve laboratory-developed tests in the U.S., certification of the laboratory is required under CLIA to ensure the quality and validity of the tests.

Natera Contacts
Investor Relations: Mike Brophy, CFO, Natera, Inc., 650-249-9090
Media: Andrea Sampson, Sullivan & Sampson, 714-374-6174, asampson@sullivanpr.com

References

1. Coombes RC, Page K, Salari R, et al. Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence. Clin Cancer Res 2019.
2. American Cancer Society. About Breast Cancer, 2017. https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html. Accessed April 14, 2019
3. World Cancer Research Fund. American Institute for Cancer Research. https://www.wcrf.org/dietandcancer/cancer-trends/breast-cancer-statistics. Accessed April 14, 2019.
4. Brewster AM, Hortobagyi GN, Broglio KR, et al. Residual risk of breast cancer recurrence 5 years after adjuvant therapy. J Natl Cancer Inst 2008; 100:1179.
5. Dent R, Trudeau M, Pritchard K, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007; 13: 4429-4434.
6. Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017; 545(7655):446–451.
7. Magbanua M, Brown-Swigart L, Hirst G, et al. Personalized serial circulating tumor DNA (ctDNA) analysis in high-risk early stage breast cancer patients to monitor and predict response to neoadjuvant therapy and outcome in the I-SPY 2 TRIAL. Data presented at spotlight session: San Antonio Breast Conference Symposium; December 5, 2018. Abstract 1259.
8. Birkenkamp-Demtröder K, Christensen E, Sethi H, et al. Sequencing of Plasma cfDNA from Patients with Locally Advanced Bladder Cancer for Surveillance and Therapeutic Efficacy Monitoring. Poster presented at: European Society for Medical Oncology Annual Congress; October 20, 2018; Munich, Germany. Abstract 86P.
9. Reinert T, Henriksen TV, Rasmussen MH, et al. Serial Circulating Tumor DNA Analysis for Detection of Residual Disease, Assessment of Adjuvant Therapy Efficacy and for Early Recurrence Detection in Colorectal Cancer. Poster presented at: European Society for Medical Oncology Annual Congress; October 21, 2018; Munich, Germany. Abstract 456PD.

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