https://orcid.org/0000-0002-4210-1593
Four years ago, Clinical Chemistry published a special issue on molecular diagnostics. The current special issue focuses on cancer and the translation of biological discoveries into clinically useful diagnostics and therapeutic aids. There is a wide world of relevant technologies with potential applications to cancer covered in this special edition. We highlight some exciting developments that will likely impact clinical practice.
Klaus Pantel
Samir Hanash
Cancer Biology
Genomic alterations play an important role in the development and progression of hematological malignancies and solid tumors. They consist of both tumor entity-specific and common genomic aberrations in oncogenes (e.g., KRAS, BRAF) or tumor suppressor genes (e.g., TP53). While progression of hematological malignancies is more driven by genomic changes (1), metastases of solid tumors (e.g., breast cancer) are in many instances the result of adaptive transcriptional changes leading to increased plasticity and selection of tumor cells with stemness properties (2). Tumor cells that metastasize can undergo an epithelial-to-mesenchymal transition that allows them to become mobile and pass through barriers such as the basement membrane or the endothelial vessel wall. Besides the release of circulating tumor cells (CTCs), tumors at the primary site also release extracellular vesicles (EVs) that contain cellular cargo such as DNA, RNAs, and proteins that may be taken up by recipient cells locally or at distant sites after their journey through the blood stream (3, 4). The uptake of EVs can change the biology of the recipient cell and contribute to metastatic progression (e.g., support metastatic niche formation). Both CTCs and EVs are therefore biomarkers with functional properties (5).
Kathleen F. Kerr
David H. Wang
Kathleen H. Burns
Catherine Alix-Panabières
Diagnostics
Peripheral blood is the main biological fluid for the analysis of biomarkers relevant to cancer and other diseases because it can be accessed in a minimally invasive way. Thus, this special issue has a major focus on blood biomarkers; however, other fluids, such as urine for urogenitial cancers or cerebrospinal fluid (CSF) for patients with primary or metastatic brain tumors, are also relevant, although technically more challenging (6). More than 10 years ago, the term “liquid biopsy” (LB) was introduced into cancer diagnostics (7). The early LB was based on CTCs but then rapidly expanded to a multitude of tumor cell products released from viable or apoptotic tumor cells, as well as to immune cells and circulating components of the immune system (e.g., immune cells, cytokines, and interleukins) (8). Tracking tumors by means of LB has been highlighted in the recent Nature Milestones edition as a key discovery of the past 20 years (9). Besides CTCs, analysis of circulating cell-free DNA (cfDNA) has become part of clinical studies as outlined in this issue (10), leading to recommendations for clinical use of ctDNA (11). In addition, other biomarker types such as extracellular vesicles, coding and non-coding RNAs, proteins, and metabolites released into the blood or other body fluids by primary or metastatic tumor lesions contribute to a more comprehensive picture of tumor evolution in cancer patients.
At present, LB is being tested in clinical studies for early detection of primary cancer or disease relapse, monitoring the efficacy of cancer therapies, and determining therapeutic targets and resistance mechanisms to personalize treatment based on the specific needs of individual patients (12).
Population screening for cancer is being pursued with different LB approaches using ctDNA, proteins, microRNAs, or various marker combinations, but the risk of overdiagnosis needs to be considered (13). Screening of high-risk groups may be an intermediate step for the development and refinement of these assays. Polygenetic risk scores could contribute to targeting the right population with the highest need for cancer screening (14).
Another promising application of LB is early detection of minimal residual disease (MRD) and relapse in patients after initial therapy. Early detection would allow new types of “post-adjuvant trials” aimed to intercept overt metastases prior to their development (10). An advanced application of cancer biomarkers, in particular cfDNA (15), is for prediction of therapy response or resistance. Blood protein biomarkers are already being used in clinical practice for monitoring the tumor burden in patients with advanced solid tumors and, as ultrasensitive methods for protein detection are developed, it is anticipated that a host of novel candidate biomarkers will become accessible for applications in cancer detection, risk stratification, and disease monitoring. For many tumor types, the molecular analysis of somatic genomic aberrations in tumor tissue is part of routine pathology examination (e.g., EGFR mutations in lung cancer or KRAS mutations in colorectal cancer). Nevertheless, many metastatic lesions are not easy to biopsy and the information obtained from one accessible lesion may not reflect tumor heterogeneity across sites. Blood-based diagnostics provide a global view of tumor status genetics and have opened a new avenue for personalized medicine. For example, in the context of immune checkpoint inhibitor therapy, the target protein programmed cell death ligand-1 (PD-L1) can be detected on CTCs (16–19) and tumor mutational burden can be assessed based on cfDNA (20, 21) to guide therapy.
Lessons from cancer biology have been translated into the development of diagnostic approaches that have opened new avenues for identifying more cancer patients at earlier, curable stages and for personalized cancer medicine. Harmonization of technologies, including preanalytical and analytic test variables, and assessments of clinical utility of the selected biomarker(s) are important objectives for the upcoming years.
Author Contributions
The corresponding author takes full responsibility that all authors on this publication have met the following required criteria of eligibility for authorship: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Nobody who qualifies for authorship has been omitted from the list.
Klaus Pantel (Conceptualization-Equal, Writing—original draft-Lead, Writing—review & editing-Equal), Samir Hanash (Conceptualization-Equal, Writing—review & editing-Equal), Kathleen Kerr (Conceptualization-Equal, Writing—review & editing-Equal), David Wang (Conceptualization-Equal, Writing—review & editing-Equal), Kathleen Burns (Conceptualization-Equal, Writing—review & editing-Equal), and Catherine Alix-Panabieres (Conceptualization-Equal, Writing—review & editing-Equal).
Authors’ Disclosures or Potential Conflicts of Interest
Upon manuscript submission, all authors completed the author disclosure form.
Research Funding
K. Pantel, support from EU/IMI (grant agreement number 115749) CANCER-ID EFPIA, Personalis. K.H. Burns, grants from Earlier.org, the Minnesota Ovarian Cancer Alliance, Friends of Dana-Farber, and NIH (P30CA006516 and P50CA240243).
Disclosures
K. Pantel, honoraria from NRich, BMS, Agena, Menarini, Novartis, Sanofi, Illumina, Abcam, MSD, Boehringer Ingelheim, and Eppendorf; Associate Editor for Clinical Chemistry, Association for Diagnostics & Laboratory Medicine (ADLM, formerly AACC). S. Hanash, K.F. Kerr, C. Alix-Panabières, guest editors for Clinical Chemistry, ADLM. D.H. Wang, declares institutional funding for participation in clinical trials from BMS, AstraZeneca, Natera, and Mirati; on advisory boards for Novartis, BMS, and Cardinal Health; guest editor for Clinical Chemistry, ADLM. K.H. Burns, Ultrasensitive Assays for Detection of ORF1p in Biofluids, patent filed in the United States Patent and Trademark Office on November 8, 2022, as application 63/423,696; relationships with Alamar Biosciences, Calico Labs, Genscript, Oncolinea/PrimeFour Therapeutics, ROME Therapeutics, Scaffold Therapeutics, Tessera Therapeutics, and Transposon Therapeutics; guest editor for Clinical Chemistry, ADLM.
