ABC News Reports Circulating Tumor DNA Has Diagnostic Significance

On the ABC evening news of August 16, 2017, a closing segment described a promising report describing direct detection of early-stage cancers using circulating tumor DNA (also see Phallen, J.; Sausen, M. et. al. Direct detection of early-stage cancers using circulating tumor DNA. Sci. Translat. Med., 2017, 9(403); eaan2415; doi: 10.1126/scitranslmed.aan2.).

Cancer screening of humans is a complex topic requiring patient selection, assay protocols, and patient follow-up over several years. The authors listed in the report are:

• Jillian Phallen¹
• Mark Sausen²
• Vilmos Adleff¹
• Alessandro Leal¹
• Carolyn Hruban¹
• James White¹
• Valsamo Anagnostou¹
• Jacob Fiksel¹
• Stephen Cristiano¹
• Eniko Papp¹ (Present address: Personal Genome Diagnostics, Baltimore, MD)
• Savannah Speir¹
• Thomas Reinert³
• Mai-Britt Worm Orntoft³
• Brian D. Woodward⁴
• Derek Murphy²
• Sonya Parpart-Li²
• David Riley²
• Monica Nesselbush²
• Naomi Sengamalay²
• Andrew Georgiadis²
• Qing Kay Li¹
• Mogens Rørbæk Madsen⁵
• Frank Viborg Mortensen⁶
• Joost Huiskens^7,8
• Cornelis Punt⁸
• Nicole van Grieken⁹
• Remond Fijneman¹⁰
• Gerrit Meijer¹⁰
• Hatim Husain⁴
• Robert B. Scharpf¹
• Luis A. Diaz, Jr.¹ (Present address: Memorial Sloan Kettering Cancer Center, New York, NY)
• Siân Jones²
• Sam Angiuoli²
• Torben Ørntoft³
• Hans Jørgen Nielsen¹¹
• Claus Lindbjerg Andersen³
• Victor E. Velculescu¹

 Affiliations

1. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
2. Personal Genome Diagnostics, Baltimore, MD
3. Department of Molecular Medicine, Aarhus University Hospital, Denmark
4. Division of Hematology and Oncology, Moores Cancer Center, University of California, San Diego
5. Department of Surgery, Herning Regional Hospital, Denmark
6. Department of Surgical Gastroenterology, Aarhus University Hospital, Denmark
7. Department of Surgery, Academic Medical Center, University of Amsterdam, The Netherlands
8. Department of Medical Oncology, Academic Medical Center, University of Amsterdam, The Netherlands
9. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
10. Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
11. Department of Surgical Gastroenterology 360, Hvidovre Hospital, Denmark

Let’s study the claims of the paper as presented in the abstract (my comments are in boldface).

Abstract

Early detection and intervention are likely to be the most effective means for reducing morbidity and mortality of human cancer.

RLS: Early detection is generally accepted as having better outcomes than late-stage discovery.

However, development of methods for noninvasive detection of early-stage tumors has remained a challenge.

RLS: Yes, obtaining early, including presymptomatic, samples is a real difficulty. Technology that facilitates at-home screening would probably help identify presymptomatic patients.

We have developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell-free DNA using massively parallel sequencing.

RLS: Good claim: How does it work? Please see https://en.wikipedia.org/wiki/Massive_parallel_sequencing.

We have used this approach to examine 58 cancer-related genes encompassing 81 kb. Analysis of plasma from 44 healthy individuals identified genomic changes related to clonal hematopoiesis in 16% of asymptomatic individuals but no alterations in driver genes related to solid cancers. Evaluation of 200 patients with colorectal, breast, lung, or ovarian cancer detected somatic mutations in the plasma of 71, 59, 59, and 68%, respectively, of patients with Stage I or II disease.

RLS: This sounds like the protocols can pick up a significant fraction of potential patients, including those who are presymptomatic. Classifying the cancers by location is obsolete. It is more useful to curate the cancers by mutation, not location.

Analyses of mutations in the circulation revealed high concordance with alterations in the tumors of these patients.

RLS: This is a promising claim and certainly merits further study and evaluation.

In patients with colorectal cancers, higher amounts of preoperative circulating tumor DNA were associated with disease recurrence and decreased overall survival.

RLS: I’ve heard similar claims/correlations for several years.

These analyses provide a broadly applicable approach for noninvasive detection of early-stage tumors that may be useful for screening and management of patients with cancer.

RLS: Agreed. This report seems to merit further study.

Conclusion

The original publication will not be freely available until one year after the publication date. However, this is a promising update on an important topic. I expect it will be cited as one of many corroborating reports of the benefits of early detection of genetic mutations.

Robert L. Stevenson, Ph.D., is Editor Emeritus, American Laboratory/Labcompare; e-mail: [email protected].