“It is possible that within the next several years, perhaps 75% of cancers can be detected by screening,” Bert Vogelstein, MD, PhD, projected at the Society of Surgical Oncology (SSO) 2021 International Conference on Surgical Cancer Care.1 “I anticipate that perhaps 50% of cancers can be detected by liquid biopsies of one sort or another and 25% by conventional methods like colonoscopy or mammography,” he added. Liquid biopsies would be “additives, not replacements, for techniques that are as good as mammography or colonoscopy,” Dr. Vogelstein noted. “I don’t think at present it will be feasible to detect 100% while preserving adequate specificity, but I think a reasonable, albeit ambitious, goal would be 75%.”
Dr. Vogelstein made these comments while delivering the James Ewing Lecture, the SSO’s highest award, given to a physician whose work has had a major impact on surgical oncology. “I have a particular affinity for surgical oncology because I believe surgery remains the best way to treat cancers,” he commented. Dr. Vogelstein is Clayton Professor of Oncology and Pathology and Co-Director of the Ludwig Center at Johns Hopkins Medical School and Sidney Kimmel Comprehensive Cancer Center, Baltimore.
Bert Vogelstein, MD, PhD
Earlier Diagnostic Tests
“Currently, less than 20% of cancers that occur in the United States are detected via screening,” Dr. Vogelstein noted. Most cancers “are detected only after signs and symptoms develop, which is why so many patients with cancer die.” According to Dr. Vogelstein, to change that around, “we have been looking at blood as a way to detect all solid tumors, or as many as we can, using earlier diagnostic tests,” he said.
One result is the CancerSEEK blood test, which was developed in Dr. Vogelstein’s lab by Joshua D. Cohenan, an MD-PhD student, and colleagues. “It is based on plasma and looks at selected regions of 16 genes and 8 proteins,” Dr. Vogelstein explained. Applied to 1,005 patients with nonmetastatic, clinically detected cancers, as reported in Science,2 “CancerSEEK tests were positive in a median of 70% of the eight cancer types,” and “its specificity was greater than 99%: 7 of 812 healthy controls tested positive.”
Prospective Interventional Study
Dr. Vogelstein shared results from a prospective interventional study by Lennon et al,3 which focused on 10,006 women between the ages of 65 and 75. “There were no exclusions other than a previous cancer. It involved a blood test followed by diagnostic PET-CT to confirm the existence of a cancer and localize it within the body,” he explained. “I believe this was the first time that liquid biopsies had been used in such a formal study.”
The study addressed several questions. The first was whether a multicancer blood test could prospectively detect cancers in individuals whose cancer was not previously detected by other means. “This had not been evaluated previously,” Dr. Vogelstein pointed out. “Virtually all the studies published before were retrospective rather than prospective or interventional. And the answer to this question was yes. There were 26 cancers first detected by the blood test,” including cancers of the lungs, colon, and ovaries.
The second question was whether such a test could be used to intervene in the progressive process, leading to therapy, primarily surgery, with an intent to cure. “Unless the cancers were detected early enough to be treated surgically, it was unlikely these patients would have benefited from the test,” commented Dr. Vogelstein. And the answer to that was also yes. Many of the cancers were excised; although there is not long-term follow-up to know for sure that these patients were cured, “in the follow-up available, they appear to have no recurrence. Based on their stage and other clinical parameters, they had a high likelihood of being cured—not all of them, but a reasonable fraction of them,” he said.
The third question concerned whether such a test would be clinically useful, conferring more benefit than risk to the screened population. “This is the most difficult question and one that we have not yet answered,” Dr. Vogelstein acknowledged. “This test was designed to assess safety and feasibility; it was not designed for clinical utility. A much larger prospective interventional trial will be required to assess that, and such a trial is now in the design stage.”
Cancer Gene Quantification
Liquid biopsies represent an example of how knowledge about the number and nature of cancer genes can be exploited for diagnostic purposes. “The total number of driver genes in the 26 most common cancer types are surprisingly few,” Dr. Vogelstein noted, “about 120 to 200,” with about 60% being tumor-suppressor genes and 40% being oncogenes. Although it is far from fully understood how these driver genes work, “we know enough at least to begin to develop new therapies and diagnostic agents,” he explained.
“Mutation accumulation is not a quick process,” commented Dr. Vogelstein. It requires “three strikes: initiation, expansion, and invasion,” and it “generally takes 10 to 30 years to get from that first mutation that initiates the tumor to the third mutation that is responsible for invasion and the ability of cancers to metastasize. This is extremely important because it means that, if we can intervene in this process anywhere between the first mutation and metastasis, some tumors can be cured by surgery alone.”
Exploiting Knowledge for Therapeutics
“Immunotherapies are some of the most exciting new therapies for cancer,” Dr. Vogelstein said, and the “most successful to date are immune checkpoint inhibitors.” The checkpoint inhibitor pembrolizumab “brought about terrific remissions in patients with melanomas and lung cancers but had virtually no effect in patients with other tumor types.” An international effort was mounted to explain why.
As Dr. Vogelstein noted: “Most cancers have about 50 total coding mutations, of which only a few of them, perhaps 3 or 4, are driver genes. The rest are passengers.” However, lung cancer and melanoma have many more mutations, “on the order of 150 to 200 mutations. The reason they have mutations is because of patients’ exposure to mutagens, sunlight in the case of melanomas and cigarette smoke in the case of lung cancer.”
The more mutations there were, the more mutation-associated neoantigens there would be, the more likely there would be an endogenous immune response against the cancers. And, the more likely it is that you can ‘rev up’ this response with immune checkpoint inhibitors.”
Another tumor type, “mismatch repair–deficient cancers, sometimes referred to as those with microsatellite instability, had even more mutations than lung cancers or melanomas. The average number was in the thousands for mismatch repair–deficient cancers. So, our hypothesis was that patients with mismatch repair–deficient tumors may be even more sensitive to immune checkpoint inhibitors,” Dr. Vogelstein said. The results of a trial “were quite remarkable,” he reported, “and several years later, the U.S. Food and Drug Administration (FDA) approved drugs for mismatch repair–deficient cancers.” The FDA stated: “The approval marks a new paradigm in the development of cancer drugs that are ‘tissue agnostic.’”
The results did not depend on tissue type, and the approval was not just for colon or breast cancer, Dr. Vogelstein pointed out. The approval was “for any cancer, simply on the basis of the genetic alterations that were present, which is, in a sense, the realization of precision medicine or personalized medicine.”
Direct Targeting
According to Dr. Vogelstein, the second type of immunologic approach can be called direct targeting. “This does not rely on the host to have an endogenous immune response. Instead, it directly targets some sort of abnormality in the cancer cell. This second strategy is needed because, unfortunately, the immune checkpoint inhibitors will not induce long-term remissions in most patients with cancers. Perhaps, they can be improved in the future, but we and other groups have been working on alternative strategies.” Dr. Vogelstein cited “classic examples” of this direct targeting approach: antibodies to epidermal growth factor receptor and chimeric antigen receptor T cells against B-cell lymphomas.
“Our basic approach is to develop new antibodies against mutation-associated neoantigens,” Dr. Vogelstein said. “Do we expect these antibodies to cure people? No, I think it is quite clear that people develop resistance to anything we can throw at them,” he admitted. “But, hopefully, if the drugs ever get to the clinic, they will induce remissions that last for some time. Remissions of advanced cancers of course, only last temporarily, unlike surgery of the primary tumors, which can induce true cures.”
DISCLOSURE: Dr. Vogelstein is a founder of Thrive Earlier Detection and Personal Genome Diagnostics and serves as a consultant to Personal Genome Diagnostics, Sysmex, Neophore, CAGE Pharma, and Catalio Capital Management; owns equity in Exact Sciences, Personal Genome Diagnostics, and Catalio Capital Management. The companies named above have licensed technologies invented by Dr. Vogelstein from Johns Hopkins University and some of these technologies are relevant to the work he discussed at the meeting. Licenses to these technologies are or will be associated with equity or royalty payments to Dr. Vogelstein and Johns Hopkins University.
REFERENCES
1. Vogelstein B: Cancer genes and their implications for patients: SSO 2021 International Conference on Surgical Care. James Ewing Lecture. Presented March 18, 2021.
2. Cohen JD, Li L, Wang Y, et al: Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science 359:926-930, 2018.
3. Lennon AM, Buchanan AH, Kinde I, et al: Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention. Science 369:eabb9601, 2020.
