NEW YORK (GenomeWeb) - As a woman of "advanced maternal age," Eunice Lee, a practicing anesthesiologist, knew when she gave a blood sample for non-invasive prenatal testing that she might find out her 10-week old fetus had a chromosomal disorder. But she didn't imagine she could potentially learn something troubling about her own health.
At last week's Scripps Future of Genomic Medicine Conference, Lee described how her obstetrician told her that Sequenom, the company that performed her NIPT screen, had sent back an abnormal aneuploidy result with the suggestion that, based on the results, Lee be given a workup for cancer.
Because of the way most NIPT works — by counting the chromosomes or segments of chromosomes present in a pregnant woman's blood, and using that information to infer whether or not that woman's fetus has an aneuploidy or other abnormality — it inherently opens the door to the discovery of molecular alterations not only in the fetus, but also in the mother.
Lee's case highlights an increasingly important question not only for NIPT but for a growing landscape of assays that rely on broad genomic profiling: whether to notify patients of results that are outside the primary target of a test, and, if so, how to properly inform patients exactly what they may discover.
In Lee's case, finding out she had cancer — a colorectal adenocarcinoma — had a clearly positive impact. "I feel like the luckiest person alive," she told the conference audience last week.
The tip-off from her NIPT results, confirmed by a full-body MRI, allowed Lee to undergo early treatment that, so far, appears to have left her cancer-free. And analysis of circulating DNA may have the potential to do the same for many more individuals.
However, the consent form Lee filled out for Sequenom's NIPT didnt include the possibility of finding out she might have cancer, she said during her conference presentation.
Sequenom CSO Dirk van den Boom, who briefly joined Lee and Sequenom lab director Nilesh Dharajiya onstage at the conference, said that the company has leaned overall toward disclosing cancer-suggestive NIPT results to women, but doesn't see the choice as easy.
In an email to GenomeWeb, Sequenom clarified that NIPT cases suggestive of cancer are not considered "reportable" by the company, but that in practice, such findings nonetheless lead to a phone conversation with the ordering physician.
The company did not provide details, however, about how it presents the possibility of the receipt of these types of findings in its testing consent form.
Diana Bianchi, an NIPT specialist from Tufts University School of Medicine, also spoke at the Scripps meeting. She said that she has studied the consent forms for all the commercial NIPT companies. According to Bianchi, when she reviewed them about eight months ago, none of these forms included any indication for women to check a box allowing them to receive results apart from fetal aneuploidy status.
As part of a research project with Illumina — which markets its own NIPT service called Verifi — Bianchi and her colleagues have also identified at least 10 cases of abnormal, but inconclusive NIPT results in women who were later diagnosed with cancer, she said at the conference.
But unlike Sequenom's procedure in Lee's case, 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 explained at the conference.
"I do think Sequenom did the responsible thing by Eunice [Lee]," Bianchi told GenomeWeb. "But I think the big issue is that lab directors are seeing these findings and trying to figure out what the best thing to do is. There isn't a registry of these cases or a process for evaluating them in place in the field," she said.
Offering a full-body MRI to every woman who has a result indicating multiple aneuploidies may not be feasible or appropriate, Bianchi said, since NIPT aneuploidy results that are not confirmed to be of fetal origin can represent confined placental mosaicism, the demise of a twin, bone marrow or organ transplants in the mother, simple lab error, or another maternal medical condition.
Test makers, if they plan to return these types of findings, may need a better way to determine which suggestive results are actually linked to cancer or other diseases that should be disclosed to maternal patients, and which are not.
In a poster presented at the Association for Molecular Pathology annual meeting last year, Sequenom reported it has had at least 38 cases of positive NIPT results that were not fetal abnormalities. Of those, 26 were confirmed in one way or another to be associated with maternal cancer. Ten of these led directly to a cancer diagnosis via "detailed workups," the authors wrote.
Sequenom did not discuss in the poster how the decision was made to refer those women to comprehensive workups for cancer, or how the cancer was diagnosed in the other 16 cases.
Bianchi, meanwhile, is planning to present more data later this month on Illumina's 10 cases of maternal cancer linked to abnormal NIPT results. She said her team has done some additional research it hopes to share that may tease out some of the indicators that a discordant multiple-aneuploidy result is likely to be cancer as opposed to something else.
All these cases also highlight the potential for NIPT companies to adapt their technologies for dedicated early cancer detection. Several NIPT companies have said they are planning to develop circulating DNA tests specifically for cancer, including Sequenom and Natera.
Earlier this year, researchers from the University of Leuven in Belgium reported in a proof-of-concept study published in Lancet Haematology how an NIPT secondary finding prompted their team to develop a blood test for Hodgkin lymphoma.
But launching dedicated cancer detection tests would not remove the potential for NIPT to uncover unforeseen cancer or other diseases in pregnant women, nor the hard questions about when and how to share these results.
Currently, chromosome-counting NIPT methods like Sequenom's and Illumina's predominantly evaluate large structural changes, but that is already changing and could shift much further in the future.
Recently some NIPT companies have begun to offer microdeletion testing in addition to reporting on chromosomal aneuploidies. "It's not just cancer [anymore,]" Bianchi said at the meeting. "What do you do [for example] if you do microdeletion testing and the result is positive but the fetus is normal, and a woman then learns she has DiGeorge syndrome? That is coming up not infrequently," she said.
Researchers have also demonstrated that sequencing the entire fetal genome from maternal plasma is possible, and have published data distinguishing maternal and fetal gene expression in circulating RNA in maternal blood.
Audience members at Lee's presentation expressed anxieties about a future in which NIPT routinely analyzes an entire fetal genome down to individual base pairs, and whether results related to childhood or adult-onset conditions should someday be reported to pregnant women.
According to Bianchi, while the can of worms of secondary findings can only grow as the breadth of information analyzed in NIPT expands, Lee's case illustrates that there are plenty of worms to deal with already.
Beyond lacking information about the possibility of findings suggestive of maternal cancer, the NIPT consent forms Bianchi has reviewed have also diverged widely in their content and structure overall, she said, further highlighting the need for guidance and standardization of best practices in the field.
"It's a pressing issue, and to my knowledge it hasn't been handled at all by professional societies yet," she said.