Molecular Testing Chaos: Are We Over-Testing, Under-Testing, or Testing the Wrong Things at the Wrong Time?

In the rapidly evolving landscape of modern oncology, molecular testing has emerged as one of the most powerful tools for personalizing patient care. However, this explosion of data has also created a "molecular testing chaos" that can overwhelm even the most seasoned clinicians. In this episode of Oncology Unfiltered, Melissa Cutrona, Co-Founder and General Manager of i3 Health and Oncology Data Advisor, sits down with Dr. Matthew Hadfield, Oncology Data Advisor Editor in Chief, to discuss whether we are over-testing, under-testing, or simply testing the wrong things at the wrong time. 

This episode is also available as a podcast. Listen here!

Defining the Landscape

When oncologists discuss molecular testing today, they are typically referring to next-generation sequencing (NGS) or whole exome sequencing. These tests examine a tumor’s DNA, RNA, and proteomics to identify specific genetic alterations.

"The landscape of what we can test on a molecular level has exploded in the last decade and a half," Dr. Hadfield explains. "We’ve seen improvements in the panels, the depth of detection, the ability to characterize variant of uncertain significance (VUS) mutations, and understanding whether or not we can drug those." 

He notes that the sheer volume of information can be a double-edged sword: "It is a rapidly evolving field, and there’s a mountain of information that you can receive for a single patient. Using that to make a clinical plan can sometimes be hard in a busy clinic for a lot of oncologists, especially those who are treating multiple different tumor types and have to stay on top of all this."

The Dilemma of Over-Testing

Over-testing in molecular diagnostics often manifests as ordering NGS panels too frequently or using them in contexts where they aren't FDA-approved. One major concern is the generation of non-actionable data. 

"There are all these mutations included in an NGS panel that are oftentimes carrier mutations, meaning that they're just present in the cancer, but they're not causing the cancer or driving the cancer," says Dr. Hadfield. "What do you do with that information? Is it helpful to have that, or is it not?" 

He emphasizes the need for patient-centered medicine when deciding to order these tests: "Are the patients going to incur costs from this testing? Is it going to cause them any type of emotional and mental harm by having this testing done when we may or may not have a clinical decision that's going to be impacted by the results?"

The Persistent Problem of Undertesting

Despite the risks of over-testing, undertesting remains a significant hurdle, particularly in community and rural settings. This is most critical in diseases such as non–small cell lung cancer (NSCLC). "Every single patient with NSCLC should have NGS testing at the time of diagnosis," Dr. Hadfield emphasizes. "Whether that's an actionable mutation panel, meaning that they get tested for the mutations that have drugs available, or a full expanded panel that gives you the whole landscape of genomic and other RNA proteomic information, that's still not happening."

Failing to test can lead to less effective—and potentially more harmful—treatments. "We know that if you have an EGFR mutation and you're treated with an immune checkpoint inhibitor, which would not be the first-line option, the rates of pneumonitis are actually higher. By not discovering that mutation, you may start a potentially less effective treatment that causes more harm." 

Timing and Technology: Tissue vs Liquid Biopsies 

The "chaos" is often a matter of timing. Testing can be done too early, too late, or repeated unnecessarily because previous results are inaccessible. Dr. Hadfield notes that liquid biopsies are helping to bridge this gap, offering a less invasive way to characterize tumors.

"If someone is going to have a biopsy anyway, it would be good to get NGS testing on tissue. But if they’re not, and you want to have that information—if they're starting to progress, but they don't have an area that's easily biopsied—that would be a time where a liquid biopsy may be a less invasive way to get information that's going to help guide your treatment decisions."

Moving Toward Standardization

To bring clarity to the field, Dr. Hadfield suggests that institutional and policy-level changes are necessary to bridge the gap between scientific advancement and clinical practice.

"Just 10 years ago in 2016, molecular testing was much smaller. We were really just coming into the EGFR and BRAF spaces for melanoma and NSCLC, and now there are dozens of these therapies," Dr. Hadfield concludes. "The science and the medicine are getting better for patients, but there is most definitely a big gap in how systems are going to standardize this testing. And I think that’ll be something that happens more and more over the next several years.”

Key Takeaways

• Molecular testing, specifically NGS, has become a cornerstone of oncology, but the rapid expansion of panels and targeted therapies can create a "mountain of information" that is difficult to manage in a busy clinical setting.

• Over-testing often involves collecting data that is not clinically actionable, such as carrier mutations or VUS, which can lead to unnecessary patient costs and emotional distress.

• Under-testing remains a critical issue in certain regions and tumor types; for instance, every patient with NSCLC should receive NGS testing at diagnosis to avoid potentially harmful or less effective treatment paths.

• Liquid biopsies offer a vital, less invasive alternative to traditional tissue biopsies, particularly when a patient is progressing but does not have an easily accessible area for a new tissue sample.

• Effective molecular testing requires a patient-centered approach and shared decision making, ensuring patients understand why a test is being ordered, what the results could mean, and the potential financial implications.

• Standardization of testing practices and better integration of results into electronic medical record (EMR) systems are essential next steps to reduce the current logistical "chaos" in oncology care.

Thank you for watching Oncology Unfiltered. Check out our playlist and stay tuned for next month’s topic, Choosing not to treat: how do you know when the best treatment is no treatment?