Historically, studies of disseminated tumour cells in bone marrow and circulating tumour cells in peripheral blood have provided crucial insights into cancer biology and the metastatic process. More recently, advances in the detection and characterization of circulating tumour DNA (ctDNA) have finally enabled the introduction of liquid biopsy assays into clinical practice. The FDA has already approved several single-gene assays and, more recently, multigene assays to detect genetic alterations in plasma cell-free DNA (cfDNA) for use as companion diagnostics matched to specific molecularly targeted therapies for cancer. These approvals mark a tipping point for the widespread use of liquid biopsy in the clinic, and mostly in patients with advanced-stage cancer. The next frontier for the clinical application of liquid biopsy is likely to be the systemic treatment of patients with 'ctDNA relapse', a term we introduce for ctDNA detection prior to imaging-detected relapse after curative-intent therapy for early stage disease. Cancer screening and diagnosis are other potential future applications. In this Perspective, we discuss key issues and gaps in technology, clinical trial methodologies and logistics for the eventual integration of liquid biopsy into the clinical workflow.

Liquid biopsy enters the clinic - implementation issues and future challenges.

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Clinical Prediction Models

Early detection has the potential to reduce cancer mortality, but an effective screening test must demonstrate asymptomatic cancer detection years before conventional diagnosis in a longitudinal study. In the Taizhou Longitudinal Study (TZL), 123,115 healthy subjects provided plasma samples for long-term storage and were then monitored for cancer occurrence. Here we report the preliminary results of PanSeer, a noninvasive blood test based on circulating tumor DNA methylation, on TZL plasma samples from 605 asymptomatic individuals, 191 of whom were later diagnosed with stomach, esophageal, colorectal, lung or liver cancer within four years of blood draw. We also assay plasma samples from an additional 223 cancer patients, plus 200 primary tumor and normal tissues. We show that PanSeer detects five common types of cancer in 88% (95% CI: 80–93%) of post-diagnosis patients with a specificity of 96% (95% CI: 93–98%), We also demonstrate that PanSeer detects cancer in 95% (95% CI: 89–98%) of asymptomatic individuals who were later diagnosed, though future longitudinal studies are required to confirm this result. These results demonstrate that cancer can be non-invasively detected up to four years before current standard of care. Patients whose disease is diagnosed in its early stages have better outcomes. In this study, the authors develop a non invasive blood test based on circulating tumor DNA methylation that can potentially detect cancer occurrence even in asymptomatic patients.

/pdf/non-invasive-early-detection-of-cancer-four-years-before-1alc02y5ya.pdf

Non-invasive early detection of cancer four years before conventional diagnosis using a blood test.

Over the past 10 years, circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) have received enormous attention as new biomarkers and subjects of translational research. Although both biomarkers are already used in numerous clinical trials, their clinical utility is still under investigation with promising first results. Clinical applications include early cancer detection, improved cancer staging, early detection of relapse, real-time monitoring of therapeutic efficacy, and detection of therapeutic targets and resistance mechanisms. Here, we propose a conceptual framework of CTC and ctDNA assays and point out current challenges of CTC and ctDNA research, which might structure this dynamic field of translational cancer research. SIGNIFICANCE: The analysis of blood for CTCs or cell-free nucleic acids called "liquid biopsy" has opened new avenues for cancer diagnostics, including early detection of tumors, improved risk assessment and staging, as well as early detection of relapse and monitoring of tumor evolution in the context of cancer therapies.

Liquid Biopsy: From Discovery to Clinical Application.

Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set.

Cancer treatments are often more successful when the disease is detected early. We evaluated the feasibility and safety of multi-cancer blood testing coupled with PET-CT imaging to detect cancer in a prospective, interventional study of 10,006 women not previously known to have cancer. Positive blood tests were independently confirmed by a diagnostic PET-CT, which also localized the cancer. Twenty-six cancers were detected by blood testing. Of these, 15 underwent PET-CT imaging and nine (60%) were surgically excised. Twenty-four additional cancers were detected by standard-of-care screening and 46 by neither approach. 1.0% of participants underwent PET-CT imaging based on false positive blood tests, and 0.22% underwent a futile invasive diagnostic procedure. These data demonstrate that multi-cancer blood testing combined with PET-CT can be safely incorporated into routine clinical care, in some cases leading to surgery with intent to cure.

https://science.sciencemag.org/content/sci/early/2020/04/27/science.abb9601.full.pdf

Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention

A growing epidemic of atrial fibrillation (AF) has been predicted, although no data on the AF burden has been reported for the United States since 2010. The objectives of this study were to (1) describe trends in AF incidence, prevalence, and postdiagnosis survival from 2004 to 2016 within a large health-care system and (2) extrapolate observed prevalence rates to the entire US population to estimate the national AF burden. This retrospective cohort study incorporates the patients and electronic medical record of the Geisinger Health System, an integrated health-care delivery system serving central and northeast Pennsylvania. Standardized incidence rates were calculated per 1,000 person-years by calendar year, and point prevalence rates estimated on July 1st of the respective years from 2004 to 2016. Rate ratios were estimated from Poisson regression as the annual relative change over time. A total of 464,363 patients met study inclusion criteria. Age- and sex-adjusted AF incidence rates increased over the study period: 4.7, 5.0, 5.8, and 6.2 in 2004, 2008, 2012, and 2016, respectively (rate ratio 1.03 per year, 95% confidence interval 1.02, 1.03). Age- and sex-adjusted prevalence rates increased consistently over time from 2.7%, 3.0%, 3.4%, to 4.1% in 2004, 2008, 2012, and 2016, respectively. In 2004, an estimated 6.1 million Americans had diagnosed AF, increasing to 6.7, 7.8, and 9.3 million in 2008, 2012, and 2016, respectively. Postdiagnosis survival has not improved in recent years. In conclusion, AF incidence and prevalence have increased steadily since 2004, whereas postdiagnosis survival has not improved.

Temporal Trends in the Incidence, Prevalence, and Survival of Patients With Atrial Fibrillation From 2004 to 2016

BackgroundThough warfarin has historically been the primary oral anticoagulant for stroke prevention in newly diagnosed atrial fibrillation (AF), several new direct oral anticoagulants may be prefe...

Ashley Honushefsky

Papers

Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention

Temporal Trends in the Incidence, Prevalence, and Survival of Patients With Atrial Fibrillation From 2004 to 2016

Clinical Prediction Model for Time in Therapeutic Range While on Warfarin in Newly Diagnosed Atrial Fibrillation.

The Albumin Globulin Ratio in Chronic Heart Failure—Implications for Mortality

A clinical prediction model for time in therapeutic range while on warfarin in newly diagnosed atrial fibrillation