TORONTO – Women who receive a "non-reportable" result from a noninvasive prenatal cell-free DNA test carry a high risk of having cancer and should be referred for further testing, preferably a whole-body MRI, according to early results from an ongoing clinical study.
Diana Bianchi, director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, who presented results from the trial here at the American College of Medical Genetics and Genomics annual meeting on Wednesday, said there is great urgency "to follow up on non-reportable results and get these women treated before it is too late."
Cell-free DNA analysis for fetal aneuploidies in maternal blood has become a widespread screening test over the past decade, as it has a high positive predictive value. It has also been known since at least 2015 that there can be incidental findings: Multiple chromosomal or sub-chromosomal gains or losses — usually returned as a "non-reportable" result — often indicate that a pregnant woman has an undetected malignancy.
Women in other countries, such as the Netherlands and Belgium, are already referred for follow-up testing if they receive a non-reportable result, Bianchi said, but that is not the case in the US, where at least 12 companies offer cell-free DNA-based noninvasive prenatal tests, or NIPTs, and differ in their reporting procedures.
To demonstrate that NIPT can essentially act as a liquid biopsy for early cancer detection, and to determine the best approach for further diagnostic workup in women with a non-reportable result, her lab at the National Human Genome Research Institute, in collaboration with the National Cancer Institute and the NIH Clinical Center, launched a prospective study in 2019 called IDENTIFY, for Incidental Detection of maternal Neoplasia Through non-Invasive cell-Free DNA analysis. Another goal of the study is to identify DNA sequence patterns and other biomarkers that correlate with the presence of cancer, Bianchi noted.
The study is open to adult women with an abnormal or non-reportable NIPT result from one of 12 commercial tests offered in North America who had a normal follow-up ultrasound or diagnostic genetic test for their fetus and who are currently pregnant or up to two years postpartum. They must also be asymptomatic for cancer at the time of their NIPT or only have nonspecific symptoms and be willing to travel to the NIH Clinical Center for clinical evaluation.
The evaluation consists of a confirmatory NIPT, performed by a single laboratory, other blood tests to obtain hematological and biochemical profiles or to measure serum tumor markers, and a fecal occult blood test. In addition, participants receive a rapid whole-body MRI, with or without contrast depending on whether they are still pregnant. They also undergo a physical examination by a medical oncologist and placental microarray studies when indicated.
Bianchi's report focused on 120 individuals who enrolled in the study, most of them while they were still pregnant. This was only about half of those initially referred, which she attributed in part to the pandemic, as many women did not want to travel during that time. Of those enrolled, 107 participants — from the US and Canada — were fully evaluated and included in the analysis.
A total of 52, or almost 50 percent, were found to have cancer. In particular, women with copy number gains or losses in three or more chromosomes were highly likely to have a malignancy. Hodgkin lymphoma was the most common cancer type, making up almost 40 percent of cases, followed by non-Hodgkin lymphoma, colorectal cancer, and breast cancer. In addition, there were two cases of cholangiocarcinoma, and one case each of Ewing sarcoma, adrenocortical carcinoma, pancreatic, non-small cell lung, and renal cancer. Bianchi said that while lymphomas were an expected cancer type in this young age group, her team was surprised by the high number of colorectal and breast cancer cases. Also, while most of the lymphomas were detected at an early stage, all the colorectal cancer cases were stage IV.
Of the 55 participants where no cancer was detected, 30 had a biological explanation for their non-reportable NIPT result: They had fibroids, confined placental mosaicism, trisomy in their baby despite a normal secondary test, or clonal hematopoiesis. Another 15 had normal results on the NIPT repeat test, and the remaining 10 are still being followed, for up to five years, to see if they might develop cancer.
Both women who were found to have cancer and those who were not had previously reported a variety of symptoms, ranging from pain and fatigue to palpable lumps and rectal bleeding. These symptoms were often dismissed or attributed to their pregnancy, so the women were not initially further tested for cancer.
Whole-body MRI was the best of the clinical follow-up tests, including the physical examination, to confirm or rule out cancer in participants, having the highest sensitivity and specificity. Other blood tests were "nearly useless," Bianchi reported, often returning "completely unremarkable results." She added that most of the women who came to the NIH for their clinical evaluation "looked perfectly fine" and had no obvious signs of cancer. One of her goals now is to convince health insurers to cover whole-body MRI as a work-up for women with a non-reportable NIPT, she said.
While there is debate whether to delay treatment for pregnant women found to have cancer, or to have them deliver early, treatment can often be started safely during pregnancy, she said. "Pregnancy is not a reason to delay," Bianchi said, noting that six participants in the study have died of their cancer so far.