GSJ Interview
Liquid Biopsy May Help Guide Treatment Decisions for Advanced Solid Tumors

Blood Test Offers a Non-Invasive Alternative
to Tissue Biopsy

A study presented at one of the recent ASCO Scientific Symposia highlights the potential of liquid biopsy to help guide treatment decisions. The fact that genomic mutations vary not only from patient to patient, but also change over time has been a constant challenge in cancer treatment, especially in he precision medicine era, according to Sumanta Kumar Pal, MD, ASCO expert in developmental therapeutics. “Having a good, reliable option beyond a tumor biopsy could have a major impact on our ability to select the right therapy for the right patient. In this interview Philip Mack, PhD, reviews essential information on a blood test that could offer a noninvasive alternative to tissue biopsies. Dr. Mack is Professor and Director of Molecular Pharmacology at the University of California Davis Comprehensive Cancer Center, Sacramento, California. A large-scale genomic analysis has found that patterns of genetic changes detected in blood samples (liquid biopsy) closely mirror those identified in traditional tumor biopsy. With blood samples from more than 15,000 patients and 50 different tumor types, this is one of the largest cancer genomics studies ever conducted.

Q. How would you characterize the overall value and applicability of liquid biopsy?

Dr Mack: Findings suggest that analysis of shed tumor DNA in patient blood, also known as a liquid biopsy, can be a highly informative, minimally-invasive alternative when a tissue biopsy is insufficient for genotyping or cannot be obtained safely. Moreover, this test, known as Guardant360 – a digital next-generation sequencing panel, provides an unparalleled opportunity to monitor changes in the cancer as it evolves over time, which can be critical when patients and physicians are discussing treatment options for continued tumor control.

Q. What are the most widely used applications of liquid biopsy currently?

Dr Mack: The clinical use so far has mostly been in non-small cell lung cancer, but it also has had application in colorectal cancer, breast cancer and other tumor types. There have been additional applications using it to track biological markers.

Q. Do you see a potential application to soft-tissue sarcomas?

Dr Mack: Yes. Since there are molecularly targeted agents being used in this disease, it would have potential value in this setting. Perhaps most importantly, there is a good chance that liquid biopsy can be used to detect emergent resistance mechanisms, that could help assign effective therapies.

Q. What about speculation that liquid biopsy could ultimately replace tissue biopsy? Will tissue biopsy become obsolete?

Dr Mack:  ctDNA results will not necessarily replace tissue biopsy but will be an additional tool. I think there is always going to be a role for tissue-based histology. Tumor biopsy will remain the gold standard, as it yields important information about morphology, tumor type, possible site of origin, and somatic mutations. At least in the foreseeable future, that will always be required. Additionally, in about 15% of patients, no tumor DNA can be detected by the ctDNA test. There are simply tumors that do not shed DNA into the circulation at identifiable levels and tissue biopsy will be required to genotype those tumors. More likely, liquid biopsy will be used when tissue is of insufficient quality or quantity to allow a broader array of testing. Probably, the biggest benefit of plasma analysis is its convenient serial collection of samples over time. As the cancer continues to spread and the patients are progressing on therapies, their tumors are evolving, and we will need rapid, convenient ways to monitor genetic changes in those cancers.

Q. Can you further delineate the role of liquid biopsy in terms of identifying the genetic changes in a tumor as well as other related advantages that clinicians need to be aware of?

Dr Mack: A liquid biopsy can be used periodically to monitor disease progression, response to therapy, and development of treatment resistance. If a repeat test suggests that the cancer is progressing or becoming resistant to treatment, physicians can modify the treatment plan. Periodic liquid biopsy, which requires a simple blood draw, may be preferable to repeat tissue biopsy in terms of patient safety and convenience. In addition, because genetic changes in ctDNA often occur before signs of tumor growth are apparent on a scan, liquid biopsy can help doctors adjust treatment sooner.

Liquid biopsy has another important advantage over tissue biopsy. The genetic changes that drive tumor growth often differ in different parts of the tumor. Because tissue biopsy removes only small pieces of the tumor, key mutations can be missed, depending on what area of the tumor is sampled. Analysis of ctDNA provides information on all the different genetic changes that may be present in the tumor. Detection of tumor-specific mutations in a blood draw is an attractive alternative when tissue biopsies are not feasible. It is easy to do in any clinic and avoids biopsy-related complications. The ctDNA assay also facilitates disease monitoring and can potentially identify mutations in metastatic lesions and treatment-induced resistant mutations not observed in the original, archival tumor biopsy.

Q. Please discuss some of the findings from a large study in which liquid biopsy was used. You reported on this at last year’s sessions of the American Society of Clinical Oncology.

Dr Mack: This study included 15,191 patients with advanced lung cancer (37%), breast cancer (14%), colorectal cancer (10%), and other cancers (39%). Each patient provided one or more blood samples for analysis of ctDNA. This study assessed the accuracy of liquid biopsies, as compared to tumor samples, in two ways. First, it compared the patterns of genomic changes in ctDNA to those found in 398 patients with available results of genetic testing of the tumor tissue. When ctDNA was positive for key abnormalities in EGFR, BRAF, KRAS, ALK, RET, and ROS1 that drive tumor growth, the same mutations were reported in tissue 94-100% of the time.

Q. How do you know that liquid biopsy provides an accurate snapshot of the tumor?

Dr Mack: The study also assessed consistency in the distribution and frequencies of specific changes in ctDNA against previously published data from genomic analyses of tumor tissue, including data from The Cancer Genome Atlas. The studies showed highly significant concordance between the ctDNA and the published data. The findings suggest that liquid biopsy provides an accurate snapshot of the genomic landscape of the tumor.

Across multiple cancer genes and different classes of alterations, correlations typically ranged from 0.92-0.99. However, one general exception was found in which ctDNA findings were often not seen in tumor biopsies: detection of new genomic alterations associated with resistance to targeted cancer drugs, such as the EGFR T790M resistance mutations in patients on EGFR inhibitor therapy. The study hypothesized that these alterations would be absent in the tissue-based population data because those patients had yet to receive treatment.

In summary, the results of the assay were compared with publicly available, population-scale tumor-sequencing data, most notably from The Cancer Genome Atlas. We found that ctDNA mutation patterns were highly consistent with distribution in tumor tissue by the [The Cancer Genome Atlas]. This was seen with commonly altered tumor suppressors and oncogenes alike. In the cancer genes we evaluated, we saw the exact same hot-spot and activating mutations as observed in The Cancer Genome Atlas and other publications, at very similar frequencies. Furthermore, we identified additional mutations associated with emergent resistant mechanisms that are not normally present at the time of initial biopsy.

Most of the ctDNA alterations were found at very low levels, with half occurring at a frequency below 0.4% of the total DNA in the circulation. Anecdotally, alterations observed at ctDNA fractions as low as 0.06% responded to treatment, which highlights the importance of assay sensitivity.

Q. What are the next steps in determining the value of circulating DNA testing?

Dr Mack: The next step for researchers is to work to increase the sensitivity of the Guardant360 assay to detect mutations at an extremely low ctDNA level, which is necessary for some tumors and will also enable its use in earlier-stage cancers. In about 15% of patients, no tumor DNA could be detected by the ctDNA test. There are simply tumors that do not shed DNA into the circulation at detectable levels, so we are bound to miss them. More importantly, we need to perform rigorous clinical testing of digital next-generation sequencing approaches to prove they can predict patient benefit from targeted treatment as well as-or perhaps better than-repeat tissue biopsies. This class of technologies has earned the right to be validated in the clinical trial setting. GSJ



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