Today and beyond
James Fleck: Anticancerweb 17(01), 2019
Presently, cancer screening is based on the old-fashioned organ-oriented approach. Tumor prevalence, test positive predictive value (PPV) and timing of follow up are used to calculate the number of patients needed to be screened (NNS) to detect a single cancer. The most efficient model is colorectal cancer. The combined use of fecal immunochemical test (FIT) + colonoscopy results in an NNS of 12, leading to a US Preventive Services Task Force (USPSTF) recommendation as category A (high certainty of substantial net benefit). Additionally, only Pap smear for cervical cancer is also classified as USPSTF recommendation category A. The screening for these two malignant tumors reduces both incidence and mortality. Breast cancer mammography screening for women age 50 – 74, and lung cancer screening using low-dose CT for 30+ pack years current smokers age 55 – 80, including those quitting within 15 years, are considered USPSTF recommendations category B (high certainty of moderate net benefit). Although these organ-oriented approach does encompass the three most incident tumors in the world, it is far away from the ideal concept of a universal cancer test.
The lights came on for the first time in July 2015, when JAMA published a preliminary communication of noninvasive prenatal testing (NIPT) and incidental detection of occult maternal malignancy. A NIPT using massively parallel sequencing of cell-free DNA (cfDNA) in maternal plasma, looking for fetal aneuploidy screening in chromosomes 13, 18, 21, X and Y showed a false-positive discordance in 10/3757 patients. A possible biological explanation for the discordance with the normal fetal karyotype was maternal malignancy. Tumor DNA was presumably shed in maternal circulation and depicted by NIPT. A maternal malignant disease was detected in all 10 discordant patients and based on written consent 8/10 patients were further subjected to genome-wide bioinformatic analysis. A translational study has been recently published, detecting abnormal plasma cfDNA in both localized (50%) and metastatic (80%) malignant tumors.
A multi-organ cancer screening (universal cancer test) has being pursued. Breaking a paradigm, it should be performed non-invasively in a single medium, like blood, saliva, urine or breath and should be cost-effective. Published in February 2018 on Science, a multi-analyte blood test called Cancer-SEEK described the detection and localization of eight surgically resectable human cancer types. Using machine-based learning to analyze the data, Cancer-SEEK assessed tumor specific mutations in circulating DNA + eight circulating proteins biomarkers. The test’s sensitivity ranged from 69% to 98%, depending on the tumor type and the specificity was higher than 99%. Despite these interesting preliminary results, the test cannot yet be applied to general population. Major limitations include a wide sensitivity range combined with a gradually decrease in earlier cancer stages, reaching as low as 40% in tumor stage I. This is the most important caveat, since the main benefit of a cancer screening test is normally restricted to early detection. Additional validation using a different dataset should be pursued with prospective randomized trials demonstrating survival benefit. Additionally, epidemiological pitfalls like lead-time bias e length-time bias should be considered.
Cancer heterogeneity and evolutionary changes also restricts a reliable tumor signature. Combining cancer biological knowledge and bioinformatics, a well-designed start up called Grail, located at Menlo Park, California faced the challenge to discover the millions of unique patterns that define cancer. Grail created a universal task-force producing high quality-data and translating it into actionable information for cancer care.
Recently, the Australian Center of Personalised Nanomedicine published in Nature Communications the proposed use of Methylscape as a universal cancer biomarker. The attributed name Methylscape derived after epigenetic reprogramming cancer genome, which creates distinct DNA methylation landscape presented in most cancer types. Differences in DNA solvation and DNA-gold affinity between malignant and normal genomes sustained a colorimetric one-step assay, which can be analyzed in less than 10 minutes. Further efforts in will be necessary to translate this knowledge into clinical setting.
Despite international efforts, we are still wavering between dream and reality, trying to find the monster in Loch Ness water samples.
Paul F. Pinsky: Principles of Cancer Screening, Surg Clin North Am95(5): 953 – 966, 2015
Diana W. Bianchi, Darya Chudova, Amy J. Sehnert, et al: Noninvasive Prenatal Testing and Incidental Detection of Occult Maternal Malignancies, JAMA314(2): 162-169, 2015
Joshua D. Cohen,Lu Li, Yuxuan Wang,Christopher Thoburn, et al: Detection and localization of surgically resectable cancers with a multi-analyte blood test, Science359 (6378): 926 – 930, 2018
Abu Ali Ibn Sina, Laura G. Carrascosa, Ziyu Liang, et al: Epigenetically reprogrammed methylation landscape drives the DNA self-assembly and serves as a universal cancer biomarker, Nature Communications9: 4915- 28, 2018
Photo by Nation Cancer Institute on Unsplash