Racing into the unknown

At the end of a recent review article, the coauthors noted that approximately two-thirds of their 75 references had been published within the last 18 months. “The pace of this field is unprecedented in clinical laboratory medicine,” they wrote 1 That sound of squealing tires you hear is the highly competitive, highly lucrative, and highly unsettled field of noninvasive prenatal testing (NIPT) racing down the highway. “This is one of my major research interests, and I can barely keep up,” says Diana Bianchi, MD, professor of pediatrics, obstetrics, and gynecology at Tufts University School of Medicine in Boston, Massachusetts, and the review's lead author. Observers have hailed a series of clinical advances that have helped to deliver more information regarding chromosomal abnormalities much earlier during pregnancy and without the risks associated with more invasive tests. However, the breakneck speed of a field heavily influenced by cancer testing is threatening to outpace its ability to address ethical, legal, and logistical concerns. Y.M. Dennis Lo, PhD, a pathologist at the Chinese University of Hong Kong, who pioneered fetal DNA-based testing in the 1990s, derived his inspiration from reports suggesting that tumor DNA isolated from patient serum and plasma samples could help physicians diagnose cancer. 2 Nan Okun, MD, a maternal-fetal medicine specialist and director of prenatal screening at Mount Sinai Hospital in Toronto, Ontario, Canada, says the field took off soon after Dr. Lo isolated cell-free fetal DNA from maternal blood. Researchers, she says, have since estimated that approximately 10% to 20% of all DNA circulating through the maternal bloodstream may be fetal in origin. Cell-free fetal DNA is derived from placental cells; Dr. Okun likens it to a noninvasive placental biopsy. Although the DNA usually reflects the condition of the fetus as well, the placenta can have more than 1 cell line, meaning that its DNA profile does not always match that of the fetus. That limitation is a major reason why geneticists have stopped short of calling the test a diagnostic tool. Nevertheless, 6 companies, including 4 in the United States and 2 in China, have sped into the NIPT commercial market and are taking a leading role in research publications. Dr. Bianchi, who is herself aligned with Redwood City, California- based test provider Verinata Health, sees the industry-academic partnership as a unique and major force propelling the entire field. “Because of the competitiveness of the industry, it pushes everything faster, ” she says. All of the companies test for extra copies of chromosomes 13, 18, and 21. Some also test for extra X and Y chromosomes, an extra copy of every chromosome, and other conditions linked to extra chromosomes or chromosomes missing a substantial portion of DNA. NIPT is moving ahead at full speed. Brian Skotko, MD, MPP, a medical geneticist and the codirector of the Down Syndrome Program at Massachusetts General Hospital in Boston, says the new testing paradigm can help women determine as early as 10 weeks after gestation whether their fetus may have one of the chromosomal abnormalities. The earlier information, in turn, could help those women and their partners decide whether to continue the pregnancy or terminate it. Dr. Skotko and other physicians are careful to emphasize that confirmation of a result generally requires an amniocentesis or chorionic villus sampling (CVS), which is a direct biopsy of the placenta. Physicians note that a negative NIPT result often prompts women to decline more invasive follow-up options. “Amniocentesis and CVS both carry a chance of causing a miscarriage, so for many women, this is an opportunity to avoid the small, albeit real, risk of miscarriage by getting a noninvasive test,” Dr. Skotko says. Already, NIPT providers have reported a substantial decrease in the number of invasive testing procedures performed. “For the individual patient, there's no question that it's a huge development,” Dr. Okun says. As currently formulated, however, the test includes only a subset of known chromosomal abnormalities, and does not address single-gene mutations. She cautions that NIPT also may offer false reassurance and shift the focus away from more significant risks. “During pregnancy, our job is to be continually on the lookout for things that could affect the fetal or maternal health,” she says. Preterm birth and growth restriction, 2 of the most common complications, both carry the potential for long-term impacts. NIPT covers neither, and Dr. Okun worries whether the test may be diverting energy and resources away from more important conditions. Because some of the testing companies do not require documentation of informed consent, Dr. Skotko says that responsibility falls primarily on the ordering physician. “But it is unclear whether or not this is happening consistently within all medical practices,” he says. Some parents-to-be, he says, have reported receiving the test before realizing what they had consented to. There are financial implications as well, as not all insurers cover costs. Jaime King, JD, PhD, professor of law at the University of California at Hastings, says physicians who do not adequately explain the testing process or properly confirm the results could leave themselves exposed to legal liability if an anomaly remains undetected. “It's really important that women understand the limitations of the test, and that the test is not considered diagnostic,” she says. Proper follow-up after confirmatory results can be just as critical. Dr. Skotko wonders whether a counseling system already straining to accommodate the roughly 2% of pregnant woman who undergo amniocentesis or CVS can handle increased demand via NIPT. “The information and the literature and the parental resources are lagging far behind the pace of technology,” he says. “So how quickly will we be able to develop these neutral, nonbiased, quality pieces of information to match the results that are going to be given to parents on a regular basis now in prenatal clinics?” Several medical societies have recommended that NIPT be offered only to women with high-risk pregnancies. The vast majority of testing data have been validated only among women in this sample group, the societies assert, meaning that few data have yet accumulated to suggest how the test might perform among women experiencing lower-risk pregnancies. The American College of Medical Genetics and Genomics has recommended that what it instead calls noninvasive prenatal screening should be offered to all pregnant women because it outperforms existing alternatives that have been recommended for all pregnant women. Physicians and bioethicists are keenly aware of the implications of the expanded availability of NIPT. “These tests do raise a provocative question, and that is: as more and more people get the test and learn about Down syndrome prenatally, will more and more people choose to terminate the pregnancy?” Dr. Skotko asks. “And therefore, will babies with Down syndrome slowly start to disappear?” Any analysis of trends since the arrival of NIPT may be difficult. The highly competitive atmosphere, he believes, has encouraged testing companies to keep more of their data private amid a flurry of lawsuits and countersuits over patent infringement. The field may be racing toward another major turning point, however. Research groups at the University of Washington and Stanford University have already published proof-of-principle studies confirming that an entire fetal genome can be decoded from cell-free fetal DNA.3, 4 That means testing now confined to chromosomal-scale abnormalities may expand as sequencing costs continuing to drop, offering unprecedented information not only about fetal development but also concerning susceptibilities to cancers and other diseases later in life. “You can imagine women finding out they're having daughters, and they have BRCA1 and BRCA2 in their family. Is that something that they'd like to screen for?” Dr. King says. “I think the ethical questions surrounding it go very deep. They are questions about, just because we can, should we? And what do we want to test for on a regular basis?” Amid the many unresolved questions, Dr. Bianchi is using a mouse model of Down syndrome to explore the possibility of giving pregnant women an oral therapy after a confirmative fetal diagnosis. The treatment could begin well before major changes in brain growth and development begin appearing in the middle of the second trimester. “This is not pie in the sky,” she says. “We're definitely encouraged.” The necessary testing will undoubtedly take time. However, if successful, it could help cut down on the considerable distance between the accelerating research on prenatal testing and the treatment options lagging far behind. BRYN NELsON IS A FREELANCE MEDICAL JOURNALIST. CytoSource Reader Poll #17: Noninvasive Prenatal Testing Q: Which unresolved aspect of noninvasive prenatal testing do you think will prove most difficult to overcome? A. Ethical B. Legal C. Financial D. Scientific Take the poll online at www.cancercytojournal.com. The results will be published in the April 2014 issue. December 2013 POLL RESULTS Q: What comes closest to your views on the future of exposomics? 50% Study of the exposome will eventually become a dominant part of cancer research 0% The exposome will not be a significant factor in cancer research. 0% The massive effort and expense required to define the exposome will limit its applicability to cancer research. 50% The exposome will help complement other “-omics” disciplines in providing a more complete picture of cancer risk.

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