Twists and turns in biomarker exploration

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Dr. Jaffe

And just like that, he delivers a stark reminder that a ride in the biomarker pipeline comes with no guarantee of delivery.

Dr. Jaffe (who has not been involved in the Malmö work) isn’t dismissing either marker, and, in fact, he appeared on the AACC panel led by Dr. Maisel to talk about the underlying biology and physiology of proneurotensin and proenkephalin. He says there are experimental data suggesting there are pathways involving the neurotensin 1 and 2 receptors that could be involved in increased risk for tumor development, since they’re related to regulation of apoptosis and other factors that might facilitate cancer progression. “This might give you an early signal,” says Dr. Jaffe, though it’s not clear whether they might also be implicated in initiation of cancer.

Likewise, Sortilin-1 may be linked to cardiovascular disease through an LDL receptor. “So it has the potential to provide a parsimonious explanation as to why markers like proneurotensin may be of value in cardiovascular disease as well as breast cancer,” Dr. Jaffe says. This receptor also appears to be involved in the egress of fat in the cells, thus possibly tying it into the lipid levels and risk of developing atherosclerosis.

Moreover, he says, the breast cancer link likely has to do with proneurotensin’s origins in the hypothalamus, given the relationship between many neuroendocrine tumors and the pituitary gland.

“Now, all this is pretty speculative,” Dr. Jaffe cautions. “But it has been solidified by the data that came from the Malmö study.”

The proenkephalins do something different, “as best we know,” Dr. Jaffe continues. When opiates are high, the theory goes, they inhibit tumor progression and enhance normal killer cell activity. “If that’s the case, opiates would kill the cells, and improve prognosis, predominantly by inducing apoptosis.” It’s a provocative concept, he says.

Then the clinical utility issue rears its head: If all this is true, might these biomarkers be a good way to screen women? All of them? If not, what subsets?

“One of the tensions that’s going to exist is, How good are these markers? And what do you do about it?” asks Dr. Jaffe. If a neurotensin level is high in an asymptomatic patient, what’s the next step?

Quite possibly, as Dr. Maisel suggests, using proneurotensin and proenkephalin together might confer both high positive predictive value and also high negative predictive value. Should that be the case, says Dr. Jaffe, researchers will be in position to do the studies to answer the question, What now? “Maybe this will turn out to have the accuracy of BRCA,” Dr. Jaffe says. “That predictive accuracy is sufficiently high that people like Angelina Jolie are willing to make a decision based on it. These markers may or may not have that level of precision.”

Assuming the markers move forward toward clinical use, moreover, “There’s going to be a real issue in regard to specificity,” Dr. Jaffe says, reiterating the links to cardiovascular disease and diabetes. “We’ll eventually need to figure out the best way to triage specific elevations into the right bin.”

“I think what you’ve got,” Dr. Jaffe sums up, “are some very interesting hypotheses generating information from the Malmö study that need further exploration.”

Older breast biomarkers are having a new day in the sun as well. Like Atticus Finch, they may be worth fresh consideration even after decades of use, particularly as molecular analysis settles in alongside ER, PR, and HER2.

Dr. Hicks

Dr. Hicks and his colleagues at Rochester have been using the modified Magee equations from the Department of Pathology, University of Pittsburgh Medical Center (http://path.upmc.edu/onlineTools/mageeequations.html), to obtain information that is similar to that provided by the Oncotype DX recurrence score. In a study of 283 cases, they found that information derived from the three new equations (which use traditional markers), combined with standard histopathologic and immunohistochemical variables, closely tracked the information provided by the Oncotype test (Turner BM, et al. Mod Pathol. 2015;28:921–931).

Dr. Hicks and his pathologist colleagues found the results impressive—“It did an amazing job,” he says—and they presented them at a weekly multidisciplinary breast conference devoted to CME and new information. The clinicians in the group thought the results were interesting, he says, but that didn’t mean they wanted to stop using Oncotype DX. They now receive information from the Magee equations prospectively, however, and Dr. Hicks says this has helped his colleagues more carefully select cases for Oncotype testing. “We’ve seen a decrease in the number of cases sent out.”
The IHC4 score is another example of using traditional markers in a relatively fresh way. It looks at ER, PR, HER2, and Ki-67 results to calculate a risk score using weighting factors and an algorithm. Like the Oncotype DX, says Dr. Hicks, it provides prognostic information.

Dr. Hicks also points to the PAM50, a quantitative RT-PCR assay for use on formalin-fixed, paraffin-embedded tissue. It uses a 50-gene set for standardizing the intrinsic subtype classification of breast cancers—luminal A, luminal B, HER2, and basal phenotypes—and provides a risk of recurrence score. There’s growing interest in androgen receptor (which has shown promise in triple-negative breast tumors), too, and in PARP inhibitors, which might bring new focus to BRCA mutations.

But from Dr. Hicks’ perspective, technical innovation has burst ahead of just about everything else. “I see the technology being way ahead of our ability to know how to use it,” says Dr. Hicks. (To that point, Dr. Fleisher notes that within the past several years, methods for measuring CTCs have exploded from about four to 25, though there remains only one FDA-approved method.)

Dr. Hicks notes that medical oncologists typically are a tough sell. When, early on, the Oncotype DX test showed that patients with a high recurrence score had a worse prognosis, the response, initially, was sort of a collective shrug: “So what?” as Dr. Hicks puts it. But when the test showed that patients would benefit from chemotherapy if they had a high recurrence score, but those with a low score would not, enthusiasm for using the test grew. “As soon as it guides their treatment decisions, then they get excited,” Dr. Hicks says. Only at that point, it would seem, will promising markers start making a noise everyone can hear.
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Karen Titus is CAP TODAY contributing editor and co-managing editor.