Developing technology ushers in a new era in precision oncology.

By Lucas Dennis, PhD

Precision medicine has revolutionized the diagnosis and treatment of cancer over the past decade. Before the advent of genomic testing, most cancer patients were treated according to the stage, location, and grade of their cancer,1 but with recent advancements in genetics, next generation sequencing (NGS), and bioinformatics, precision medicine can now refine the classification of disease into many subtypes.2

Tumor tissue biopsy is the current standard for diagnostic testing and to determine the histology of the tumor. Today, this standard is accompanied by a deeper look into the mutational profile of the primary tumor, which can be used to help identify the most appropriate approved targeted therapies for patients, specific for their mutations. In some cases, physicians have the ability to use fresh biopsy samples for genomic profiling to generate insights from tumors—these results can then be used for treatment decision-making and, if the patient qualifies, enrollment in a clinical trial.1

However, performing tissue biopsies for genomic testing can pose challenges. Tissue samples are not always available for molecular analysis, due to inaccessibility during surgery, lack of viable tumor specimen after surgery, or the patient being too sick to undergo the procedure.3 For example, up to 30% of patients with non-small cell lung cancer (NSCLC) have insufficient tissue for tissue-based genomic profiling.4

Therefore, alternative testing methods are necessary to ensure that as many eligible patients as possible have access to genomic testing. Taken from a standard blood draw, liquid biopsy can be a realistic alternative to provide doctors with genomic insights when patients do not have adequate tissue for standard biomarker testing.5 Liquid biopsy analyzes circulating tumor DNA (ctDNA) within the blood,6 and its minimally invasive nature makes it increasingly practical for patients who may not otherwise have been able to have their tumors profiled for known mutations. In cases where tissue is not easy to obtain, liquid biopsy can often present oncologists with the same insights as a tumor biopsy if there is enough ctDNA circulating in the blood.7

And even when there is ample tissue available, a tumor biopsy provides a snapshot of the genomic profile of the patient’s tumor only at the time of the biopsy—because of acquired mutations that can develop during treatment, a single biopsy will not accurately reflect the tumor’s mutational profile as it changes over time. Tumors generally consist of dissimilar subclones (tumor heterogeneity), which may lead to different mutational profiles between the primary tumor and its metastases or between sequential tumor sample analysis.8 This genomic profile difference between the primary and metastatic tumor, and within the primary tumor over time, underscores the need for serial gene profiling in order to accurately understand the overall tumor molecular landscape.6,9 

Because blood samples are easy to collect, liquid biopsy is a strong candidate to meet this need for repeated longitudinal analysis to assess the potential evolution of tumor progression. If relapse occurs during treatment, liquid biopsy can shed light on discontinuing a targeted therapy or provide rationale for reassessing another targeted therapy, and it can present clinical data that may be used to inform future clinical trials designed to circumvent resistance mechanisms.1 

These factors highlight the significance of liquid biopsy as a genomic testing tool. Nonetheless, it is important to consider the needs of an individual patient to determine whether tissue or liquid biopsy is the best option. Liquid biopsy should not just be considered an alternative to tissue biopsy, but rather a beneficial complement, with these two testing methods supporting or expanding on the results of one another.

Newly Approved Tests 

Because ctDNA that can be found in a cancer patient’s blood is generally present in minute quantities of highly fragmented tumor-derived DNA, it has been historically difficult to analyze. In recent years, technological advancements10 have significantly improved the sensitivity and specificity of ctDNA detection, and liquid biopsy is now a practical approach for inquiry into tumor diagnosis. 

These advancements led the FDA in 2020 to approve two comprehensive genomic profiling (CGP) liquid biopsy tests for use in supporting doctors with their treatment decision-making. Guardant360 CDx from Guardant Health was approved in August and was followed by Foundation Medicine’s FoundatonOne CDx later that month (see sidebar “Liquid Biopsy Tests Now Available”). The rigorous review and validation done by the FDA on the path to approving these tests underscores their value in clinical practice. 

FoundationOne Liquid CDx is an NGS-based in vitro blood-based diagnostic test that detects mutations across more than 300 genes from tiny amounts of ctCNA using a standard blood draw (needing only two 8.5 mL fractions of anticoagulated peripheral whole blood).11 Results are reported less than 2 weeks after sample receipt. Importantly, FoundationOne Liquid CDx analyzes guideline-recommended genes in solid tumors, including companion diagnostic indications with a direct path to multiple FDA-approved targeted therapies.11 

FoundationOne Liquid CDx is approved as a companion diagnostic for seven targeted therapies across metastatic castration-resistant prostate cancer (mCRPC), non-small cell lung cancer, ovarian cancer, and breast cancer.

Next Generation Sequencing 

CGP is important because it can look at a multitude of potentially relevant mutations, not only those most common for a particular cancer type. It uses NGS, a high-throughput sequencing method that can detect multiple genes and mutations within the same sample.12 NGS detects genomic alterations across a broader panel of genes compared to single-gene or “hot spot” testing. Single biomarker testing may miss relevant mutations outside of the single gene tested, while hot spot testing may miss relevant mutations outside the commonly altered areas of a class of genes tested.13 The breadth of information that NGS can provide supports the ability of both tissue and liquid platforms for complementary comprehensive genomic profiling for all solid tumors. 

Although some mutations are associated with certain cancer types, such as EGFR, BRAF, and ALK in NSCLC, the process of testing for those individual genes can require much more tissue and exhaustive clinical processing time. While these mutations can be infrequent, targeted treatment can be quite dramatic for patients identified to have tumors with these mutations and certain genetic rearrangements.2 FoundationOne Liquid CDx can be used as a companion diagnostic to identify patients who may benefit from treatment with tyrosine kinase inhibitors (TKIs) against EGFR and ALK mutations in NSCLC, with PARP inhibitors against BRCA1/2 alterations in prostate cancer and BRCA1/2 mutations in ovarian cancer, and with PI3K inhibitors for PIK3CA mutations in breast cancer.11 

The application of liquid biopsy has also been amply demonstrated in the literature, with several investigations demonstrating that EGFR gene mutations detected in ctDNA are highly concordant with those detected in tumor tissue of NSCLC patients. EGFR mutation status overall and subtypes including exon 19 deletions, L858R point mutation, and T790M point mutations show high overall agreement between the diagnostic ability of the two testing methods.15,16,17 

With the high specificity of tests like FoundationOne Liquid CDx, the likelihood of incorrectly identifying an alteration using ctDNA testing is extremely low. Liquid biopsy thus provides the same high-quality insights as tissue biopsy, offering oncologists two testing options to guide treatment decisions using deep molecular insights from each individual patient. Bringing this level of reliable genomic information into clinical care ensures that every patient benefits from breakthrough advancements that can change the way their cancer is treated. 

It should be noted that a negative result from a plasma specimen when using FoundationOne Liquid CDx does not mean that a patient’s tumor is negative for genomic findings. For patients whose test detects no companion diagnostic alterations, tissue biopsy should be reconsidered, if feasible.11 Reviews of clinical studies including patients with NSCLC have found that liquid biopsy can have a sensitivity of approximately 70% to 90% or greater depending on the study.14 Observations of moderate sensitivity from liquid biopsies can often be explained by the abundance of ctDNA available for testing, which may be affected by the state of the tumor. Tumor size, tumor burden, and the presence of lymph node metastasis may lead to false negatives due to a lower abundance of ctDNA mutations.18.19 While a reflex to tissue biopsy is thus recommended in the case of a negative liquid biopsy result, liquid biopsy has been shown to be a reliable option that can act as a beneficial and rational complementary test to existing tissue-based genomic testing. 

Cancer Testing in a Pandemic  

The advent of liquid biopsy comes at a critical time for the cancer treatment paradigm, which has been severely impacted by the covid-19 pandemic. Cancer patients are generally immunocompromised and therefore are at a higher risk than most of contracting infections, which negatively impacts patients seeking diagnostic procedures and/or clinic visits essential for cancer diagnosis.20 The number of patients diagnosed with newly identified cancer has decreased for several cancer types during the pandemic, suggesting a delay in diagnosis due to covid-19.21 As a minimally invasive test, liquid biopsy could potentially be implemented in settings outside the hospital or clinic setting, such as via  home phlebotomy services.21 

Having FDA-approved liquid biopsies presents decision-making stakeholders with another high-quality tool to consider when charting a treatment path for patients. The flexibility of liquid biopsy as a complementary genomic tool has the potential to positively impact immediate diagnostic care and cancer treatment decisions, ultimately improving clinical outcomes. 

Lucas M. Dennis, PhD, Foundation Medicine.

Although precision oncology is only beginning to be realized, it is undergoing a transformation, with liquid biopsy presenting a testing option to address several unmet needs of cancer patients today. With unique properties that may complement, and in some cases overcome, the challenges faced by tissue biopsy, liquid biopsy is now poised as a contemporary genomic testing method that can potentially push the boundaries of precision oncology even further. Coupled with the rapid pace of FDA approvals of companion diagnostics and targeted cancer treatments, the outlook for precision oncology is continuing to morph treatment options for cancer patients from a blunt hammer to a high-resolution molecular scalpel. l

Lucas M. Dennis, PhD,  is vice president of franchise development at Foundation Medicine, Cambridge, Mass. Prior to joining Foundation Medicine in 2018, Dennis spent more than 9 years in the biotech industry focused on developing products to enable academic and translational research. He has authored or co-authored numerous peer-reviewed publications in several distinct areas of biology and is named on multiple US patents or patent applications. Dennis received a Bachelor of Science in Biochemistry and Molecular Biology from Ursinus College and a PhD in Biology from Massachusetts Institute of Technology.

References 

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