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Histology Agnostic FAQs

CME

Histology-Agnostic Therapies for Solid Tumors: Experts Answer Frequently Asked Questions

Physicians: Maximum of 0.25 AMA PRA Category 1 Credit™

Released: July 31, 2023

Expiration: July 30, 2024

Chul Kim
Chul Kim, MD, MPH
John Marshall
John Marshall, MD
Sapna P. Patel
Sapna P. Patel, MD
Neil H. Segal
Neil H. Segal, MD, PhD
CME/CE Information

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Key Takeaways
  • Liquid biopsy is an option for biomarker testing with the potential to address tumor heterogeneity and may be particularly useful at disease progression, but insurance coverage will vary by region.
  • Care must be taken when reviewing NGS reports and applying the results to treatment decisions, such as taking disease context into consideration.
  • If biomarker testing results show >1 histology-agnostic genomic alteration (eg, an NTRK fusion and a high TMB, or a BRAF V600E mutation and MSI-H), prioritization of targeted therapy or immune checkpoint inhibitor therapy first will depend on the tumor type.

Is it time to start sending tissue biopsies and liquid biopsies simultaneously for biomarker testing to address tumor heterogeneity? Would it be covered by insurance? How do you interpret a conflicting result, where the tissue biopsy report shows one thing and the liquid biopsy report shows another?

John Marshall, MD:
A few things come to mind that may affect whether insurance would cover simultaneous biomarker testing of tissue and blood (so-called “liquid biopsy” containing cell-free DNA from various sources, including circulating-tumor DNA [ctDNA] shed from tumor). The most obvious is that it will depend a lot on where you are. Different regions of the world, even different areas of the United States, approach precision medicine very differently. The type of tumor may also affect whether simultaneous testing would be covered. For example, the setting of lung cancer has been a trendsetter in this regard. That said, biomarker testing is a very fluid space, so coverage issues will continue to evolve.

Chul Kim, MD, MPH:
Although tissue testing is considered the gold standard for diagnosis in non-small-cell lung cancer (NSCLC), liquid biopsy is widely used these days not only at initial diagnosis, but also to track mutation burden and understand mechanisms of resistance to systemic therapy. I have not encountered major issues with obtaining insurance coverage for liquid biopsy testing, whether during the initial diagnosis of advanced NSCLC or at disease progression. However, it is important to note that coverage for liquid biopsy may vary among payers and based on individual patient's insurance details.

In the frontline setting of NSCLC, there are 9 targetable driver mutations that are associated with improved patient outcomes when the corresponding treatment is given, so it is critical that biomarker testing informs choice of first-line therapy for patients with newly diagnosed disease. Data have shown that testing both tissue and blood increases the rate of biomarker detection. When blood is the only option, such as when a tissue biopsy is not feasible or the amount of tissue is inadequate for all the tests we need to do, it is important to keep in mind that testing by liquid biopsy has up to a 30% false-negative rate, so any negative test needs to be followed by testing of a tissue biopsy.

In the academic setting, we almost always send blood for testing in patients whose disease has progressed on frontline targeted therapy. Although we still have a lot to learn, these tests can reveal a resistance mutation that is sensitive to an available targeted therapy. A role for liquid biopsy to detect resistance in real time, as well as to detect PD-L1 in the setting of immunotherapy, is under investigation.

Sapna P. Patel, MD:
There is also the unique situation where you will see a result of low variant allele frequency (VAF) for a particular mutation on a liquid biopsy report, but the corresponding immunohistochemistry or next-generation sequencing (NGS) on tissue biopsy is negative. If the patient in this scenario is receiving therapy, could you be seeing the emergence of resistance in real time? It is certainly possible, especially if the mutation absolutely cannot be traced back to the tumor, but at this point we do not have data suggesting you should change therapy based on this type of observation. We also know that treatment can affect results obtained by liquid biopsy. For example, in the rare cancer uveal melanoma, shedding of ctDNA has been shown to increase both during enucleation and 2 days following curative liver surgery, presumably through perturbation of the tumor microenvironment. 

John Marshall, MD:
There are also examples of treatment resulting in lower ctDNA shedding. Regardless, baseline testing will be important to teasing out the presence of clinical resistance at disease progression.

Is it sufficient to test for microsatellite instability‒high (MSI-H)/mismatch repair deficient (dMMR) status once during the lifetime of a patient with a solid tumor, or is it recommended to repeat this testing at disease progression? In other words, does MSI-H/dMMR status change over time, whether spontaneously or under therapeutic pressure?

Neil H. Segal, MD, PhD:
To my knowledge, MSI-H/dMMR status is stable over time in colorectal cancer where this is a feature of the tumor biology. Thus, there is very limited utility in routine retesting at progression on immunotherapy in these patients. That said, for patients with MSI-H colorectal cancer who receive a PD-1 inhibitor and progress, additional testing may be helpful to look for other mutations that may be targetable with a nonimmunotherapy drug, unless already performed.

How do you apply positive tumor mutational burden (TMB) test results to treatment decisions? Hoes does context affect application of histology-agnostic biomarker testing results to treatment decisions?

John Marshall, MD:
I do not necessarily get excited if TMB is simply positive on an NGS report. For example, if I see a TMB of 11 mutations/Mb, I will at least include it in my chart note, because I do not want to miss a chance for my patient over the course of their treatment. I have much more enthusiasm for a TMB of 30-35 mutations/Mb and may leverage that earlier in the treatment course.

Neil H. Segal, MD, PhD:
For a patient with colon cancer, I would not always give immunotherapy regardless of a high TMB. If the tumor does not also have MSI-H or harbor certain POLE/POLD mutations, a response to immunotherapy is unlikely.

John Marshall, MD:
Yes, response to histology-agnostic targeted therapy or immunotherapy can vary depending on the tumor type. For example, BRAF inhibition is more effective in BRAF V600E mutation–positive melanoma or lung cancer compared with colorectal cancer. Regarding histology-agnostic indications, it will be important to obtain more data on any limitations of these indications across tumor types.

Sapna P. Patel, MD:
There is also the conundrum of companies listing targeted therapies associated with a detected genomic alteration in NGS reports, even when the therapy is not the standard of care for the tumor type being assessed. With patients now having access to these reports, it can put the provider in a bit of a quandary when a patient asks, “Why didn’t you offer me this therapy listed on my testing report?” My typical answer is, “Your insurance will deny it”—but it’s not an easy situation to navigate.

John Marshall, MD:
I am also seeing repercussions of this in clinical practice. I currently am caring for a patient with colon cancer who was given single-agent PARP inhibitor therapy instead of traditional second-line therapy by another provider based on detection of BRCA of variant of uncertain significance (VUS) on a liquid biopsy test. I do not know how they got it approved by insurance, because the VUS designation means we do not even know if that is a real BRCA mutation. That said, I understand the urge to feel obligated to give a patient a therapy you know is associated with a mutation you see on their testing report. However, if the data do not support use of the therapy in the given disease, then it is not the right thing to do. We need to keep in mind that the information in testing reports needs to be evaluated in context, which admittedly can be challenging to keep up with.

If biomarker testing results show >1 agnostic genomic alteration (eg, an NTRK fusion and a high TMB, or a BRAF V600E mutation and MSI-H), would you prioritize targeted therapy or immune checkpoint inhibitor therapy first?

John Marshall, MD:
Because of the nature of microsatellite instability, it is not uncommon to see MSI-H and another genomic alteration with a histology-agnostic indication on the same test report. In the context of gastrointestinal cancers, when I see MSI-H with a BRAF V600E mutation, I start with immunotherapy, because there is a better chance to hit a “home run” for the patient: When immunotherapy really works, it works well. But it is a challenge we face. How about in other cancer types?

Chul Kim, MD, MPH:
In patients with advanced nonsquamous NSCLC, biomarker testing often will show a targetable driver mutation, such as a BRAF V600E mutation indicating the use of dabrafenib plus trametinib, simultaneous to high PD-L1 expression indicating the use of an immune checkpoint inhibitor. However, in lung cancer, we tend to do the opposite—we often sequence the targeted therapy before immunotherapy. While the role of immunotherapy in driver alteration–positive NSCLC is still evolving, this is because there is the potential for a larger benefit to patients with a driver mutation who receive the corresponding targeted therapy. Furthermore, we have to be careful about the risk of severe toxicities that may arise by giving a targeted therapy—such as the EGFR inhibitor osimertinib for EGFR-mutated disease—after immunotherapy. That said, in the absence of a targetable mutation, high PD-L1 expression would absolutely indicate the use of an immune checkpoint inhibitor–based regimen.

Sapna P. Patel, MD:
We also often see a BRAF V600E mutation on reports for highly mutated or neoantigen-driven tumors, such as a cutaneous melanoma with ultraviolet damage. I would ask, when will we no longer be faced with the Sophie’s choice of this or that? I look forward to a time when we figure out how to give every patient all of the treatment options available to them.

For more expert guidance on testing for histology-agnostic biomarkers and the optimal integration of these therapies into the management of your patients with solid tumors, watch this on-demand webcast of the full live symposium or download the associated slidesets developed by our experts.

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