Early detection may allow for better patient outcomes by finding cancer in patients at an early stage. For example, the US Preventive Services Task Force (USPSTF) has found that screening for colorectal cancer in patients aged 50–75 reduces mortality. Diagnosis is useful for selecting an appropriate therapy in a cancer patient who is exhibiting symptoms and may yield benefits in selecting a more effective product and avoiding less effective ones. Finally, monitoring diagnostics are beneficial in detecting changes in disease progression, such as recurrence from minimal residual disease.

*As of November 19, 2020

Challenges to Overcome for Liquid Biopsy Adoption

Clinical

Of the 3 opportunities for use, liquid biopsy for cancer diagnosis is the most advanced.  For companion diagnostic tests, Food & Drug Administration (FDA) approval is necessary on a 1-to-1 basis, meaning that the diagnostic receives approval for use with a specific therapeutic (although the FDA has proposed to update this paradigm, allowing diagnostics to be approved for a class of drugs). This can be a barrier, because other tests that find the same mutations may not be utilized if not included in the therapeutics’ FDA label.

Liquid biopsies also offer the ability for earlier detection, which can provide better options and outcomes. It is necessary, however, that the makers of the diagnostic tests prove not only that the tests work but also that they have clinical utility.  Currently, providers may have concerns about the sensitivity of liquid biopsies, which can lead to misdiagnosis caused by low levels of circulating genetic material. Additionally, specificity is a concern as these results may lead to false positives and patients being treated unnecessarily. Finally, even if a test is shown to be able to detect cancer early with a high enough degree of sensitivity and specificity to make providers comfortable, the question of how will it impact the treatment of the patient and how it improves outcomes remains.

Liquid biopsies are less invasive than solid tumor biopsies and can be used when solid tissue is inaccessible or otherwise insufficient. Because they are less invasive, liquid biopsies can be used for repeat sampling/longitudinal monitoring for disease progression as well as cancer recurrence.  But similar to early detection, these tests need to prove both adequate levels of sensitivity and specificity and need to show that they complement or improve upon other testing modalities such at PET-CT scans.

Operational

The addition of liquid biopsy into tumor biomarker guidelines for cancer diagnosis is still evolving, and a wide gap exists in how consistently these guidelines are integrated across the workflows of different oncology practices. While many physicians and laboratories follow disease-specific guidelines such as those published by the National Comprehensive Cancer Network, ordering is not always integrated into electronic health records, and physicians may differ in their implementation of test timing or specific analytes to be assayed based on internal guidelines. The COVID public health emergency has further impacted screening, diagnosing, and treating cancer patients.  While the pandemic continues to play out, liquid biopsy testing may provide a convenient option over a more invasive tissue biopsy.

As liquid biopsy providers move upstream into the patient journey and look to launch tests for early detection, additional operational challenges need to be addressed. For example, earlier detection means a shift in the setting of care, where a primary physician rather than an oncologist would likely be prescribing the tests, based either on age or on a patient’s risk profile.  Patients who are asymptomatic may be resistant to taking such a test out of skepticism concerning the accuracy of the test, a belief that they do not have cancer, or a fear of the results and their implications both medically and financially. Even if a physician is willing to prescribe, their patient may be unwilling to take the test. As liquid biopsy test providers launch their early cancer detection tests into these new settings of care, they will need to consider elements such as patient education and support services and whether holistic care coordination including genetic counseling is available.

For longitudinal applications to monitor treatment efficacy, minimum residual disease, and cancer recurrence, liquid biopsy is well positioned to complement existing modalities. Like cancer diagnosis, however, these tests—when they become available—will need to be integrated into workflows and will be material change for how oncologists follow up with a patient. Education and support services will be critical to change established habits and drive adoption.

Coverage

Ensuring coverage of this new technology can be challenging in the current landscape of diagnostics coverage. In the preventive setting, commercial coverage is largely determined by whether products have an A or B rating from the USPSTF. In these cases, coverage is mandated by the Affordable Care Act.  Broadly, diagnostics do not require FDA approval to be covered by payers but in most cases are required to be performed in Clinical Laboratory Improvement Amendments certified labs.

Payers make decisions about companion diagnostic coverage for diagnosis based not only on a high level of sensitivity and specificity (i.e., a low false negative/false positive rate), which is the basis of FDA approval, but also on a demonstration that test results can provide new information to a healthcare provider that will impact the course of patient care (i.e., clinical utility). For example, a payer may cover a companion diagnostic test that may tell an oncologist whether a particular drug is more likely to work on a patient with a specific genotypic result. Beyond utility, diagnostics manufacturers generally should demonstrate that their tests can improve outcomes, whether those outcomes are clinical (e.g., earlier detection decreasing mortality) or economic (e.g., avoidance of less effective therapeutics). Liquid biopsies are currently covered for the most part in cases of solid tissue insufficiency, but future coverage may allow for primary blood or serum sampling and avoid more invasive sampling.

Current coverage for longitudinal testing for disease progression is limited due to perceived low clinical utility. However, translational science is leading toward utility of longitudinal testing in certain cases (such as T790M testing in the EGFR gene). Multiple liquid biopsy tests are now FDA approved and otherwise on market.

Future Considerations

We expect improved coverage and physician use of liquid biopsy for early cancer detection, liquid biopsy for cancer diagnosis, and longitudinal liquid biopsy to monitor disease progression and adjust therapy in a real-time, personalized fashion or to monitor for cancer recurrence. Diagnostic developers and partner pharmaceutical developers will need to ensure that coverage and physician group recommendations (such as those in guidelines, compendia, and pathways) align with the most current evidence state, and they should consider strategies to develop new evidence of utility to address clinical, operational, and coverage barriers.

To learn more about Avalere’s clinical diagnostics work, connect with us.