By Pierre P. Massion, MD
Posted: October 2018
Early detection is key to disease management. For example, there are numerous data in hypertension, diabetes, coronary artery disease, and renal dysfunction showing strong correlation between early diagnosis and improved outcome.1 Noninvasive means of early detection of cancer is around the corner.2-4 Recent research has positioned the detection of genetic alterations in the circulating tumor DNA at the forefront of cancer management. Oncologists are already using liquid biopsies in the clinic to monitor disease and to guide personalized cancer care in advanced disease, but it is evident that such strategies can be extended to earlier stages.5-7
The recent paper by Cohen et al.8 addresses the possibility of detecting solid tumors more than 59% of the time at an early stage with a combination of ctDNA and protein biomarkers. The approach proposed by the authors is simple and low in cost, potentially resulting in a stage shift, a significant time savings for diagnosis, and improved patient survival. Although hard outcomes are not yet achieved, this manuscript advances the field.
Liquid Biopsies: Realizing the Potential
CancerSEEK, the blood test reported on by Cohen et al., is a combination of genetic testing and protein chemistry. It uses a combination of genetic variants for cancer-related genes and eight proteins related to cancer diagnosis. Such a mixed platform is both a strength and a challenge for the generalizability of such combinations. Importantly, the authors used protein biomarkers to facilitate the localization of the cancer. The importance of localization addresses the problem of detecting tumors that have similar genetic oncogenic drivers yet originate in different organs. Also, the identification of the underlying tissue of origin may be of greater clinical relevance than initially realized when trying to localize an early, presumed sub-centimeter–sized nodule. Whereas a blood biomarker is not likely to replace the use of standard imaging in the near future, it may better target the imaging and help save cost.
CancerSEEK uses a combination of genetic variants for cancer-related genes and eight proteins related to cancer diagnosis.
CancerSEEK has a sensitivity of 69% to 98% for ovarian, liver, stomach, pancreatic, and esophageal tumors with an outstanding specificity of 99%, while also achieving a less than 1% false-positive rate. The genetic signature provides cancer specificity, but oncogenic drivers are not tissue specific. The protein signature provides reasonable tissue specifi city for localization of the tumor. These are essential goals of a biomarker, which have been achieved for the most part. Sensitivity remains a bigger problem for early-stage disease. The paucity of DNA molecules shed by small tumors and the limit of quantitation of the protein analytes are big challenges to overcome. For the protein biomarker, the signal-to-noise discrimination highly depends on the analytic strength of the method. Detection of single mutations in ctDNA requires a large volume of plasma, which pushes the scientific community to discover other genetic or epigenetic alterations to increase the likelihood of success.
The study design is probably the weakest point of the paper. The biomarker is not tested in the clinical context of its intended use but rather in a casecontrol study. In the journey of biomarker development, this study positions the biomarker in phase two of five phases (from discovery to cancer control). Validation of the performance metrics in independent cohorts and in clinically meaningful settings at multiple institutions, demonstrating the added value to current standards, and ultimately demonstrating a reduction in cancer-related mortality or improved cancer control9 are the most challenging, time-consuming, and costly investigations. The authors interrogated the plasma of a relatively small number of healthy controls without matched controls for inflammatory lesions that could mimic the disease process. With 805 cancers tested and 200 controls, the false-positive rate is probably underestimated, primarily because of the protein component of the assay, where inflammatory disease is known to decrease the specificity.
A given biomarker is unlikely to fit multiple clinical scenarios but should be tested in the context where it is predicted to be most helpful. For example, candidate biomarkers could be tested in patients presenting for evaluation of indeterminate pulmonary nodules of intermediate risk (pretest probability of cancer 15% to 80%) to complement low-dose chest CT screening. Given the exquisite specificity of CancerSEEK and the expected strong positive diagnostic likelihood ratios, the test may offer a high post-test probability of cancer and significantly enhance the patient/ provider management of the nodule. Finally, these noninvasive strategies call for novel biomarker-driven diagnostic trials in which patients are enrolled prospectively in the clinical setting and, based on testing, offered customized diagnostics and therapy. These trials are urgently needed in the early detection of cancer to move strong candidate biomarkers closer to clinical utility. ✦
About the Author: Dr. Massion is Cornelius Vanderbilt Chair in Medicine and Professor of Medicine in the Division of Allergy, Pulmonary, and Critical Care Medicine, and director of the Cancer Early Detection and Prevention Initiative at Vanderbilt Ingram Cancer Center.
1. U.S. Preventative Services Task Force website. uspreventiveservicestaskforce.org. Accessed March 27, 2018.
2. Newman AM, Lovejoy AF, Klass DM, et al. Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol. 2016;34(5):547-555.
3. Phallen J, Sausen M, Adleff V, et al. Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med. 2017;9(403).
4. Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20(5):548-554.
5. Thompson JC, Yee SS, Troxel AB, et al. Detection of Therapeutically Targetable Driver and Resistance Mutations in Lung Cancer Patients by Next-Generation Sequencing of Cell-Free Circulating Tumor DNA. Clin Cancer Res. 2016;22(23):5772-5782.
6. Chaudhuri AA, Chabon JJ, Lovejoy AF, et al. Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profi ling. Cancer Discov. 2017;7(12):1394-1403.
7. Blakely CM, Watkins TBK, Wu W, et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat Genet. 2017;49(12):1693-1704.
8. Cohen JD, Li L, Wang Y, et al. Detection and localization of surgically resectable cancers with a multianalyte blood test. Science. 2018;359(6378):926-930.
9. Pepe MS, Etzioni R, Feng Z, et al. Phases of biomarker development for early detection of cancer. J Natl Cancer Inst. 2001;93(14):1054-1061.