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Status Report

Next-Generation Sequencing in 2017

Nalley, Catlin

doi: 10.1097/01.COT.0000527897.13944.2d
next-generation sequencing; oncology

next-generation sequencing; oncology

NEW YORK CITY—Precision medicine is a rapidly evolving field in cancer treatment and shows no signs of slowing down. Specifically, the role of next-generation sequencing (NGS) continues to gain momentum in oncology practices worldwide.

During a discussion at the Chemotherapy Foundation Symposium, held Nov. 8-10, Ankur R. Parikh, DO, Medical Director of Precision Medicine at Cancer Treatment Centers of America, Philadelphia, offered his insights on this growing sector of cancer treatment and its future impact on the field.

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Understanding NGS

“Upon completion of the Human Genome Project in 2003, there has been a lot of progress in NGS in terms of how many genes and mutations we are testing, as well as overall turnaround time and certainly cost,” Parikh noted. “This has led to a decreased cost per megabase, as well as an increase in number and diversity of sequenced genomes.

“The cost per raw megabase of DNA sequencing, going back to 2003, was very expensive and it has come down significantly over the past 10 years,” he continued, “And how much does it cost to sequence the whole genome? It was very expensive when they were working on the Human Genome Project, but now you can do an NGS test for anywhere from $500 to $5,000 depending on where you are getting your test from.”

NGS is a “high-throughput method used to determine a portion of the nucleotide sequence of an individual's genome,” Parikh noted during his presentation. Additionally, NGS utilizes DNA sequencing technologies that can process multiple DNA sequences in parallel.

The technology is “utilized to assess the unique and complex set of genomic alterations that occur in malignant neoplasms” and can improve patient care through personalized diagnosis as well as prognosis and therapy.

Through the utilization of NGS, oncology researchers and clinicians now have a better understanding of new subtypes of cancers and development of biomarkers, and it has led to the establishment of novel therapeutic targets, according to Parikh.

“The goal of [molecular profiling] is to identify a biomarker that can predict treatment responses and then use these to implement a treatment that is better than just chemotherapy or something in second- or third-line that has less response rates,” he explained. “And then utilizing this and measuring its success.”

The process for NGS testing, according to Parikh, includes a tumor biopsy, which is then sent to a commercial lab unless an institution conducts in-house genomic sequencing. Oncologists will then receive a report and it is up to the treating physician to act on the results. “Additionally, if a patient is treated with a targeted therapy and then relapses, oftentimes they will be re-biopsied to determined what changes, if any, occurred,” he noted.

With multiple clinical platforms available that test anywhere from 20 to more than 500 genes, Parikh acknowledged it could be an overwhelming task. But he emphasized the need to focus on your patient to determine if this is the right course of treatment for them right now. “And ask yourself, ‘What am I going to do with the results and how can they benefit my patient?” he advised. “This makes you more confident when treating your patient.”

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Identifying Patients

So, how do you know NGS is the right option for your patient? While there are no set guidelines on who is the right patient to treat using this technology, Parikh offered a look at the thought process he uses when determining if NGS would benefit his patient.

“My personal approach [focuses on] patients with metastatic cancer who, and this is not an all-inclusive list, are newly diagnosed,” he noted. “I used to lean towards using it in later-line therapy, after a patient has failed multiple lines of treatment, but oftentimes outcomes weren't as good because patients were sicker at that point and had more tumor burden.

“Especially now with the NGS panels, you do get [microsatellite instability (MSI)] and tumor mutational burden, which you may be able to implement earlier in therapy,” Parikh continued. “So, at this point, as long as there are not multiple, viable treatment options for patients, I utilize those who are newly diagnosed. Additionally, I definitely use NGS if a patient has failed first-line therapy, especially if response rates in second-line therapy are very low.”

Other deciding factors that make NGS a suitable option include whether or not a patient has a rare malignancy, if there are no available standard therapies, and evaluation for a clinical trial.

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Benefits of NGS

This technology benefits cancer treatment and patients in a variety of ways.

NGS testing can assist the oncologist in determining if a patient is eligible for a clinical trial. “For example, my institution is involved in the TAPUR trial with ASCO, so that is one opportunity for my patients to get specific medications based on their tumor profile if they failed first-line standard therapy,” noted Parikh.

Additionally, data gathered from this technology can assist in the identification of biomarkers, such MSI status, tumor mutational burden, and PD-1/PD-L1, for immune checkpoint inhibitors.

Another benefit of NGS includes the identification of resistance mutations (i.e., T790M in non-small cell lung cancer). “If you have a patient who is on a targeted therapy and then they relapse, NGS can help determine if they have any acquired mutations in their tumor now,” Parikh suggested.

It is important to note, according to Parikh, that NGS is now incorporated into NCCN guidelines. For instance, beyond the standard recommendations for patients with metastatic non-small cell lung cancer, it is now encouraged to do some type of broad molecular profiling because there could be other effective drugs out there that may be beneficial to these patients who don't necessarily have a driver mutation.

“Down the road, I think we are going to see more solid tumors get something similar incorporated into their testing, and all of this helps in terms of getting insurance approval for these tests,” Parikh said. “A lot of times these companies have patient-assistance programs already. But if a request is denied, it is always nice to have some kind of evidence to support the fact that this is the right thing to do for your patient.”

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Challenges & Successes

Like with any new innovation, there are always hurdles that must be overcome.

“With all of this, there are certainly challenges and limitations,” Parikh acknowledged. This includes a limited understanding of the genome, as well as the complexity of reports and the costs of testing.

Additionally, Parikh noted, other factors contributing to the challenges of NGS may include epigenetic changes, tumor microenvironment, and variants of uncertain significance (VUS). Parikh discussed the issues that arise when a patient who has a mutation linked with a certain treatment does not show the expected response rate.

“This puts pressure on us to keep that in mind because, if down the road that does become a relevant gene/mutation, you have to know that and react to it because you aren't always necessarily going to get that update immediately.”

Parikh noted four critical success factors for molecular profiling: 1) evidence must be clinically validated; 2) the report should be easy to understand; 3) the analysis requires the highest quality standards; and 4) the interpretation should include a multidisciplinary approach. “We are just at the tip of the iceberg right now to truly understand what all this means and what is relevant,” he emphasized. “Get help if you need it.”

Moving forward, Parikh believes NGS will continue to develop and its benefit will continue to grow. The future of NGS is very bright,” he concluded.

Catlin Nalley is associate editor.

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