• by Bruce Carlson
  • December 4 2018


Where Clinical Sequencing Is Now

Where Clinical Sequencing Is Now

It has been little more than a year since the U.S. Food and Drug Administration (FDA) approved the first next generation sequencing (NGS) test for clinical use, and only a few months since the U.S. Centers for Medicare and Medicaid Services (CMS) announced it would provide national coverage for NGS tests for advanced cancer patients. Yet clinical sequencing is already advancing rapidly. In vitro diagnostics companies and individual clinical laboratories are creating ever-broader test panels for cancer diagnostics and non-invasive prenatal testing, and studies are underway exploring whether everybody should have their entire genome sequenced at birth.

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As sequencing technology has moved from science fiction to reality, many of the social and ethical questions they raise have grown more pressing. Should people be told about incidental findings when their genes are sequenced? Do NGS test really offer useful insights beyond routine testing for targeted mutations and are the high costs justified? And of course, how long before NGS is cheap enough that consumers will choose to skip the doctor entirely and pay out of pocket to have their whole genomes sequenced?

These are just some of the topics that have been appearing in news reports and academic journals in recent months related to clinical sequencing.

Should we sequence everybody at birth?

Until recently, the debate about whether healthy people should have their genomes sequenced at birth was an abstract discussion. Now that the cost of sequencing is falling, the question is suddenly concrete and urgent. Geneticist Robert C. Green, coleader of the federally funded BabySeq Project, predicted in a 2017 Scientific American article that genome sequencing would be widely available, even given away for free, within 5 years.

That’s why the U.S. National Human Genome Research Institute (part of the National Institutes of Health) is supporting research efforts, such as the BabySeq project, to explore the ethical and social implications of routine newborn genome sequencing. These studies are exploring how parents use genetic information, particularly if it reveals information about untreatable diseases; to what extent sequencing data could lead to privacy concerns and discrimination; and whether parents even want this information and, if so, if it will make a difference in the clinical care of the child.

One of the most recent publications out of the BabySeq project was a study published in September 2018 that examined why more than 80 percent of families declined the opportunity for free whole exome sequencing of their babies through enrollment in the BabySeq study. While many parents of newborns did not want to participate in any research study, regardless of the genetic component, many attended an enrollment session and declined afterward, citing concerns about receiving potentially troubling genetic information about their child and about potential discrimination in insurance coverage.

A new federally-funded multi-center study is looking at a more targeted approach to sequencing babies. The “Precision Medicine in the Diagnosis of Genetic Disorders in Neonates” trial, which began in August 2018, is evaluating offering only actionable sequencing results rather than the whole genome. The trial will offer whole genome sequencing to some newborns, while others will receive a targeted gene sequencing panel developed by Quest Diagnostics for 1,722 genetic disorders known to affect newborns.

“When a newborn’s entire genome is sequenced, unintended information may be learned, including potential issues that could affect the child later in life,” said Jill Maron, MD, co-principal investigator at Tufts Medical Center, one of the study sites, in a press release. “Since the targeted panel only screens for genetic disorders that appear in the newborn stage and can be addressed immediately, its use would eliminate any ethical dilemmas for physicians and avoid burdening families with information on adult onset diseases they may not want to know about.”

 While these studies delve into the ethical issues of genome sequencing for babies, a panel of experts associated with the BabySeq trial and other related NIH-sponsored research recently released a report recommending against large-scale programs to sequence healthy babies. The report, “The Ethics of Sequencing Newborns: Recommendations and Reflections,” published in August 2018 by the Hastings Center, argues that sequencing may be useful in the diagnostic work-up of a newborn with disease symptoms. However, they write, sequencing has limited usefulness as a tool for screening healthy individuals, while it exposes the individual to the risk of discrimination, distress, and the burden and expense of follow-up care, monitoring, and counseling.

Should patients be told about incidental findings?

One of the success stories that the coleader of the BabySeq project has described is the anecdote of the baby who was discovered to have a BRCA2 mutation, meaning they would be at high risk for developing breast or ovarian cancer as an adult. The knowledge of that mutation was not actionable for the baby at that moment, which raised the question of whether it should be reported? What would be the benefits and risks of sharing that information?

The American College of Medical Genetics and Genomics (ACMG) takes the position that there are some genetic variants that the laboratory and clinician should report whenever they are discovered in clinical sequencing, even if that discovery is incidental. The BRCA2 mutation is one of nearly 60 variants on the current list, most of which are related to cancer or cardiovascular disease.

In the BabySeq case, the team did reveal the information to the baby’s family. As a consequence, the mother got tested and discovered she, too, has the BRCA2 mutation. If the mother now has a better chance of avoiding or surviving cancer, it benefits the whole family, including the baby, Green said in an interview with GenomeWeb. Green cites another case from BabySeq in which a newborn was discovered to be a carrier for an inherited disease. This prompted the child’s parents to get tested, which revealed that they both carried the recessive trait and their future children had a 25% risk of inheriting the disease. Knowing this, they used preimplantation screening of their embryos to ensure their second child was healthy.

An October 2018 study found that reporting incidental sequencing results generally did not cause undue distress or other adverse impacts on patients. The study looked at participants in the Clinical Sequencing Exploratory Research (CSER) Consortium program and found that only about 1 percent of the more than 6,000 participants had an incidental finding for one of the genes on the ACMG list. It also found that reporting these results lead to only modest costs for medical follow-up, at least within the first year.

Will clinical sequencing actually improve care?

One of the fastest growing areas of clinical sequencing has been in cancer diagnostics, which has only intensified since the CMS decision in March 2018 to offer national coverage for NGS testing in advanced cancer patients.

Yet an August 2018 article in the Journal of the American Medical Association offered a sobering evaluation of NGS cancer testing so far. The authors reviewed the electronic medical records of more than 5,000 patients with advanced non-small cell lung cancer at 191 community oncology practices in the United States during the first 7 months of 2016. They concluded that the patients who received broad-based genomic sequencing (any multigene panel sequencing assay examining more than 30 genes) had no better survival rates than those who received only routine testing for specific mutations and/or rearrangements.

These results are not meant as a call to clinicians to stop using broad-based sequencing for patients with advanced cancer, a study co-author told GenomeWeb. Rather, they highlight the reality that many patients who could benefit from targeted cancer therapies do not receive them, even when their genes have been sequenced, whether due to the cost or a lack of access to clinical trials.

They concluded that the patients who received broad-based genomic sequencing (any multigene panel sequencing assay examining more than 30 genes) had no better survival rates than those who received only routine testing for specific mutations and/or rearrangements.

Research presented by at the American Society of Human Genetics meeting in October 2018 suggested that clinical sequencing could be helpful for pediatric cancer patients. Although the researchers didn’t examine survival outcomes, they reported that in a sample of 253 pediatric cancer patients who had whole genome or exome sequencing at St. Jude Children’s Research Hospital, 79 percent had at least one finding that could help guide care.

What if consumers want genome sequencing anyway?

While the medical community considers the nuances and tradeoffs inherent in clinical sequencing, the market for direct-to-consumer genetic tests is racing ahead at remarkable speed.

An August 2018 report in Genome Biology said consumer genomics has been growing exponentially since 2016 and could increase 10-fold by 2021 when, the authors predict, more than 100 billion people will have been genotyped.

While the big names in direct-to-consumer ancestry and personal health genetic testing do not use NGS technology, new startups such as Helix (backed by Illumina) and Veritas Genetics are commercializing whole exome and whole genome sequencing, alone or in combination with existing methods of direct-to-consumer genetic testing.

The Hastings Center’s “Ethics of Sequencing Newborns” report recommends that health care providers discourage patients from using direct-to-consumer sequencing, noting that often these companies have a business model that depends on sharing genomic data with third parties for drug development and other purposes. They worry that these companies will hype the benefits of sequencing while downplaying the negatives.

The authors of a 2016 report on consumer genome sequencing in Applied & Translational Genomics agree, highlighting the lack of transparency in how these companies use the genomic information they collect and questioning whether customers have enough information to give informed consent.

Yet there’s only so much the medical community can do to caution consumers, write the authors of the Hastings Center report.

“We recognize that strictly precautionary admonitions may prove insufficient in the face of rapid industry growth and advertisement-driven consumer demand,” they write.

While academics continue to ask the tough questions about clinical sequencing – What are the risks? When are the benefits worth costs? How should results be disclosed? – consumers may end up being the ultimate drivers of rapid adoption of this exciting and fraught new technology.