Reflection on the discovery of carcinoembryonic antigen, prostate-specific antigen, and cancer antigens CA125 and CA19-9.

One of the hottest current areas of research is the discovery and validation of novel biomarkers for many diseases, including cancer. For cancers, the reality is that no new major cancer biomarkers have entered the clinic in the last 30 years. Despite the emergence of highly powerful genomic, proteomic, epigenomic, metabolomic, microarray, and other omic technologies, which have been used intensively for the discovery of novel cancer biomarkers, the yield has been poor. In previous analyses, I pinpointed the possible reasons for such failures, and I proposed remedies for avoiding common and repetitive mistakes (1–4). Other accounts have done the same, including some articles in this issue (5, 6). It is astonishing that some of the most useful cancer biomarkers were discovered in the 1960s [e.g., carcinoembryonic antigen (CEA) and -fetoprotein], the late 1970s [prostate-specific antigen (PSA)], and the early 1980s [cancer antigen 125 (CA125), CA19-9, and some others]. The discoverers of these biomarkers achieved their goals by means of classic analytical techniques, especially the more or less primitive (by today’s standards) immunologic and chromatographic assays, or by taking advantage of the then new monoclonal antibody technology, which originated in 1975. If we compare the technological tools of the 1960s to the 1980s with those we have today and the volumes of data that we can generate in the same time with the new high-throughput technologies, we can conclude that contemporary technologies have not delivered the goods promised in the arena of cancer biomarker discovery, at least to date. We should admire the pioneers of cancer biomarker research, who used more ingenuity and inventiveness and less technology to reach their goals. Every major discovery, such as the 4 representative examples described below, has a story behind it, a group of characters, and, similar to a movie, a script, actors, and a director. Obviously, we could not cite all the unsung heroes (technicians, graduate students, and postdocs) who participated in these discoveries, but we can certainly identify the “directors.” Four of these directors comment on their teams and the environment associated with their discoveries, the impact of these discoveries in clinical care, and their projected future in cancer research. As others have said, we should look to the past for the important lessons we can use to shape the future. I hope these essays on the discovery of 4 major and clinically useful biomarkers will teach us some lessons that can guide us in overcoming the current difficulties with cancer biomarker discovery, and I hope this field will become more fertile in the years to come.