Detection of maternal malignancies in 2 million pregnant women by NIPT

Aneuploidy caused by chromosome instability is a hallmark for most solid tumors. Multiple chromosomal aneuploidies (MCAs) from failed noninvasive prenatal tests (NIPTs) have been reported to be associated with maternal malignancies. In this study, a cancer risk model called the Cancer Detection Pipeline (CDP) was established by assessing copy number variations from the low-coverage NIPT sequencing data (i.e. 0.06 - 0.1x whole genome sequencing) of more than 1.93 million pregnant women who underwent NIPTs between January 2016 and December 2017. Of the 639 subjects who tested positive for MCAs in the initial NIPTs, 41 maternal malignant cancer cases were diagnosed with a median follow-up of 399 days (IR, 303 - 487 days). The 41 cancer patients presented a wide spectrum of cancer types, the most frequent being breast cancer (10 cases), liver cancer (9) and lymphoma (9), at stage II to IV. Application of the CDP model allowed 34 of the 41 (83%) cancer cases to be identified with a positive predictive value (PPV) of 30.1% and specificity of 84.2%. Moreover, combining the CDP model with 8 plasma tumor markers gave PPV of 75.0%. Taken together, these data suggest that integrating of tumor markers into cfDNA (cell free DNA) analysis is a promising approach for detecting presymptomatic cancers and warrant further investigation in large clinical trials, particularly in populations at high risk of cancer. This study also makes evidence-based recommendations for how clinicians can proceed if a NIPS test detects multiple chromosomal aneuploidies in a pregnant woman.