Historically, tests for chromosome-number irregularities in a fetus, such as Down syndrome (three copies, or trisomy, of chromosome 21), have involved taking samples from the amniotic fluid or placenta — invasive, painful procedures that carry a slight risk of miscarriage and other harms to the mother and fetus.
In contrast, noninvasive prenatal testing (NIPT), which became commercially available in 2011, uses a simple blood draw to more safely assess the risk of these disorders, which are collectively known as fetal aneuploidy. NIPT detects cell-free DNA (cfDNA) from the fetus that floats through the placenta into the mother’s bloodstream. It’s currently recommended for all pregnant people regardless of aneuploidy risk. An estimated two million patients in the United States undergo the procedure each year.
Approximately 90% of circulating cfDNA is maternal in origin; only a small fraction comes from placental DNA. Most cfDNA is released from the mother’s cells into the blood during normal physiological processes, such as cell death.
But tumors also can shed DNA into the bloodstream. Indeed, not long after NIPT was introduced, reports emerged of unusual testing results in mothers subsequently found to have cancer. Although their babies were healthy, the tests indicated aneuploidy, most likely because cancer cells often have extra chromosomes.
Because NIPT tests are not designed to detect cancer, clinical laboratory professionals have generally been reluctant to report NIPT findings as “cancer-suspicious,” preferring instead to label unusual results as “nonreportable” or “atypical” without offering further clarification.
But that may be changing. Recent studies have shown that maternal NIPT can accurately suggest a cancer diagnosis even in asymptomatic mothers. In fact, up to half of patients who receive abnormal results that can’t be attributed to fetal aneuploidy may have cancer. These results raise questions about how these incidental findings should be handled and what the clinical laboratory’s role should be in interpreting and responding to them.
Identifying maternal cancer
The initial finding that NIPT can detect maternal cancer motivated the IDENTIFY study, an effort led by the National Institutes of Health (NIH). Its purpose is to identify the cause of abnormal NIPT results and determine the best approach for evaluating pregnant patients whose results suggest cancer.
“The point of the IDENTIFY study is to generate prospective data to inform maternal medical management,” said Amy Turriff, MS, a genetic counselor and co-lead investigator on IDENTIFY. “We bring patients with nonreportable NIPT results to the NIH Clinical Center and put them through a standardized cancer-screening workup to see what’s the best way to evaluate women who receive these results.”
In a December 2024 study published in the New England Journal of Medicine (NEJM), 107 patients without known cancer who were either pregnant or postpartum underwent a cancer-screening protocol that included whole-body magnetic resonance imaging (MRI), blood tests, and physical examinations (N Engl J Med 2024; doi: 10.1056/NEJMoa2401029). Fifty-two patients, or 48.6% of those studied, were subsequently found to have cancer, as confirmed via biopsy. The most common cancer diagnoses were lymphoma (31 patients, 59.6%), followed by colorectal cancer (9 patients, 17.3%), and breast cancer (4 patients, 7.7%). More than half of the cancer-positive participants were asymptomatic, while an additional 25% had symptoms ascribed to pregnancy and other noncancer–related causes.
Of the various screens evaluated, whole-body MRI was easily the superior method for detecting cancer. It showed possible cancer in 48 out of 49 participants confirmed to have the disease. Physical examinations and blood-based laboratory tests had lower sensitivity and specificity.
Additionally — and crucially — cfDNA sequencing revealed that certain kinds of aneuploidies were far more likely to result in cancer than others. Gains and losses of partial or entire chromosomes across at least three chromosomes were found in 49 samples, 47 of which (95.9%) were from patients with cancer. Other patterns were mostly attributed to a source other than cancer, such as fibroids and placental mosaicism.
Taken together, these results suggest that pregnant people with chromosomal gains and losses should be highest priority for a follow-up MRI, the most accurate cancer-detection method in this context.
“Through the sequencing patterns, you can identify the people at highest risk for cancer, who should undergo the whole-body MRI,” Turriff said.
She explained that many laboratories use genome-wide platforms that generate information for all chromosomes. However, NIPT most often assesses only for abnormalities in chromosomes 13, 18, 21, and the sex chromosomes, the most common fetal aneuploidies that result in a live birth. In the event of an unusual result, lab professionals can look at the whole genome to assess if there’s a technical or sample-related issue — or if cancer is lurking.
“That unmasking of the data is when you can see what’s happening across the genome and potentially identify these sequencing patterns that we described in the NEJM paper. The data are there,” Turriff said.
Spotlight on the Netherlands
A link between aberrations in multiple chromosomes and maternal cancer also has been identified retrospectively in studies from the Netherlands, a world leader in NIPT.
In 2014, a group of clinical laboratory geneticists and obstetricians and gynecologists formed the Dutch NIPT Consortium, which offered NIPT nationwide as part of the TRIDENT studies (TRIal by Dutch Laboratories for Evaluation of Non-invasive Testing). More than 200,000 tests were performed from 2017-2020, and of the 48 (0.03%) genome-wide NIPT results that were reported as suspicious for a malignancy, 16 (33.3%) of those patients had received a cancer diagnosis. When gains and losses across multiple chromosomes were found, the risk of a confirmed malignancy was nearly 70%.
Furthermore, for pregnant patients who received a diagnosis of blood cancer during pregnancy or within 2 years after delivery, genome-wide aberrations in NIPT raised, in retrospect, suspicions of cancer every time — suggesting that further diagnostic examinations could focus on specific cancer types.
“As hematologic malignancies arise from blood forming organs or lymph nodes, and maternal cfDNA originates from leukocytes, it is plausible that genomic instability occurring in neoplastic transformation of these cells can be detected relatively more often in the blood,” compared with other cancers, explained Catharina J. Heesterbeek, MD, an oncologist at Maastricht University Medical Center in the Netherlands and one of the researchers on the TRIDENT studies. Similarly, because more advanced stages of cancers were more likely to show up in the blood, cancer stage could also affect the predictive value of NIPT for cancer in certain cases.
“If you have a stage-one breast cancer … it’s to be expected that there’s not much cell-free DNA of the tumor in your blood, so the chance to pick it up with NIPT is really low,” she added.
Thanks to the success of TRIDENT, NIPT is now offered free of charge to all pregnant people in the Netherlands. National uptake is about 70%, according to Merryn Macville, PhD, a clinical laboratory geneticist a lead researcher on the TRIDENT studies. Midwives and gynecologists provide pretest counseling to pregnant people, during which they explain that NIPT can turn up cancer in rare instances.
A multidisciplinary effort
In the Netherlands, aberrant NIPT results are reported to a clinical geneticist, who acts as a case manager in working with oncologists and obstetrician-gynecologists. This approach allows for multiple perspectives and areas of expertise to be shared when determining a course of action for patients.
“You need a multidisciplinary team of caregivers to make sure that women are well-informed and well taken care of,” Macville said.
Testing and care are not as integrated in the United States. Even the way the same results are reported can vary from lab to lab.
“Each lab is really making its own decision as to how to report results, and even within the same lab, different laboratory directors might make different decisions about these cases,” Turriff said.
In thinking about how to standardize the detection of NIPT results, Turriff believes that clinical laboratory experts should take the lead.
“Clinical laboratories are best positioned to identify these cases — they’re the ones with access to the sequencing information. They have the expertise to identify those cases that are most concerning for a maternal malignancy.”
However, she continued, “I think where there’s room for improvement is in the handoff step. Right now, it is typically very unclear from the written laboratory report alone when there is a concern for maternal malignancy.” This could mean that the clinician treating a pregnant person lacks information that would shape their decision-making, like ordering cancer screening when warranted.
While it’s understandable that lab professionals may feel hesitant to report cancer-suspicious results from a test intended to detect fetal aneuploidy, studies such as IDENTIFY and TRIDENT make a strong, evidence-based case for doing so. They’ve shown that NIPT can raise a red flag for cancer, reassuring laboratories in a position to report it. According to Turriff, a couple of laboratories now document that certain sequencing patterns they find in NIPT have previously been reported to have an association with cancer.
“Having something transparent and a common language will improve this process for women,” Turriff said. “I think we’re starting to move in the right direction.”
Yaakov Zinberg is a writer based in the Boston area. +Email: [email protected]
