Does Every Cancer Patient Need Comprehensive Genomic Testing – NGS Analysis?

Cancer and Genomic Medicine

Because cancer is a genetically based disease, changes in our genes can influence its formation and development. Advances in technology and genetics in recent years have made it more common to sequence cancer patients’ tumor DNA. This is an important aid in identifying new treatment approaches. However, some researchers question whether every cancer patient can benefit.

The Human Genome Project and DNA Sequencing Technology

The Human Genome Project marked the start of a period of major technological evolution. The project was seen as a major scientific achievement when the “final” sequence of human DNA and its approximately 3.2 billion nucleotide bases was announced in six papers published in Science in 2002. This work used an improved DNA sequencing method known as Sanger sequencing.

DNA sequencing is a method used to determine the precise order of nucleotides, or “bases,” in a strand of DNA. Many geneticists consider Sanger sequencing the gold standard because it can identify specific mutations, translocations or variants (changes) in targeted genes with a high degree of accuracy. However, the process focuses on just one DNA fragment and can be costly and time-consuming.

More recently developed sequencing methods have been able to read longer stretches of the genetic code accurately. This has filled gaps in the human genome that were overlooked amid the excitement surrounding the Human Genome Project’s initial results. However, the technique that has found the most immediate application for doctors and patients is next-generation sequencing, or NGS.

Massive Parallelism: Next-Generation Sequencing

NGS can sequence millions of DNA fragments simultaneously, allowing hundreds or even thousands of genes to undergo mutation or biomarker testing at the same time. In genomic terminology, NGS is a “high-throughput” sequencing method.

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

Many oncologists now routinely order NGS panels as a genetic diagnostic technique and treatment-planning aid to identify changes that may drive a cancer or reveal “actionable” vulnerabilities.

Routine Sequencing and Its Effects on Patients

The cost and turnaround time of NGS sequencing have steadily declined over the past decade. Some cancer centers order these tests for all their cancer patients, such as the Dana-Farber Cancer Institute in the United States. However, it is also necessary to recognize that sequencing, seen as essential by some, may be inaccessible or unaffordable for others.

In 2013, gene expression profiling cost around 400 dollars. A decade later, the cost had fallen below 25 dollars for a single sample testing 65 targets, according to genetics company Illumina. But the issue is not just the price of the test: bioinformatic interpretation of its results is at least as important as the testing technique.

Useful or Not? The Controversial Use of NGS

However, Spanish researchers argue in a recent paper that although NGS is useful for many cancer patients, it may not be useful for everyone.

Dr. Ramon Colomer and colleagues at Universidad Autónoma de Madrid and Hospital Universitario La Princesa in Madrid, Spain, found in a study published online in eClinical Medicine that NGS had little effect on patient outcomes.

This was an observational study of 139 cancer patients whose tumors underwent NGS testing between 2017 and 2020.

Small Chances, Big Gains

In 111 of the 139 cases, the researchers found no significant difference between patients with drug targets identified by NGS and those without identified drug targets in terms of progression-free survival (PFS).

In addition, there was no significant difference in PFS between patients who received a specific drug based on NGS findings and those who did not. Nor were there significant differences in PFS according to whether tumors were suitable for targeting under the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT).

However, there was a significant difference when NGS was performed because the doctor thought there might be a clinical benefit.

Patients in the proposed “useful” categories had a median progression-free survival of 319 days. These categories included patients with advanced non-small cell lung and colon cancers and malignant melanoma with molecular markers relevant to initial treatment.

However, for cancer patients in whom NGS was considered “unlikely to be useful”—those with rapidly progressing cancers, a short life expectancy, poor performance status or advanced cancers without standard therapies—the median PFS was only 123 days.

The researchers also determined that NGS was unnecessary for early-stage cancers with curative treatment and cancers with a standard treatment that did not require genetic profiling.

The paper’s lead author, Colomer, and colleagues wrote: “Our data show that real-world outcomes following NGS testing make an important contribution to clinical decision-making in settings such as advanced cancers that generally require multiple genetic markers, advanced rare cancers or screening for molecular clinical trials. However, NGS does not appear to add value in patients with poor overall performance status, rapidly progressing cancers, a short life expectancy or no standard treatment options.”

Another researcher at Dana-Farber, Dr. Nilay Sethi, who was not an author of the study, said that the researchers had taken too strict an approach. Even when a patient’s chance of benefiting from NGS is small, sequencing may reveal unexpected actionable targets.

Sethi said, “It would be hard for me to tell a patient, ‘We don’t think sequencing will work for you.’” He added, “For that small percentage in whom the sequence information could lead to a drug with substantial activity, I would sequence the patient’s tumor.”

He also noted that genetic panels are continually evolving and that identifying previously unknown or unexpected alterations and targets has real clinical value for improving care in the near future.

Sethi said, “I feel that everything is moving in a positive direction from a sequencing perspective,” he said.

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Milestones in Human Molecular Genetics and Genomics – A Brief History

Abbreviations: Cas9: CRISPR-associated protein 9 / CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats / HGP: Human Genome Project / NIH: National Institutes of Health of the United States

• 1973 – Herbert Boyer and Stanley Cohen developed recombinant DNA technology.
• 1977 – Walter Gilbert and Fredick Sanger discovered techniques for DNA sequencing.
• 1983 – Kary Mullis invented the polymerase chain reaction (PCR) technique.
  The first disease-associated gene was molecularly mapped to a human chromosome by James Gusella and Nancy Wexler.
• 1986 – Leroy Hood invented the automated DNA sequencer.
• 1990 – NIH and the Department of Energy launched the Human Genome Project (HGP).
• 1994 – The HGP’s human genetic mapping goals were achieved. 
• 1995 – The HGP’s human genetic mapping goals were achieved.
• 1996 – The HGP began testing strategies for large-scale sequencing of the human genome.
• 1997 – In what would be called the “Bermuda Principles,” HGP researchers endorsed the rapid public release of genome sequence data without restrictions on its use.
• 2001 – The international HGP consortium published the first draft of the human genome sequence; J. Craig Venter’s group at Celera Genomics published another version of the sequence.
• 2002 – The International HapMap Project was launched to collect data on human genetic variation that could be used to accelerate the identification of genes associated with common diseases.
• 2003 – The HGP was completed two years ahead of schedule, producing a reference sequence of the human genome.
• 2006 – NIH launched The Cancer Genome Atlas (TCGA) to molecularly characterize more than 20,000 samples covering 33 cancer types.
• 2008 – The United States Genetic Information Nondiscrimination Act became law to protect against discriminatory use of genetic information in health insurance and employment.
• 2009 – In a clinical first, Wisconsin researchers sequenced all the genes of a 5-year-old boy and used the data to pinpoint a new disease, leading to life-saving treatment.
• 2012 – The Human Heredity and Health in Africa (H3Africa) consortium held its inaugural meeting in Addis Ababa, Ethiopia.
• Emanuella Charpentier and Jennifer Doudna demonstrated that CRISPR can edit DNA in vitro (earning them the 2020 Nobel Peace Prize in Chemistry); approximately 6 months later, Feng Zhang and George Church independently demonstrated CRISPR editing in mammalian cells.
• 2018 – TCGA published the Pan-Cancer Atlas, a collection of cross-cancer analyses based on the entire dataset.
  NIH began enrollment in “All of Us,” a research program and large-scale research resource of more than 1 million participants who would contribute genetic, health and environmental data.
• 2020 – The first patient with sickle cell disease was treated using an ex vivo approach with CRISPR – Cas9.