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Liquid Biopsy Complements Tissue Biopsy In NSCLC Management

Nichole Tucker
Published Online:6:00 PM, Wed July 3, 2019
Ilaria Alborelli, PhD
Ilaria Alborelli, PhD
A new study shows comparability between liquid biopsy and tissue biopsy in both diagnostics and monitoring of non–small cell lung cancer (NSCLC). However, based on the results, liquid biopsies may be preferable to help oncologists make swifter decisions that help manage the disease.

With a cohort of 159 patients with NSCLC, a group of researchers isolated 4 mL plasma from a minimum of 10 mL of blood to obtain cell-free DNA (cfDNA) for molecular profiling. At the time of blood draw, 136 patients were confirmed to have metastatic disease, and 94 patients had concurrent (<1 month interval) tissue and liquid biopsies at the time of diagnosis. With the aid of a next-generation sequencing based cfDNA assay, researchers were able to track the mutational status of 11 genes and 169 cancer-hotspots with liquid biopsy.

During the analysis, 83 out of 94 samples showed the same results after a liquid biopsy as they did after a tissue biopsy, achieving concordance of 88%. Plasma samples had a shorter turnaround time than tissue (P<.0001; n = 113). The original driver mutation was still detectable in plasma for 72% (n= 47) of samples up to 68 months after initial tissue biopsy. Additionally, liquid biopsy allowed the researchers to detect other clinically relevant gene mutations that were not present in tissue. 

From the analysis headed by José Luis Costa, MD of the IPATIMUP in Portugal, presented in a poster at the European Association for Cancer Research Joint Conference on Liquid Biopsies, the researchers concluded that liquid biopsy is beneficial for complementary use with tissue biopsy for detecting mutations in patients with NSCLC and monitoring disease progression. 

Lead study author, Ilaria Alborelli, PhD, of the Institute of Pathology, University Hospital Basel in Switzerland, interviewed with Targeted Oncology to explain the study in full detail and provide an opinion on what further information is required to make the use of liquid biopsy more prominent around the world.

TARGETED ONCOLOGYWhat was the purpose for your study?

Alborelli: Our study is a retrospective study. It was done using the results of 2 molecular pathology institutes—the Institute of Pathology in Basel and the IPATIMUPin Porto. The results of our study come from a routine diagnostic setting. The idea was to assess the clinical performance of the assay that we have used and to compare the liquid biopsy results to the gold standard for molecular profiling of patients with cancer, which currently is tissue biopsy. 

So, while our overall aim is to better understand how to harmonize and fully integrate the results obtained with a liquid biopsy test into the patient’s clinical management and diagnostics scheme, the purpose of our study was to compare liquid biopsy information to the gold standard in terms of providing a comprehensive picture of the molecular status of the tumor.

TARGETED ONCOLOGYWhat are the main findings and conclusions of this study?

Alborelli: Our study was divided into 2 sections. First, we focused on characterizing the concordance between tissue and liquid biopsy at the time of diagnosis. For this, we analyzed samples from 94 patients that had concurrent tissue and liquid biopsy at diagnosis  and we saw a concordance of 88%. Eighty-three out of 94 patients showed exactly the same oncogenic driver mutations in liquid and tissue biopsy. Additionally, in the second section of our study we focused on monitoring the disease from a molecular prospective. To this end, we analyzed 65 patients with NSCLC, mostly advanced stages, and we used liquid biopsy to observe the molecular evolution of the tumor several months after the initial diagnosis with intervening treatment.

Liquid biopsy, in general, is faster than tissue biopsy because the processing and histological characterization that goes into the tissue biopsy timing is not required for blood. We also assessed this in our study, and we had a turnaround time of 6 days for liquid biopsy and 10 days for tissue biopsy—from sample reception to the delivery of the molecular report. So, there was a 4-day median difference in our samples.

TARGETED ONCOLOGYCan you explain the methodology for this study?

Alborelli: We used an assay provided by Thermo Fisher Scientific. It's the Oncomine Lung cfDNA Assay. This assay covers 11 genes, most of which are recommended by molecular testing guidelines. It's a cancer hotspot-based assay and it's what we use in our molecular diagnostic routine. By using 20 ng of cfDNA you can obtain a sensitivity of 0.1% of allelic frequency. So, it allows us to detect mutations at a very low frequency.

TARGETED ONCOLOGYAre there any patient populations or aberrations where you notice a higher or lower concordance, or possibly increased sensitivity for the liquid biopsy?

Alborelli: At diagnosis, even if we observed excellent concordance, we detected additional clinically relevant mutations in 3 patients by using liquid biopsy. Interestingly, in one of these patients, a mutation that was not detected by tissue but only by liquid biopsy was the EGFRT790M resistance mutation. Indeed, this is very valuable information for guiding treatment decisions, particularly regarding which generation of tyrosine kinase inhibitors a clinician should use. 

When liquid biopsy was used for monitoring, we still observedEGFRT790M as the most frequent mutation detected only by liquid biopsy. However, in this case, because of the intervening treatment and time, we rather believe that the mutation appeared in the tumor later on as a mechanism of acquired resistance to therapy. Here liquid biopsy is a recapitulating the tumor evolution and not tumor heterogeneity by itself.

TARGETED ONCOLOGYWere there any issues you found with completing the profiling with the liquid biopsy?

Alborelli: A general problem with the molecular analysis of liquid biopsy is the low abundance of circulating tumor DNA (ctDNA). However, the level of ctDNA depend on the cancer stage. For patients in advanced stages, like most of the people enrolled in this study, we had enough ctDNA for performing our analysis. For patients in early stage you would expect to recover less ctDNA, which would make it more difficult to reach a high sensitivity. We did not encounter this problem in this specific study.

Moreover, this is a study done on routine diagnostic samples; therefore, they are highly heterogeneous samples and also, they are representative of the population of patients that are coming to our molecular pathology centers, which might differ from a prospective study or in different institutions.

TARGETED ONCOLOGY: Are there any plans to open this test up to further genes, such as RET and NTRK?

Alborelli: There is a plan to initiate a prospective study based on these results. It will still be a collaboration between our institute at the University Hospital Basel and the IPATIMUP  of Porto. [In this study] we plan to use a broader assay, called Oncomine Pan-Cancer Cell-Free Assay from Thermo Fisher Scientific, which covers over 50 genes. We plan to again compare liquid biopsy to tissue biopsy molecular results, but in addition we will have radiological imaging data [to monitor] the tumor burden and tumor progression.

TARGETED ONCOLOGY: Are there any next steps with this research?

Alborelli: Yes, we want to add another layer of complexity to our study by linking information received by liquid biopsy to the treatment outcome of the patient. For patients that were monitored over time, we've collected molecular data based on liquid biopsy only, that were used to inform treatment decisions. Most patients found to be positive for EGFRT790M were treated with osimertinib (Tagrisso), based on liquid biopsy results. It is already clinical practice to use results obtained by liquid biopsy regarding EGFRmutational status if a tissue biopsy is not possible or if there isn't enough tissue. Adding treatment outcome data to our study would show that just based on liquid biopsy a patient can be treated and respond to therapy, to address the question of clinical utility of cfDNA analysis.

TARGETED ONCOLOGY: How is liquid biopsy changing the way oncologists diagnose and also manage NSCLC? 

Alborelli: It's difficult to say because I think we need to work on informing more clinicians that it is worth it to use liquid biopsy in a way that is complementary to tissue biopsy. Large prospective clinical studies are needed to prove clinical utility of ctDNA analysis, but there is already evidence in clinical routine. There are several advantages to liquid biopsy, one of which is turnaround time. The sooner you receive information about the indication for treatment of the patient, the better it is. 

In the future, I think it would be a smart idea to perform a liquid biopsy analysis together with tissue biopsy. Liquid biopsy results will arrive first, supporting the physician in considering treatment options earlier and saving days for the patient for starting treatment. The early results can then be confirmed and complemented by tissue analysis. The second major point is that tumor heterogeneity can be missed by tissue biopsy, so if there are different clones in the tumor and different metastatic sites, it is possible they could be missed by a single tissue sampling. In such cases, liquid biopsy could recapitulate tumor heterogeneity better than tissue biopsy. Of course, there are still things we don’t understand, such as the differential shedding of tumor clones DNA in blood. In conclusion, using liquid biopsy in a complementary manner to tissue could provide a more complete picture of what might be going on overall at all tumor sites.

TARGETED ONCOLOGY: What other information is needed to make liquid biopsy more prevalent in the field?

Alborelli: As I mentioned, there is the need for large prospective clinical studies that employ liquid biopsy to convince of the benefit and the accuracy of using this approach. Studies like ours prove the feasibility and advantages of using liquid biopsy in a routine setting with a real distribution of patients and sample types. In such a setting, liquid biopsy can be a very valuable tool in the hands of an experienced oncologist. I believe that talking about liquid biopsy and how the application of liquid biopsy works already now in the clinics is a very big step. The fact that some key agencies are seeking to obtain FDA approval might cause a shift and increase the use of liquid biopsies in diagnostics.

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