By What should have been one of the most joyous times of Dr. Naseem Khorram’s life turned into one of the most terrifying.
The Los Angeles-based nephrologist was getting routine bloodwork during her second pregnancy, standard testing to screen for any chromosome abnormalities in the fetus, such as Down syndrome.
Khorram was healthy, and her pregnancy was progressing well. “I thought nothing of it,” she said.
She was shocked when the test results came back. They were “atypical for maternal chromosomal DNA variants”: Her baby was healthy, but there was something unusual about her own health.
Test results can come back as “atypical” for many reasons, such as noncancerous growths like uterine fibroids. But atypical results can also be associated with a “very high rate” of malignancy, Khorram said. Her obstetrician-gynecologist recommended that she have a full-body MRI, or magnetic resonance imaging, which scans images of the body to check for cancer.
“This is one of the most terrifying times of my life that I went through,” said Khorram, now a 36-year-old mother of two young girls.
“It wasn’t something I anticipated,” she said. “When someone tells you that you might have a cancer, the first thing that comes to mind is, ‘Am I going to see my daughters grow up?’ But I will.”
Khorram’s insurance approved coverage for a full-body MRI, but the hospital where she was receiving care declined it, stating that it does not perform whole-body scans, she said. Instead, she enrolled in a study at the National Institutes of Health that involved examining women who received abnormal prenatal DNA-sequencing test results like hers. Through that research, Khorram received a full-body MRI scan and was diagnosed with stage II Hodgkin lymphoma, a cancer of the lymphatic system.
“Part of the reason why I wanted to get involved in the NIH study and to share my story is that we need a protocol in place – the health care system, insurers, radiologists – need to recognize that additional imaging is needed, additional investigation is needed, and we can’t just turn our heads away” when someone gets an atypical test result, Khorram said.
Khorram began chemotherapy immediately after diagnosis and continued to have a healthy pregnancy.
She completed treatment two weeks before her daughter was born.
“It’s really easy to be terrified by these results, and that’s normal,” she said. “But I really encourage people to advocate for themselves, to have additional diagnostic workup done, because it could be lifesaving.”
‘We’re so lucky to both be here’
Khorram now is cancer-free. She will have a checkup with her doctors next year so they can continue monitoring her health, but overall, she has been feeling well.
She’s focusing on having a quiet holiday season with her husband and two daughters, now 3 years and 4 months old.
“My older daughter, she’s really smart; she’s very kind; she is intuitive. When I was going through all of this, we didn’t explain it to her, because she was only 3, but she knew that something was off, and she just kind of stuck by me,” Khorram said. “My younger daughter, she’s amazing. I can’t believe she’s only 4 months old. She’s so happy all the time. She’s always smiling. I look at her, and I think, ‘we’re so lucky to both be here.’”
Khorram was one of 107 volunteers in the NIH study, which examined how prenatal cell-free DNA sequencing may incidentally detect cancer in mothers. Cell-free DNA or cfDNA refers to fragments of DNA circulating in blood and other bodily fluids outside of cells.
In the study, the results of which were published this month in the New England Journal of Medicine, almost half – 48.6% – of the participants who had unusual prenatal DNA-sequencing results also were found to have cancer somewhere in their bodies.
“First of all, we don’t want all pregnant people to be worried by the study. This is a small subset but an important subset,” said Dr. Diana Bianchi, senior author of the new study and director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
“It also doesn’t mean that if you get a result like this, that you have a 48% chance of having cancer,” she said. “It means that you need the workup, and it means that we need to take the results seriously.”
Prenatal genetic testing is done to screen for genetic conditions known as fetal aneuploidy, such as Down syndrome, in which a fetus has one or more extra chromosomes or the absence of one or more chromosomes.
The screening – which is routinely offered to all pregnant people – involves analyzing cell-free DNA fragments from the placenta that circulate in the mother’s bloodstream.
The placenta is the organ that develops in the uterus during pregnancy. It provides oxygen and nutrients to the fetus while removing harmful waste from the baby.
Prenatal genetic testing can pick up cancer because tumors also shed fragments of DNA into the bloodstream just like the placenta does, Bianchi said.
“If you take a blood sample, you’ve got a mixture of the mother’s fragments, which are normally there; you’ve got the placenta, which are only there if you’re pregnant; and now you have a tumor – and so you have a mixture of these three things, and it kind of messes up the results,” she said.
All the participants in the study, who were enrolled from December 2019 to December 2023, were either pregnant or up to two years postpartum; they had not noticed any signs or symptoms of cancer but had received abnormal or nonreportable prenatal DNA-sequencing results as part of their routine care.
The researchers used whole-body MRIs and standard diagnostic tests to identify participants with previously undetected cancers.
They found that 52 of the 107 participants who received unusual or nonreportable sequencing results had an occult cancer, meaning the disease was present but the site of the tumor was unknown.
A total of 51 participants underwent biopsies to confirm the cancer diagnoses. Some of the cancers were later determined to be lymphoma, colorectal and breast. Two patients with solid tumors had stage I disease, five had stage II or III, and 13 had stage IV, Bianchi said. Six of 13 patients with stage IV cancer were still eligible for potentially curative treatment.
Sequencing results showing a particularly “chaotic” pattern across multiple chromosomes were observed in 47 of the 51 participants with cancer. One participant with cancer did not have available sequencing results.
That specific pattern in the sequencing results “looks like a very chaotic sawtooth pattern that is involving more than three human chromosomes, and you see lines going up, you see lines going down, which represent parts of the genome that are missing or that are duplicated,” Bianchi said.
This suggests that people with this distinct sequencing pattern may have the highest risk of cancer, “and such patients should be identified on a written laboratory report so that timely cancer screening can be pursued,” the researchers wrote.
Other potential factors behind an unusual test result include uterine fibroids or problems with the placenta. But when physicians look at a pool of unusual test results, the chaotic sequencing pattern could flag whether something more serious may be going on and the mother could benefit from additional testing, Bianchi said.
“There are safe ways to do additional testing, and we know that we have been able to save some lives because we acted quickly,” she said. “We also know that there were other people in the study whose workups were deferred until after delivery, who suffered from the several-months delay in which the cancer progressed.”
The chaotic pattern of chromosomal abnormalities seen in most of the test results associated with cancer was “a very important” finding in the study, said Dr. Britta Weigelt, a molecular geneticist at Memorial Sloan Kettering Cancer Center, who was not involved in the new research.
“That’s a big finding of the study: that it is a certain pattern of chromosomal abnormalities in cfDNA sequencing that is associated with maternal cancer,” Weigelt said. “Future studies should probably test whether this particular pattern of aberrations can be used as biomarkers potentially for the detection of maternal cancer.”
‘These are truly hidden cancers’
Many of the study participants with cancer – 29, or 55.8% – showed no symptoms of the disease, while 13 or 25% had symptoms that they thought were due to pregnancy.
“These are truly hidden cancers in people,” Bianchi said.
One participant with pancreatic cancer reported pain in the abdomen that she thought was due to reflux. Bianchi said another patient with cancer had rectal bleeding and assumed it was due to hemorrhoids, which are common in pregnancy.
“The bottom line of our study is that pregnant people should be treated just like anybody else. Their treatment should not be delayed because they are pregnant,” Bianchi said.
“There’s quite a lot of medical information and research studies out there showing which chemotherapy drugs are safer than others to give during pregnancy,” she said. “There’s good information to show now that generally after about 19 weeks into the pregnancy – so halfway through the pregnancy – for that second half, you can treat safely.”
The researchers noted that the sample of participants “is not representative of the general pregnant population” and that more research is needed to investigate how cell-free DNA sequencing among pregnant people may hold insights into identifying cancer cases on a larger, real-world scale.
For instance, if a patient has an unusual prenatal DNA-sequencing test result – and it shows the chaotic pattern that has been associated with cancer – their physician could present that result as reason to order an MRI.
Bianchi said that is her hope.
“Since we showed that the MRI imaging was so sensitive, a limitation is whether or not we’re going to be able to obtain MRIs in the pregnant people with the chaotic DNA sequencing pattern and whether Medicaid or whether private insurance will pay for the MRIs,” Bianchi said. “I’m hoping with these data in showing how effective the MRIs were, that at least in this circumstance, that MRIs will be paid for, because ultimately, it will save lives.”
It’s estimated that only about 1 in 1,000 women each year are diagnosed with cancer during pregnancy in the US. But it could be helpful to have some guidelines around what to do if a patient has an atypical prenatal DNA-sequencing test result and when to order additional testing, Weigelt said.
Although the new study suggests that abnormal findings on cfDNA require additional workup, that is not currently the standard of care, said Dr. Emeline Aviki, gynecologic oncologist at NYU Langone’s Perlmutter Cancer Center – Long Island.
And the study methodology “does not tell us whether or not early detection will translate to a difference in outcomes for all of the cancers that were identified, as this was not its intended purpose,” Aviki, who was not involved in the new study, wrote in an email.
Cell-free DNA has the potential to identify cancer, but “the way in which we adopt these technologies remains important, as it can create significant anxiety and additional testing for 50 percent of women who, in fact, have no issue, while potentially benefits the others, who have an unknown cancer,” she said. “Future studies will need to test how to optimize use so that we can garner the most benefit and least harm from this very exciting technology.”
It’s a timely discussion, as the incidence of cancer among adults under 50 has been increasing in the United States, said Dr. Sarah Kim, a gynecologic surgeon at Memorial Sloan Kettering Cancer Center who was not involved in the new study.
Among adults 65 and older, adults 50 to 64 and those younger than 50, “people aged younger than 50 years were the only one of these three age groups to experience an increase in overall cancer incidence” from 1995 to 2020, according to a report released earlier this year by the American Cancer Society.
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As this trend emerges, the United States could see more cancer cases among the specific population of pregnant people.
“More cancers are being diagnosed in younger patients,” Kim said. “In this special population of pregnant patients, because noninvasive prenatal testing has become mainstream, I think it does provide a unique opportunity to potentially diagnosis patients with cancer.”
But she said that when it comes to tests like prenatal cell-free DNA sequencing, certain cancers may be more easily detected through the bloodstream than others.
“Gynecologic cancers specifically have a lower amount of cell-free DNA that’s released into the bloodstream, just because of the way it spreads inside of a patient, as compared to, for instance, colon cancers or breast cancers that spread through the bloodstream,” Kim said.
“While the technology is not quite there to be used as a screening tool for cancer, I think it’s something that’s important and needs to be developed,” she said. “Because the goal should be to catch cancers earlier, when they are treatable.”