In Oncology, Advancing Targeted Treatment Starts with Testing

In oncology, we hear a lot about precision medicine and targeted therapies. What do those terms mean?
Precision medicine is a term that has emerged in the last 15 or so years, where diagnosis and treatment decisions are made based on the understanding of the individual patient’s disease at the molecular level.

Precision medicine can start at diagnosis and extend to other characteristics of the disease, and based on that information, we create a more individual, or personalized treatment. This of course doesn’t have to be limited to oncology, although it’s a term used very often in oncology.

In oncology, there are three categories of pharmacological treatments: cytotoxic chemotherapy, immunotherapy, and targeted therapy. Targeted therapy is designed to “target” a specific molecular alteration in the cancer.  

What is a biomarker? How does it support precision medicine approaches in oncology?
In oncology, a biomarker is a way to identify the disease’s intrinsic, biological characteristics. We often use gene mutations as a biomarker to match the appropriate targeted therapy, though a biomarker doesn’t have to be associated with a treatment—it could also be used to understand a patient’s prognosis, or to track response to treatment.  

What is Next Generation Sequencing (NGS)? How is this testing completed?
Next Generation Sequencing is also called massive parallel sequencing. It is named “next generation”, as compared to the traditional, “gene-by-gene” sequencing approach. With new targets being continuously identified, using gene-by-gene sequencing alone is not enough. The power of NGS is that many genes (hundreds to thousands) can be sequenced all at once. Samples can be gathered from tissue biopsy or from the blood, with liquid biopsy.  

What progress has been made in the last 5-10 years in terms of understanding of biomarkers and the ability to identify them?
Since the initial discovery of EGFR mutation being a biomarker in lung cancer to predict response to EGFR inhibitors in 2004^1,2, we continue to discover new targets and develop new targeted therapies. With this progress, most of the oncology community at this time is aware that we need gene panels for genetic testing.  In large academic cancer centers, we are using Next Generation Sequencing as a standard of care. With the growing use of NGS, the testing platforms have been made more user-friendly so that samples can be more easily obtained, and the turnaround time can be shorter (now as little as ten days). As a field—across academic, industry and other partners in oncology—we know this optimization needs to happen for patients, and many stakeholders are making an effort in this area.

The other area we’ve seen progress is in the understanding of co-mutations. If a gene is truly at the source of the cancer, we call that the “driver oncogene.” In most cases for newly diagnosed patients, the tumor will only have one driver oncogene, such as EGFR mutation. However, other co-occurring genomic alterations, or co-mutations, are also biomarkers and impact response and long-term outcomes for patients. We may not have the answers yet as to how to best serve some of these populations—but by discovering the problem first, we can move forward with research. And one day, this may inform new therapies as well.  

How do we see NGS used in clinical practice today? Is this something that most patients diagnosed with cancers such as lung have access to?
I’m fortunate to have all of the testing resources available right within our center for shorter turnaround times. For newly diagnosed non-small cell lung cancers, I routinely do a panel of immunotherapy markers in the tumor and simultaneously perform NGS in the tumor or in the blood. Based on this information, I can identify the most appropriate treatment approach. The uncertainty and waiting time of those first two weeks while testing is coming in can be difficult for patients and family. I explain the response rate and duration of response may be better if we guide potential treatment based on deeper understanding of the tumor.

There has been progress with being able to offer more treatment options. This is good for patient care, but it does not negate the need for genetic testing options. More progress needs to be made to ensure NGS is being performed, and more widely available. The more we understand a given patient’s tumor, the more options we have.

Raising physician awareness of NGS is important, but also awareness for patients. Patients should be empowered to ask their doctor, “did you do the gene testing for my tumor, and what are the results?”  

What progress has there been in the types of testing, and gathering of samples, in recent years?
Both tissue-based testing and blood-based biopsy, also known as liquid biopsy testing, have a role in clinical practice. For patients who have greater tumor burdens, liquid biopsy with a simple blood draw often works well. For tumor burdens where the tumor is shedding less DNA into the blood, tissue samples may be best. Each approach has pros and cons, but the key is to test.  

Your research has taken a particular focus on biomarker analyses. As the body of data grows around biomarkers, what are we learning? How could these findings further impact patient care?
The first area of growth is continued discovery of new driver oncogenes as targets. In recent years, more uncommon targets such as ROS1 alterations, RET fusion, etc. are gaining recognition and we are seeing clinical studies being developed for these targets. I look forward to seeing more driver oncogenes in lung cancers to become actionable.

Additionally, the field is also using biomarkers to identify and better understand co-ocurring genetic mutations and what their contribution is to treatment response or long-term outcomes. There is a growing body of work, including mine and the work of many others, showing that having new mutations at disease progression can render tumor resistance. This could potentially lead to development of novel therapeutic options.  

How does liquid biopsy play a role in biomarker analysis? What are some active areas of research for liquid biopsy?
Integrating liquid biopsy as part of the biomarker analysis is a very exciting area. In some clinical trials, we are enrolling patients based on their liquid biopsy results. I expect to see more targeted therapy trials where liquid biopsy can be used to detect certain mutations, and track patient responses.

Liquid biopsy has matured in detection and logistics, such that this form of testing is a more accessible, less invasive diagnostic tool for patients and providers in clinical practice. Beyond being convenient and safe in the clinic, liquid biopsy also represents an active research area.  With the ability to more easily and frequently test tumor response over time, we have learned that we can also detect methylation changes of tumors and characterize other tumor features using liquid biopsy.

There is a lot more we can continue to learn that can impact patient care and further research.  

Dr. Xiuning Le is Assistant Professor, Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center Houston, Texas, US.

Dr. Le discloses compensated advisory services to EMD Serono, as well as consultant and advisory fees from Eli Lilly, AstraZeneca, and research funds from Eli Lilly, Boehringer Ingelheim, and Spectrum Pharmaceuticals.

References

¹ Paez, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500.
² Lynch, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39.

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