Should Every Cancer Patient Have Next-Generation Sequencing?

Patients with cancer are increasingly having tumor DNA sequenced: The technology has improved, prices have dropped, and such sequencing can identify a new treatment approach. But some investigators question whether every cancer patient can benefit. 

The technology has evolved since the establishment of The Human Genome Project, hailed as a triumph of science when the “final” sequence of human DNA and its roughly 3.2 billion nucleotide bases was published in six papers in the journal Science in 2002. That was carried out using an enhanced version of a DNA sequencing method known as Sanger sequencing.

As the name implies, DNA sequencing is a method for determining the exact order of nucleotides, or “bases” in a strand of DNA. Sanger sequencing is considered by many geneticists to be the gold standard because it can pinpoint with a very high degree of accuracy specific mutations, substitutions, or variants in targeted genes, but the process focuses on only a single DNA fragment at a time, and it can be costly and time consuming.

More recently developed sequencing methods that can read longer stretches of genetic code with accuracy have been able to fill in the gaps in the human genome that were glossed over in the hype surrounding the original release of The Human Genome Project results, but the technique with the most immediate application for clinicians and patients is next-generation sequencing, or NGS.

Massively Parallel

NGS can sequence millions of DNA fragments simultaneously, allowing testing for mutations or biomarkers in hundreds or even thousands of genes at the same time. In genomics speak, NGS is a “high-throughput” sequencing method.

In oncology, NGS genomic profiling has led to new approaches to treatment. For example, NGS has helped to identify tumor-cell vulnerabilities that have led to the development of targeted agents such as tyrosine kinase inhibitors, and also has identified inherited mutations in cancer-related genes such as BRCA1 and BRCA2, which has led to treatment with PARP inhibitors.

Many oncologists now routinely order NGS panels as a genetic diagnostic technique and as an aid for treatment planning, with the goal of identifying targetable or “actionable” vulnerabilities in a given malignancy.

Routine Sequencing

“At Dana-Farber, every patient is sequenced,” said Nilay Sethi, MD, PhD, a medical oncologist at the Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

“I understand that we may be in a different resource setting [from other centers], but at Dana-Farber sequencing of patient tumors is either covered by insurance or by the institute, so this doesn’t impact costs to patients,” Sethi told Medscape Medical News.

Dana-Farber patients undergo sequencing of the primary tumor at diagnosis, and the tumor will be resequenced if patients have treatment-refractory disease, experience recurrences, or if a drug in their treatment regimen develops resistance.

Sethi noted that the costs and turnaround time of next-generation sequencing have continuously decreased over the last decade. He also acknowledged, however, that sequencing may be considered a necessity by some, but an unaffordable or unavailable option for others.

In 2013, gene expression profiling cost about $400, according to an editorial published in the journal Genome Medicine. A decade later, the cost of targeted gene expression profiling for a single sample testing for 65 targets is less than $25, according to the genomics company Illumina.

Useful vs Not Useful

Yet NGS, while beneficial to many patients with cancer, may not be useful for everyone, Spanish investigators contend.

Ramon Colomer, MD, PhD, from the Universidad Autónoma de Madrid and Hospital Universitario La Princesa in Madrid, Spain, and colleagues found little impact from NGS on patient outcomes in a study published online in eClinical Medicine.

This was an observational study of 139 patients with cancer who had NGS testing of tumors from 2017 through 2020.

The teams found that in 111 of the 139 cases there were no significant differences in progression-free survival (PFS) between patients with druggable alterations identified by NGS compared with those with no identified drug targets.

In addition, PFS did not differ significantly between patients who received a specific drug based on NGS findings when compared with patients who did not, nor were there significant differences in PFS based on tumors graded as favorable or unfavorable for targeting according to the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT).

In contrast, when the decision to perform NGS was based on the clinician’s judgment that there might be a clinical benefit, there was a significant difference.

The median PFS was 319 days for patients who met recommended “useful” categories, including those with advanced non–small cell lung and colon cancers and malignant melanoma with molecular markers relevant for initial therapy.

But for patients with cancers for which NGS was thought to be “not useful,” such as those with rapidly progressive cancers, short life expectancy, poor performance status (PS), or patients with advanced cancers for which there are no standard therapies, the median PFS was just 123 days.

The investigators also determined that NGS was not necessary for patients with early cancers for which definitive therapy exists, and those with cancers for which there is a standard of care without the need for genomic profiling.

“According to our data, real-world outcomes after NGS testing provide evidence of the benefit of clinical judgment in patients with either advanced cancers that routinely need multiple genetic markers, patients with advanced rare cancers, or patients that are screened for molecular clinical trials. By contrast, NGS does not seem to be valuable when performed in cases with a poor PS, rapidly progressing cancer, short expected lifetime, or cases with no standard therapeutic options,” Colomer et al wrote.

Small Odds, Big Payoff

Dana-Farber’s Sethi, however, who reviewed the study for Medscape Medical News, said that the investigators appear to be taking too stringent an approach, because even when the likelihood of a benefit from NGS in a particular patient is likely to be small, sequencing may reveal previously unexpected actionable targets.

“It would be hard for me to tell a patient, ‘We don’t think sequencing’s going to work for you,’” he said. “In [that] small percentage of cases where sequencing information could lead to a drug that has significant activity, even if it’s only a 5% chance, I will sequence the patient’s tumor.”

He also noted that genomic panels are improving all the time, and that there is real clinical value in identifying previously unknown or unsuspected alterations and targets that could improve care in the near future.

“I feel like everything is moving in a positive direction from a sequencing standpoint,” Sethi said.

The study by Colomer et al was funded by the Carlos III Health Institute, European Regional Development Fund, and CRIS Contra Cancer Foundation. Multiple co-authors reported honoraria, travel grants, and/or research contracts from various pharmaceutical companies. Sethi reports no relevant financial relationships.

eClinical Medicine. Published June 2023. Abstract.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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