NIPT as a Potential Cancer Screening Tool in Pregnancy
A handful of studies have found that NIPT can detect unexplained aneuploidies in maternal blood samples not present in the fetus
Cancer screening in pregnant individuals can be challenging. Luckily, receiving a cancer diagnosis during pregnancy is a relatively rare phenomenon that occurs in approximately 1 in 1,000 pregnancies.1 The most commonly diagnosed cancers in pregnant individuals include breast cancer, cervical cancer, Hodgkin’s lymphoma, melanoma, leukemias, ovarian cancer, colorectal cancer, and thyroid cancer.
For pregnant individuals, the symptoms of these cancers are similar to nonpregnant individuals. But they are also similar to physiologic changes expected during pregnancy, such as bloating, headaches, and breast changes. As a result, these symptoms can be overlooked and diagnosis delayed. Another challenge in cancer diagnosis in pregnancy is that several of the imaging techniques used to identify potential malignancies, including PET and CT scans, cannot be used because they expose the fetus to unsafe levels of radiation.1 For these reasons, a noninvasive cancer screening tool for pregnant individuals is an exciting prospect.
Noninvasive prenatal testing as a cancer screening tool
Noninvasive prenatal testing (NIPT) is a liquid biopsy screening method used to detect fetal aneuploidies in pregnant individuals.2 First introduced into clinical practice in 2011, this test involves sequencing cell-free fetal DNA (cffDNA) derived from the placenta in maternal blood samples and analyzing results for the most frequently observed aneuploidies on chromosomes 13, 16, 18, 21, 22, X, and Y. This assay has a false positive rate of less than one percent for detecting fetal chromosomal abnormalities, decreasing the risk that pregnant individuals would have to undergo unnecessary invasive procedures like amniocentesis to confirm an erroneous result.
After introducing NIPT into clinical practice, clinicians noticed that the test detected unexplained aneuploidies in maternal blood samples that contradicted other analyses for fetal aneuploidies. The first instance of this was reported in a 2013 case study in which a 37-year-old woman opted to perform NIPT because of her advanced maternal age.3 The results from the test suggested fetal aneuploidies on chromosomes 13 and 18, and she subsequently underwent amniocentesis to determine the fetal karyotype. However, FISH and whole-genome oligonucleotide array results were consistent with a normal male fetus.
A second NIPT performed later in her pregnancy revealed the same chromosomal abnormalities. After giving birth to a healthy baby with a normal karyotype, the woman began complaining of persistent and worsening pelvic pain. Clinicians detected a vaginal small cell carcinoma that had metastasized. FISH performed on a paraffin-embedded biopsy of the patient’s tumor revealed that more than 80 percent of the cells had aneuploidies in chromosomes 13 and 18, consistent with the earlier NIPT findings.
Since this first case, several other studies have reported similar results. For example, in 2015, Bianchi et al. examined 125,426 samples from asymptomatic women who underwent NIPT.4 Based on their analysis, the researchers identified 3,757 abnormal results, 10 of which were identified as maternal cancers. Interestingly, maternal cancer most frequently correlated with the rare finding of more than one aneuploidy, which occurred in the first described case study. Further research into this finding could help increase the specificity of NIPT for cancer screening.
It is not surprising that these assays can detect maternal chromosomal abnormalities. NIPT analyzes all cell-free DNA in a blood sample. cffDNA makes up between 10 and 20 percent of the total cell-free DNA in a maternal blood sample;5 therefore, most of the DNA being analyzed comes from the mother. Just like the placenta, tumors also shed cell-free DNA into the blood through apoptosis and necrosis, and that tumor DNA can make up between three and 93 percent of the total cell-free DNA in the blood of nonpregnant individuals depending on tumor size.6 Because NIPT is not specific for cffDNA, it is just as likely to detect cell-free tumor DNA as it is cffDNA and return an abnormal result.
Potential for cancer screening
Most recently, a 2020 study investigated the sensitivity of a genome-wide NIPT pipeline for breast cancer screening in a cohort of 25 pregnant and 25 nonpregnant individuals who had received a breast cancer diagnosis.7 This research was specifically designed to determine the specificity and sensitivity of these tests in individuals who had received a cancer diagnosis.
NIPT detected 26 percent of cancer cases across the entire cohort. Two of these cases included asymptomatic individuals who had been diagnosed through other screening programs. Interestingly, the sensitivity of the assay was higher for pregnant women than nonpregnant women (36 percent versus 16 percent). However, a larger study population is needed to confirm this result. Additionally, NIPT was more likely to detect cancer in individuals with triple-negative breast cancer and with higher tumor burden.
While the prospect of using NIPT for cancer screening is exciting, there are ongoing ethical discussions about whether pregnant individuals who have opted to perform this test should be told about unexplained abnormal results.8 In a survey of over 300 genetic counselors in the US,9 77 percent shared that they would disclose NIPT results that suggested a malignancy, and 91 percent felt that there should be institutional or national guidelines on how to handle these findings with regards to patient disclosure.
The lack of specificity of NIPT for detecting malignancies does have the potential to cause unnecessary harm if the results are disclosed. For example, in the study by Bianchi et al.,4 only 10 out of 3,757 abnormal results correlated with malignancies. Nevertheless, disclosing these results could also lead to early detection, better treatment options, and improved treatment outcomes for those who do have malignancies. For instance, early diagnosis of colorectal cancer can reduce the need for potentially toxic treatments while improving patient survival.
Further research is required
Further research is still required before NIPT can become a standard tool for cancer screening in pregnant individuals. To be useful, the test requires increased specificity to eliminate false positives as well as established guidelines to ensure best practices and inform the next steps. With further research, NIPT has the potential to be an important resource for cancer screening in pregnant individuals.
1. Voulgaris, E., George Pentheroudakis, and Nicholas Pavlidis. "Cancer and pregnancy: a comprehensive review." Surgical Oncology 20.4 (2011): e175-e185.
2. Allyse, Megan, et al. "Non-invasive prenatal testing: a review of international implementation and challenges." International Journal of Women's Health 7 (2015): 113.
3. Osborne, C. Michael, et al. "Discordant noninvasive prenatal testing results in a patient subsequently diagnosed with metastatic disease." Prenatal Diagnosis 33.6 (2013): 609-611.
4. Bianchi, Diana W., et al. "Noninvasive prenatal testing and incidental detection of occult maternal malignancies." JAMA 314.2 (2015): 162-169.
5. Rafi, Imran, et al. "Non-invasive prenatal testing: use of cellfree fetal DNA in Down syndrome screening." British Journal of General Practice (2017): 298-299.
6. Jahr, Sabine, et al. "DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells." Cancer Research 61.4 (2001): 1659-1665.
7. Lenaerts, Liesbeth, et al. "Breast cancer detection and treatment monitoring using a noninvasive prenatal testing platform: utility in pregnant and nonpregnant populations." Clinical Chemistry 66.11 (2020): 1414-1423.
8. Benn, Peter, Sharon E. Plon, and Diana W. Bianchi. "Current controversies in prenatal diagnosis 2: NIPT results suggesting maternal cancer should always be disclosed." Prenatal Diagnosis 39.5 (2019): 339.
9. Giles, Meagan E., et al. "Prenatal cfDNA screening results indicative of maternal neoplasm: survey of current practice and management needs." Prenatal Diagnosis 37.2 (2017): 126-132.