Overlooked and underserved, patients missed for cancer biomarker testing risk worse outcomes

It’s been known for about 20 years that people who have the slow-growing disease chronic lymphocytic leukemia (CLL) and a mutation called 17p deletion do not respond well to chemotherapy and should only be treated with novel targeted agents, said oncologist Jacqueline Barrientos, MD, MS. Since 2018, guidelines from the International Workshop on CLL have recommended laboratory testing for additional biomarkers, such as TP53 mutations and immunoglobulin heavy chain variable (IGHV) status, to help oncologists risk-stratify patients and identify appropriate therapies.

So Barrientos, chief of hematologic malignancies and director of oncology research at Mount Sinai Medical Center in Miami Beach, Fla., said she was surprised to see — in a multisite, 1,462-patient registry she helped create — that biomarker testing occurred in less than one-third of patients, especially as the tests can be run on easy-to-obtain blood samples.

Fluorescence in situ hybridization (FISH) to detect chromosomal abnormalities was performed in just 28% of patients, TP53 mutation testing in 11%, and IGHV mutation testing in 12% (Blood Adv 2023 Sep 12;7(17):4760-4764). What’s worse, a third of patients continued to receive chemoimmunotherapy, including those with del(17p)/TP53 mutation — a high-risk population known to experience poor outcomes with the therapy — which highlights the need for greater awareness of the guidelines among oncologists.

CLL is a heterogeneous disease for which biomarker testing is crucial to pinpointing the right treatment, Barrientos said. “There are people that have no issues when they’re diagnosed, and they can live a long life without the need for therapy, and there are other people whose disease progresses very quickly,” she said. “It’s the same disease. The same cancer. The difference is the prognostic markers that they have, and that’s why we have to do the testing, to help us identify how to optimize their management and their care.”

“Cancer is kind of like playing chess,” Barrientos added. “You are always thinking about your next move, because at some point, the original therapy may stop responding.” Biomarker testing can identify future therapies to use in those cases. Those recommended for CLL besides 17p/TP53 include 13q, trisomy 12 and 11q, according to the International Workshop on Chronic Lymphocytic Leukemia guidelines.

CLL is one of several cancers, along with lung and colorectal cancers, where biomarker testing is underutilized. Lung cancer has seen a surge in biomarkers identified over the past 10–15 years to help direct therapy, said Benjamin Levy, MD, a thoracic medical oncologist and clinical director of medical oncology for the Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital in Washington, D.C. Yet only 45% of patients seen in community oncology practices get next-generation testing, he said.

It started with one or two genes discovered that could affect patient response to therapy, he said. Now, “It just blossomed into multiple genetic alterations that we can now wed to particular targeted therapies … The diagnostic capabilities have been advancing much more quickly than what we can do with the drugs, but the bottom line is this: We now have the capability to do next-generation sequencing to unearth the genomic alterations that are relevant.”

Guidelines from the National Comprehensive Cancer Network (NCCN) recommend testing for 10 genetic mutations: EGFR exon19, EGFR exon 20, HER2 exon 20, KRAS G12C, BRAF V600E, MET exon 14 skipping alteration, ALK fusions, RET fusions, ROS1 fusions and NTRK fusions, along with immunohistochemistry to study PD-L1 and, more recently, HER2 overexpression.

While it seems like all oncologists should be doing this, there have been multiple challenges, said Levy. One is an educational gap. The science evolves so quickly that some oncologists can’t keep up, and not all commercial testing platforms offer the latest next-generation sequencing techniques. Additionally, he said, the tissue collected from a lung or lymph node biopsy is imperfect and may not be substantive enough for study or sending off to a third-party testing company, a problem known as tissue insufficiency. This could result from the collection itself or because a pathologist aiming for correct diagnosis performs too many immunostains, leading to tissue exhaustion.

Some busy physicians order testing and forget to follow up about results, Levy said. Or even when they do, with next generation testing returning results for 500 genes, the reports are too complicated to interpret.

A study Levy co-authored (Oncologist 2015 Oct;20(10): 1175-1181) for oncologists on how to implement evidence-based recommendations for molecular testing for non-small cell lung cancer remains applicable today, he said. First, understand that next-generation sequencing platforms that include both DNA and RNA testing is most important to unearth a particular genetic alteration. Get help from specialists in interpreting reports and appoint a physician champion within a health system to make sure these tests are ordered.

Good communication between the oncologist and pathologist or other staff procuring tissue also holds importance, said Levy, to make sure they use the optimal procedure and sample the best location, as well as ongoing education about testing, and reminders to conduct both tissue and blood-based testing to best detect a genetic target.

“There’s a new biomarker test that comes out every few months now in lung cancer,” he said. “The complexity of this is no doubt a turning point and an inflection point. It’s a testament to the science that we’re getting a lot better and we’re advancing patient care. We’re developing these new drugs that are better tolerated that lead to better outcomes, which are specifically tailored to the patient, but at the same time, it’s confusing.”

Low testing rates for colorectal cancers also contribute to disparities in care, according to one recent report (JAMA Netw Open. 2024;7(7):e2419142). In this retrospective cohort study of 41,061 patients from the National Cancer Database who had metastatic colorectal cancer, just 28.8% underwent recommended biomarker testing for KRAS and 43.7% received testing for microsatellite instability (MSI). Factors associated with a lower likelihood of MSI testing included being age 70–79, receiving treatment at a community cancer program, living in a rural location, living in an area where the percentage of adults with no high school diploma was 17.6% or higher, and receiving treatment at facilities in the East South Central portion of the country including Alabama, Mississippi, Kentucky and Tennessee. Similar patterns were observed for KRAS testing.

Genetic biomarkers such as MSI and alterations in the BRAF and RAS genes have been the mainstay of precision medicine for colorectal cancers, said Arun Nagarajan, MD, senior author of the study and section head of gastrointestinal medical oncology at the Cleveland Clinic Weston Hospital in Florida. KRAS-positive alterations alone are reported to be present in 35–45% of cases. NCCN also recommends looking at biomarker targets such as NRAS, HER2, POLE/POLD1, RET, and NTRK.

“It’s really important to have the biomarker information,” Nagarajan said. “If a patient is microsatellite-unstable or microsatellite-high, you would not use systemic chemotherapy as the backbone, you would start immunotherapy with FDA-approved agents such as pembrolizumab, nivolumab, or ipilimumab.”

Life expectancy also can vary based on biomarkers, he said. “Patients who are MSI-unstable and who don’t have liver metastasis have a much better outcome than patients who have the KRAS mutation and who are MSI-stable. You can really counsel families about their life expectancy, prognosis, and the choice of treatment.”

Additional barriers to testing may stem from Medicare rules or insurance companies declining to pay for next-generation sequencing, Nagarajan said. To cut costs, Nagarajan said that in-house laboratories could test for the following key biomarkers for colorectal cancer: MSI, KRAS, NRAS, HER2 and BRAF. “If you can include these five tests, that solves 99% of all the questions.”

When testing does occur, it is often patient-driven, Nagarajan said. The more educated patients are, and the higher their socioeconomic status, the more likely they are to ask about testing. “It’s the same adage that nobody manages your money like yourself: Nobody manages your health like yourself,” he said.

Patient advocacy groups also are making a difference in pushing for testing. Through COLONTOWN, a community of more than 100 Facebook groups for colorectal cancer patients, individuals share information about biomarkers to test for and clinical trials linked to those biomarkers, Nagarajan said. The CLL Society also pushes biomarker testing, with the motto “Test Before Treat.”

“I think in the future, cancer [treatment] is not going to be [based on] where your cancer is but driven by your mutation,” Barrientos said. “The mutation is what is driving the disease, so you try to attack that mutation with targeted agents.”

Karen Blum is a freelance medical/science writer in Owings Mills, Maryland. +Email: [email protected]