Dreams can come true: the first steps toward a peripheral blood screening test for the early detection of tumors have been taken
Authors: C. Haferlach, T. Haferlach
Journal: Annals of Oncology (2018)

In this issue, Lenaerts et al. [1.Lenaerts L. Vandenberghe P. Brison N. et al.Genomewide copy number alteration screening of circulating plasma DNA: potential for the detection of incipient tumors.Ann Oncol. 2019; 30: 85-95Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] report on a study testing a novel non-invasive tool for cancer screening using a genomic imbalance profiling based on sequencing of cell-free DNA (cfDNA). Therefore, they carried out whole-genome sequencing on cfDNA extracted from plasma in 1002 people aged 64 years and older. In 3% of participants, chromosomal imbalances were detected. Clinical follow-up analyses confirmed the presence of five hematological malignancies. Furthermore, one monoclonal B-cell lymphocytosis (MBL) was identified. From their data, Lenaerts et al. conclude that genomewide profiling of cfDNA in apparently healthy individuals has the potential as an unbiased screening approach for hematological malignancies and premalignant conditions. In 1997, cfDNA was identified as a plasma analyte when Y chromosomal ‘fetal’ DNA was extracted and amplified from the blood of pregnant women carrying male fetuses [2.Lo Y.M. Corbetta N. Chamberlain P.F. et al.Presence of fetal DNA in maternal plasma and serum.Lancet. 1997; 350: 485-487Abstract Full Text Full Text PDF PubMed Scopus (2336) Google Scholar]. This was the starting point of a success story of modern genomic medicine leading to non-invasive prenatal testing, allowing genomewide detection of fetal chromosomal imbalances, which was reviewed recently by Bianchi and Chiu [3.Bianchi D.W. Chiu RWK. Sequencing of circulating cell-free DNA during pregnancy.N Engl J Med. 2018; 379: 464-473Crossref PubMed Scopus (172) Google Scholar]. Several groups incidentally detected copy number alterations in cfDNA that could not be attributed to the maternal or fetal genomic constitution. Clinical work-up led to the diagnosis of several different types of cancer in so far asymptomatic pregnant women [4.Bianchi D.W. Chudova D. Sehnert A.J. et al.Noninvasive prenatal testing and incidental detection of occult maternal malignancies.JAMA. 2015; 314: 162-169Crossref PubMed Scopus (280) Google Scholar, 5.Amant F. Verheecke M. Wlodarska I. et al.Presymptomatic identification of cancers in pregnant women during noninvasive prenatal testing.JAMA Oncol. 2015; 1: 814-819Crossref PubMed Scopus (147) Google Scholar]. These observations prompted researchers in all fields of oncology to evaluate the power of this technique for the genetic characterization of malignancies based on cfDNA omitting tumor biopsies and thus called ‘liquid biopsy’. In this setting, cfDNA is often referred to as circulating tumor DNA (ctDNA). In addition to copy number alterations, structural variants and single nucleotide variants can also be evaluated. As clinical use of analytical tests to assess genomic variants in ctDNA is increasing, an expert panel from ASCO and the College of American Pathologists conducted a literature review on the use of ctDNA assays for solid tumors in 2018, including pre-analytical variables, analytical validity, interpretation and reporting, and clinical validity and utility [6.Merker J.D. Oxnard G.R. Compton C. et al.Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review.J Clin Oncol. 2018; 36: 1631-1641Crossref PubMed Scopus (527) Google Scholar]. The conclusions at that timepoint were that only some ctDNA assays have demonstrated clinical validity and utility in certain types of advanced cancer. In some studies, discordance was noticed between the results of ctDNA assays and genotyping tumor specimens, which was mainly due to lower sensitivity of ctDNA analyses. The authors found no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection. In addition, no evidence for the usefulness of ctDNA assays for cancer screening outside of a clinical trial was noticed. However, the experts stated that given the rapid pace of research, re-evaluation of the literature will shortly be required. The data published by Lenaerts et al. [1.Lenaerts L. Vandenberghe P. Brison N. et al.Genomewide copy number alteration screening of circulating plasma DNA: potential for the detection of incipient tumors.Ann Oncol. 2019; 30: 85-95Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] in this issue suggest that a re-evaluation will be necessary soon. Just recently the application of cfDNA analysis to cancer treatment has been reviewed, covering its potential in molecular profiling at diagnosis, tracking of molecular response, and monitoring of resistance and tumor heterogeneity [7.Corcoran R.B. Chabner BA. Application of cell-free DNA analysis to cancer treatment.N Engl J Med. 2018; 379: 1754-1765Crossref PubMed Scopus (422) Google Scholar]. Also the topic of early cancer detection was covered. While technical progress has been achieved and studies in various settings and tumor entities have been carried out, still numerous hurdles have to be overcome. One of these is the fact that the transition between natural aging and malignant tumors is fluent. For colon cancer, the sequence from normal tissue to invasive, metastatic colon cancer and its genetic basis has been described many years ago [8.Vogelstein B. Fearon E.R. Hamilton S.R. et al.Genetic alterations during colorectal-tumor development.N Engl J Med. 1988; 319: 525-532Crossref PubMed Scopus (5898) Google Scholar]. In hematology, the transition from monoclonal gammopathy of unknown significance (MGUS) to smoldering multiple myeloma and multiple myeloma is also well established and the risks for transition from one step to the next over time have been estimated [9.Dhodapkar MV. MGUS to myeloma: a mysterious gammopathy of underexplored significance.Blood. 2016; 128: 2599-2606Crossref PubMed Scopus (88) Google Scholar, 10.Kyle R.A. Remstein E.D. Therneau T.M. et al.Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma.N Engl J Med. 2007; 356: 2582-2590Crossref PubMed Scopus (630) Google Scholar]. The same holds true for low-count MBL, high-count MBL, and chronic lymphocytic leukemia [11.Shanafelt T.D. Ghia P. Lanasa M.C. et al.Monoclonal B-cell lymphocytosis (MBL): biology, natural history and clinical management.Leukemia. 2010; 24: 512-520Crossref PubMed Scopus (176) Google Scholar] . The most recent sequence described starts with normal hematopoiesis to age-related clonal hematopoiesis to clonal hematopoiesis of indeterminate potential to clonal cytopenia of undetermined significance to low-risk myelodysplastic syndrome to high-risk myelodysplastic syndrome and to acute myeloid leukemia [12.Steensma D.P. Bejar R. Jaiswal S. et al.Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes.Blood. 2015; 126: 9-16Crossref PubMed Scopus (1102) Google Scholar, 13.Bejar R. CHIP, ICUS, CCUS and other four-letter words.Leukemia. 2017; 31: 1869-1871Crossref PubMed Scopus (56) Google Scholar]. Along this line based on the pattern of mutations and variant allele frequencies, the risk for progression from cytopenia to a myeloid malignancy has been estimated [14.Malcovati L. Gallì A. Travaglino E. et al.Clinical significance of somatic mutation in unexplained blood cytopenia.Blood. 2017; 129: 3371-3378Crossref PubMed Scopus (283) Google Scholar]. Two recently published studies lay the foundation for the development of a predictor for acute myeloid leukemia [15.Desai P. Mencia-Trinchant N. Savenkov O. et al.Somatic mutations precede acute myeloid leukemia years before diagnosis.Nat Med. 2018; 24: 1015-1023Crossref PubMed Scopus (307) Google Scholar, 16.Abelson S. Collord G. Ng S.W.K. et al.Prediction of acute myeloid leukaemia risk in healthy individuals.Nature. 2018; 559: 400-404Crossref PubMed Scopus (426) Google Scholar]. They demonstrated the presence of detectable mutations years before diagnosis and developed a predictive model. Thus, data on risk of progression are accumulating. Another challenge is to determine the optimal time to start intervention, which could range from intensive monitoring to start of treatment. From a biological view, it is likely that outcome can be improved if treatment starts earlier; however, this has to be proven. The decision when to start treatment has to take into account the risk of progression toward a malignancy during lifetime of the patient, available treatment options and their side-effects as well as symptoms, comorbidities, and patients wish. The more well-tolerated drugs are available the earlier treatment may be started. In Island, a screening study for MGUS has been initiated. This is the first prospective randomized clinical trial with the aim of evaluating the impact of screening and the best follow-up strategy for MGUS to reduce mortality from multiple myeloma (MM) (https://clinicaltrials.gov/ct2/show/NCT03327597). In a previous trial, it was demonstrated that patients with MM with prior knowledge of MGUS had better MM survival, suggesting that earlier treatment of MM leads to better survival [17.Sigurdardottir E.E. Turesson I. Lund S.H. et al.The role of diagnosis and clinical follow-up of monoclonal gammopathy of undetermined significance on survival in multiple myeloma.JAMA Oncol. 2015; 1: 168-174Crossref PubMed Scopus (78) Google Scholar]. Interestingly, a recent cohort study, including 2003 MGUS patients with diabetes mellitus, found that those who were on metformin (for diabetes mellitus) had a significantly lower risk of MM transformation than non-metformin users [18.Chang S.H. Luo S. O'Brian K.K. et al.Association between metformin use and transformation of monoclonal gammopathy of undetermined significance to multiple myeloma in U.S. veterans with diabetes mellitus: a population-based cohort study.Lancet Haematol. 2015; 2: e30-e36Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar]. The early detection of malignancies using a blood sample and the prevention of cancer by detecting premalignant states was always a dream of oncologists, which might come true step by step in the next years. The study of Lenaerts et al. [1.Lenaerts L. Vandenberghe P. Brison N. et al.Genomewide copy number alteration screening of circulating plasma DNA: potential for the detection of incipient tumors.Ann Oncol. 2019; 30: 85-95Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] is one step of many further steps to be taken. Weighing the balance between the benefits and harms of screening is essential for decision making and could be guided by suggested criteria [19.Wilson J.M. Jungner YG. Principles and practice of mass screening for disease.Bol Oficina Sanit Panam. 1968; 65: 281-393PubMed Google Scholar]. Let us continue along this path and take the next step! None declared.