Biomarkers for cancer — often reported with great publicity — routinely fail to be of clinical use, a Canadian researcher said.
Despite large investments and investigation by competent researchers, no new major cancer biomarkers have been approved for clinical use in the past quarter-century, according to Eleftherios Diamandis, MD, PhD, of Mount Sinai Hospital in Toronto.
In a commentary published online in the Journal of the National Cancer Institute, Diamandis said that’s because a range of common analytical errors lead to what he called “false discovery,” even when reports undergo detailed peer review and appear in high-profile journals.
“Press releases and news conferences that immediately accompany publication of a high-profile biomarker generate high expectations about the new biomarker,” he wrote, but such a high level of publicity does not usually accompany the failure of studies attempting to validate the original findings.
“Consequently,” Diamandis argued, “the general public receives skewed information about the biomarker.”
To be a useful biomarker for early diagnosis, Diamandis noted, a molecule has to be released in easily detectable amounts by an otherwise asymptomatic tumor. The molecule should also be highly specific for the tissue of origin and a tumor should produce levels that are markedly higher than background.
With a handful of possible exceptions, Diamandis wrote, “very few, if any, molecules have been identified that are expressed only by a cancer tissue but not by the corresponding normal tissue.”
Cancer biomarkers are missing in action despite the availability of “highly sophisticated and powerful technologies” to discover them, as well as large investments, Diamandis wrote, adding that the last biomarker approved by the FDA — in 2009 — was HE4 protein, indicated for monitoring recurrence but not early detection of ovarian cancer.
Indeed, he argued, most cancer biomarkers in clinical use are not suitable for population screening or for early diagnosis.
“Notable exceptions,” he wrote, are human choriogonadotropin for germ cell tumors and gestational trophoblastic disease and α-fetoprotein for hepatocellular and testicular carcinoma.
The lack of such markers is also in contrast with other areas of medicine, where biomarkers such as cardiac troponin for heart attack or serum creatinine for renal function are successfully used in the clinic, Diamandis wrote.
In a series of case studies, he offered examples of highly publicized putative biomarkers that failed.
For example, Diamandis wrote, the 1986 report that proton nuclear magnetic resonance of plasma samples could detect malignant tumors could not be validated, because the original data actually varied with plasma lipid composition rather than cancer.
Plasma lipid composition, in turn, was associated with age, sex, and diet, but the original authors did not control for any of those factors. In a validation study that matched cases and controls by age and sex, there was no ability to distinguish between cancer and no cancer, Diamandis wrote.
The lesson, he wrote, is that patient selection can bias results.
The analysis “makes an incredibly important point,” according to Otis Brawley, MD, chief medical officer of the American Cancer Society and a long-time critic of the overhyping of screening tests.
“The biomarkers listed [in the commentary] have not been successful in screening,” he told MedPage Today in an e-mail.
Even prostate-specific antigen — perhaps the most widely used cancer screening test — remains controversial. It may eventually “prove useful but the jury is still out,” Brawley said.
“I am very worried that doctors and others have overpromised the power of screening and the public expects too much,” Brawley said. That increases medical costs but also “prevents us from asking the right scientific questions that can ultimately improve health,” he said.
The key issue is whether a given test reduces mortality, he added — something that is often forgotten in the early publicity over a new test.
Another problem, he said, is overdiagnosis. “We cure some people who do not need to be cured and this makes our screening appear more successful than it is.”