Biomarker Development Is Key to the Future of Precision Oncology

Stanley R. Hamilton, MD

No one doubts that molecular testing has rapidly improved care for patients with colorectal cancer (CRC), Stanley R. Hamilton, MD, told his audience at the 2nd Annual International Congress on Oncology Pathology, which was hosted by Physicians’ Education Resource® in New York.

Results from germline and somatic testing assays are contributing important information and are also moving into the areas of surveillance and prevention, providing further benefits to patients and their families. But the development of biomarkers to test for is key to predict tumor behavior and to guide the use of targeted therapies and immunotherapy.

“The collaboration between us and the laboratory and our clinical colleagues who use our tests has never been more important. These assays have various characteristics to them in terms of sensitivity, specificity, and performance characteristics, and those will vary depending on what the use of them is going to be in the patient population, so it’s important that we talk to each other,” said Hamilton, a gastrointestinal and molecular pathologist, and professor and head of pathology and laboratory medicine at The University of Texas MD Anderson Cancer Center.

“We are going to need to figure out a way to make sense of the testing that comes back and understand what the association of this is going to be with drugs in the signaling pathway to affect the tumor cells themselves,” he added.

Biomarkers, Hamilton said, are vital in the development of individualized, precision oncology, helping clinicians deliver care that is more effective, less toxic, and less expensive. Hamilton led his audience through an overview of the current use of biomarker data in CRC, how that use doesn’t always adhere to best practices recommended in the clinical guidelines, and how the slow pace of writing those guidelines could hamper the growth of biomarkers.

A Bad Biomarker Is as Bad as a Bad Drug

Biomarkers seem to have their greatest impact in predicting response to therapy. However, Hamilton borrowed a quote from Daniel F. Hayes, MD, a medical oncologist at the University of Michigan, saying, “The markers have to perform as well as the drugs for the precision medicine component to go forward.”

“In terms of what we’re going to do with these markers, it becomes a fit-for-purpose issue,” Hamilton added. “We have to be sure that the markers we’re going to use are related to what we’re trying to find out about patients, and how we’re going to look at them.”

The rate of deaths from CRC has fallen over recent years, due in large part to improved screening. However, more than 40% of the population doesn’t get screened, which Hamilton attributed to the nature of the testing. Examining molecular characteristics by venipuncture or fecal collection can make screening easier and more attractive than a colonoscopy with anesthesia.

Hamilton said that pathologists and oncologists have known for years that testing for microsatellite instability (MSI) status is essential because some MSI-high CRC patients can avoid adjuvant therapy with fluorouracil (5-FU) monotherapy. Now practitioners recognize that 5-FU with oxaliplatin can work in that setting and is particularly useful for older patients who need to minimize therapy to avoid complications.

“Furthermore, now we recognize with clinical trials that the checkpoint inhibitors work very well in the setting of microsatellite instability—that’s probably the best marker we’ve got for that at the moment,” he added. “As a result, this is a triple threat of why we should be doing immunohistochemistry and/or molecular testing for microsatellite instability status in all patients with colorectal cancer.”

Hamilton said that, at present, the application of tumor genomics and how they work with the currently available therapies is the main focus in the diagnosis, classification, prognosis, and prediction of CRC. Using liquid biopsies, which may offer much higher sensitivity and specificity than what is currently available with diagnostic imaging procedures, oncologists and pathologists may soon be able to move from the radiographic monitoring of patients for the development of recurrence or for response or resistance to therapy.

Current practice, on the other hand, “is a terrific example of [how] what it looks like we ought to be doing and what we are are miles apart,” Hamilton said.

Hamilton cited Biomarker Tests for Molecularly Targeted Therapies: Key to Unlocking Precision Medicine, an evidence-based guideline developed by the National Academies of Sciences, as a “primer” on biomarker test development.¹The monograph identifies useful biomarkers and how to use them well, a key element to using biomarkers that often gets overlooked.

“The quality of what we do with biomarkers is extremely important because if they don’t function well, we’re not doing patients any good with those markers,” Hamilton said.

Discovery Moves Faster Than Publishing

Hamilton was part of a team that that published a guideline on using molecular biomarkers in CRC last year; it included investigators with the American Society of Clinical Oncology, the American Society for Clinical Pathology, the College of American Pathologists, and the Association for Molecular Pathology.²A great amount of effort went into drafting the guidelines, but Hamilton said that, ultimately, they were too narrow in scope. He cited the use of panitumumab (Vectibix) and cetuximab (Erbitux) as examples.

“The first statement was related to anti-EGFR therapy because the panitumumab/cetuximab therapies at the time were receiving a great deal of attention relative to resistance in the presence of KRAS testing and was recognized in extended RAS. [But] it wasn’t just KRAS at codons 12 and 13; it also needed to have NRAS and broader expanse of the genes looked at,” said Hamilton.

Hamilton now suggests extended RAS and BRAF mutation testing in patients being considered for anti-EGFR therapy.

He added that sometimes testing methodologies do not adhere to the latest and strongest evidence. He pointed to a widely available immunohistochemistry test for the BRAF V600E mutation that works well in melanoma and thyroid cancer but is ineffective in CRC.

“It’s got about a 10% to 15% inaccuracy rate in colon cancer and this has not been widely recognized,” he said. “We as pathologists would far rather do an immunohistochemistry overnight than having to send a specimen [to the] lab and wait for days for it to come back. [However,] that testing [in CRC] is not sufficient for clinical use, as has been published in several papers.”

Hamilton noted that the pace of clinical trials moves faster than guideline development. The guidelines he helped draft in 2017 took 2 years to write and included recommendations that were obsolete before the paper was published. As a result, clinical practice can change long before the guidelines catch up, and clinicians may not be aware of the most recent developments. Moreover, payers use those guidelines when deciding which procedures to cover.

“Even though the clinicians are out there at ASCO and come back from the sessions that show that a particular set of biomarkers is useful, when we submit the bill to third-party payers, it gets rejected,” he said. “This is a major issue in trying to move biomarkers forward, not just in colorectal cancer but across the whole environment for how biomarkers are going to be used in precision medicine.”

References:

1. National Academies of Sciences, Engineering, and Medicine. Biomarker Tests for Molecularly Targeted Therapies: Key to Unlocking Precision Medicine. Washington, DC: The National Academies Press; 2016. doi: 10.17226/21860.
2. Sepulveda AR, Hamilton SR, Allegra CJ, et al. Molecular biomarkers for the evaluation of colorectal cancer: guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology. J Clin Oncol. 2017;35(13):1453-1486. doi: 10.1200/JCO.2016.71.9807.