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Noninvasive prenatal testing (NIPT) for fetal aneuploidy screening using cell-free DNA (cfDNA) can incidentally discover maternal cancers, according to a Dutch retrospective study.

The analysis included 48 women who received suspicious NIPT results as part of a national implementation program. The women were then referred to clinical geneticists and oncologists for further management. A total of 23 (48%) were found to have multiple aneuploidies detected by genome-wide NIPT, and in 70% of these a maternal malignancy was confirmed. Two additional cases of malignancy were diagnosed in women who had a single abnormality detected by targeted NIPT of chromosomes 13, 18, and 21.

As shown in the study in the , most women were asymptomatic and had normal physical examinations, but their diagnoses ranged from early stage to metastatic disease. Lymphomas, both classical Hodgkin and non-Hodgkin, were the most common malignancy detected.

In an accompanying , Diana W. Bianchi, MD, director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and a senior investigator in the National Human Genome Research Institute, and two co-authors emphasized the importance of timely workup and management of pregnant women.

In the following interview, Bianchi elaborated on the implications.

What does the study add to the literature?

Bianchi: In early clinical experience, clinicians originally believed that NIPT results were false positives. Now, we have more proof that nothing is wrong with the test; we are detecting cfDNA from a maternal tumor that is being shed into the maternal circulation.

If cfDNA sequencing patterns associated with different cancer types can be established, this would help to inform subsequent investigations. The Dutch results add to a growing body of literature suggesting that nonreportable NIPT results, or those with multiple aneuploidies, should be taken seriously by obstetricians and oncologists and equally by the patient.

It's important for U.S. oncologists to be aware that the test functions as a liquid biopsy. This test looks at ratios between reference chromosomes and test chromosomes. The bioinformatics algorithms used in the Netherlands and Belgium are more transparent. They are small countries with laboratories that all use the same techniques. In the U.S. we have different companies using different techniques, each with proprietary algorithms, which has led to disagreements about how to report incidental genomic findings detected by NIPT.

What does your editorial show about the importance of a timely workup and management in pregnant women to detect maternal cancers?

Bianchi: These screening findings are extremely important. The tendency is to underplay them. There is also a general perception that clinicians can't prescribe chemotherapy for a pregnant woman. A large body of evidence shows that, in the third trimester, it is better to provide chemotherapy and keep the baby in utero than to deliver the baby early.

We are conducting an ongoing, longitudinal research study at NIH called (Incidental Detection of maternal Neoplasia Through non-invasive cell Free DNA analysis). IDENTIFY collects prospective laboratory and imaging evidence to determine the best approach for a clinical diagnostic workup, and then evaluates the risks and benefits of disclosing NIPT results suggestive of malignancy.

These findings are actionable. Many of our research participants who had positive NIPT results and received additional diagnostic testing as part of the study have had surgery or received chemotherapy earlier than they would have if they waited for clinical symptoms to develop. In addition to lymphomas, we have detected colon, adrenal gland, and other rare cancers.

How could IDENTIFY address some of the current challenges that U.S. providers face?

Bianchi: Our primary goal is to collect evidence that results in a rational, evidence-based care plan. Right now, clinical care varies from doing nothing to an enormous workup that may not be covered by insurance plans. When participants join our study, all testing is free, and participants receive the results of the studies to inform their care.

There are currently no professional guidelines for follow-up of these unusual NIPT results. We do a variety of blood tests and a whole-body MRI. The MRI is the most useful test to show whether something is there. It's not always cancer; alternative explanations for the NIPT results include uterine fibroids and placental abnormalities.

How should oncologists coordinate efforts with obstetricians and geneticists to facilitate timely follow-up evaluations and clinical management?

Bianchi: First, we need to get a definitive diagnosis. Then, the oncologist can create a care plan in collaboration with an obstetrician and a geneticist or genetic counselor. The doctors need to make informed decisions about when and where to biopsy the tumor and deliver the fetus. We are looking for a team approach to treat the mother and keep the baby safe and in the womb for as long as possible.

What is the most important message for the practicing oncologist?

Bianchi: Pregnancy should not be a reason to delay treatment for cancer. Many oncologists are unaware that prenatal testing for genetic conditions can also potentially detect cancer in the mother. Pregnant women who are otherwise healthy, young, and asymptomatic are sent to oncologists with suspicious NIPT findings and oncologists often do not want to treat the cancer.

This concept also often comes as a surprise to the pregnant woman. Prenatal care concentrates on the fetus, not the mother. Ninety percent of circulating cfDNA comes from the mother and 10% from the placenta, which represents the fetus.

We need to improve pre-test counseling to warn patients and physicians ahead of time. Tests that detect fetal genetic problems can also possibly detect problems in the mother's health, such as the genetic condition mosaic Turner syndrome.

Read the study here.