How do we deal with NIPGS and ‘The Big C’?

Stories have been circulating for a while now that anomalous non-invasive prenatal genetic screening (NIPGS) results may sometimes indicate maternal cancer. Recently, however, these anecdotes have given way to more rigorous data, from a group of researchers at University of Leuven in Belgium, and from US companies Sequenom and Illumina.

Laura Linney in The Big C; photo from
Laura Linney in television show “The Big C” (photo from

For many this new discovery is not all that surprising. For several years now, researchers have been pursuing a test, based on cell-free DNA, that would provide a reliable “liquid biopsy.” Indeed, such tests are already being used clinically in limited circumstances, though–as with NIPGS–the rapid translation of this technology has left important questions about reliability and actionability as yet unanswered. Even more promising, sequencing cell-free DNA may circumvent some of the problems recently proposed with sequencing tumor DNA without matched controls from normal tissue–because both kinds of DNA will be present in serum, and can be distinguished by their relative frequency, much as NIPGS does with fetal and maternal cell-free DNA. Yet GenomeWeb reports (paywall) that, at the annual meeting of the American Society of Clinical Oncology last week,

Geoffrey Oxnard, a researcher at Dana Farber, said in the ASCO actionability session that while it’s clear that liquid biopsy has the potential to offer information that is impossible to derive from tumor tissue sequencing, developers of broad panel-based liquid biopsy test must prove that the alterations they detect in blood that aren’t present in a tumor are valid, let alone useful.

Last week, Diana Bianchi of Tufts University published a commentary in Nature that addressed the issue of NIPGS results indicative of cancer. The commentary also brought new attention to an issue that members of our research consortium have emphasized for some time: the need for ethical best practices in delivering NIPGS, and, in particular, for written consent documents with up-to-date and patient-friendly information about the test, what it can and can’t do, and its informational risks (including incidental findings of potential cancer in the mother). At the moment, Sequenom appears to be alerting clinicians when a NIPGS test they have ordered gives anomalous results that may indicate a tumor, while Illumina is not. According to a March report in GenomeWeb (paywall):

As part of a research project with Illumina — which markets its own [NIPGS] service called Verifi — Bianchi and her colleagues have also identified at least 10 cases of abnormal, but inconclusive [NIPGS] results in women who were later diagnosed with cancer, she said at the [Scripps Future of Genomic Medicine] conference.

But unlike Sequenom’s procedure … Illumina did not return these results to its clients as an indication of cancer risk, Bianchi said. Instead, the women’s physicians later independently reported back to Illumina that their patients had developed a cancer, she said at the conference.

Is cell-free DNA’s potential to reveal cancers hopeful or alarming? It depends on who you ask. Testing laboratories clearly see this as a new opportunity to expand their markets even further, as evidenced in Natera’s recent IPO filing, which GenomeWeb reports (paywall) is spurred at least partly by its potential to move into cancer diagnostics. GenomeWeb (paywall) also reported last October:

Natera has a number of ongoing trials, in which the company is or will be collecting samples from a variety of cancers with the goal of seeing for each one the fraction of cell-free DNA present in the plasma at the different stages of disease.

Current cancers being investigated in such trials include breast, colon, lung, and ovarian cancer. Natera also intends to study its technology in prostate, bladder, melanoma, pancreatic, liver, and endometrial cancer, as well as in glioblastoma.

Yet some clinicians are troubled by this step toward more and more powerful genetic sequencing during pregnancy. While Bianchi rightly brings up the challenge of adequately informed consent for such expanded testing in her recent Nature commentary, this may only be the tip of the iceberg. At the Scripps conference at which Bianchi discussed her research on cancer diagnoses among women with abnormal NIPGS results, Sequenom gave a platform to Eunice Lee, a physician whose inconclusive NIPGS results pointed her toward an eventual diagnosis of–and successful treatment for–colorectal cancer. In Lee’s case, the suspected cancer was diagnosed by a full-body MRI. While she considers herself “the luckiest person alive” (paywall), Lee’s case also points to the health care burden that expanded cell-free DNA screening may place not only on individual patients, but on health care systems more broadly. Genetic counselor Katie Stoll recently discussed a case presented at last fall’s meeting of the National Society of Genetic Counselors, in which abnormal NIPGS results led first to an amniocentesis, and then (finding no fetal abnormality) to “an extensive work up for possible cancer.” Stoll mused,

My first thought in hearing this case was – That poor woman! First a lost twin pregnancy, then concern for a severe condition in her baby, anxiety about the amnio, and worry that she may have Cancer. Although I am not a health economist, my second thought was – Holy Cow! How can our healthcare system afford all of the follow-up testing that may come downstream from these tests? [NIPGS] is promoted as a test that will lessen the need for follow-up procedures such as amniocentesis, but will that remain true as the list of screened conditions increases?

Indeed, if cancers of various types are also added to the roster for non-invasive genetic screening, follow-on testing is likely to balloon, and at this early stage it is entirely unclear who will bear the multiple and intersecting burdens of ordering, making decisions about, and paying for these additional tests. Weighing benefits and risks in these increasingly complex situations will pose many new challenges: for patients, for clinicians, and for our entire health care infrastructure.


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