Breast Cancer Detection and Treatment Monitoring Using a Noninvasive Prenatal Testing Platform: Utility in Pregnant and Nonpregnant Populations

Abstract

Background Numerous publications have reported the incidental detection of occult malignancies upon routine noninvasive prenatal testing (NIPT). However, these studies were not designed to evaluate the NIPT performance for cancer detection. Methods We investigated the sensitivity of a genome-wide NIPT pipeline, called GIPSeq, for detecting cancer-specific copy number alterations (CNAs) in plasma tumor DNA (ctDNA) of patients with breast cancer. To assess whether a pregnancy itself, with fetal cell-free DNA (cfDNA) in the maternal circulation, might influence the detection of ctDNA, results were compared in pregnant (n = 25) and nonpregnant (n = 25) cancer patients. Furthermore, the ability of GIPSeq to monitor treatment response was assessed. Results Overall GIPSeq sensitivity for detecting cancer-specific CNAs in plasma cfDNA was 26%. Fifteen percent of detected cases were asymptomatic at the time of blood sampling. GIPSeq sensitivity mainly depended on the tumor stage. Also, triple negative breast cancers (TNBC) were more frequently identified compared to hormone-positive or HER2-enriched tumors. This might be due to the presence of high-level gains and losses of cfDNA or high ctDNA loads in plasma of TNBC. Although higher GIPSeq sensitivity was noted in pregnant (36%) than in nonpregnant women (16%), the limited sample size prohibits a definite conclusion. Finally, GIPSeq profiling of cfDNA during therapy allowed monitoring of early treatment response. Conclusions The results underscore the potential of NIPT-based tests, analyzing CNAs in plasma cfDNA in a genome-wide and unbiased fashion for breast cancer detection, cancer subtyping and treatment monitoring in a pregnant and nonpregnant target population.

Initial Clinical Experience with NIPT for Rare Autosomal Aneuploidies and Large Copy Number Variations

“…Due to the size limitations for a positive CNV call with the NIPT method used, it is possible that other CNVs remained undetected due to a smaller size below 7 megabases. Cancer detection per se by NIPT lacks performance metrics, and in case of breast cancer specifically, depends largely on the tumor stage and immunophenotype [40]. Taken together, the details of this case provided proof-of-principle for NIPT serving as a liquid biopsy screening method for neoplasia, although further studies are necessary.…”

“…Multiple aneuploidies, defined as more than one aneuploidy and unique and non-specific CNVs, have been described as incidental NIPT results pointing towards occult maternal malignancies [38,39]. The isolated CNV of patient F seems to be atypical for breast cancer, since the majority of patients show several CNVs on multiple chromosomes [40,41]. Due to the size limitations for a positive CNV call with the NIPT method used, it is possible that other CNVs remained undetected due to a smaller size below 7 megabases.…”

Comprehensive genome-wide analysis of routine non-invasive test data allows cancer prediction: A single-center retrospective analysis of over 85,000 pregnancies

“…First, our approach relies on stringent scoring parameters, potentially resulting in a number of false negative cases. This is underscored by the case with a borderline GIPSeq profile that was not classified as being suggestive of a malignancy but that could be finally linked to a cancer diagnosis, and by our data evaluating GIPSeq profiling in pregnant cancer patients [35]. Second, current NIPTbased algorithms are restricted to the detection of copy variable tumours and will miss copy neutral tumours.…”

“…Fig. 1 E) ID-11 33 12 3.59 4.43 13 no amniocentesis performed no congenital disease axillary lymph adenopathy palpable no abnormalities breast mass and axillar lymphadenopathies invasive breast carcinoma of no special type, hormone receptor-positive HER2-negative; stage II 25 cfDNA aberrations confirmed in tumor DNA (low-pass sequencing; reported in [35] ) ID-12 32 11 11.46 17.67 18 normal amniocentesis termination of pregnancy normal bone marrow punction and blood tests suggestive for acute myeloid leukemia diffuse infiltration of liver, spleen and bone marrow, suggestive for hematological malignancy acute myeloid leukemia; FAB M5 17 cfDNA aberrations confirmed in tumor DNA (FISH; reported in [40] ) ID-13 40 12 23.2 10.38 12 NA no congenital disease normal no abnormalities mass in the spleen, multiple adenopathies retroperitoneal, gastro-hepatic, gastrosplenic, pericardial and pancreatic non-Hodgkin lymphoma, diffuse large B-cell; Ann-Arbor stage II 19 cfDNA aberrations confirmed in tumor DNA (FISH; Fig. 4 ) ID-14 22 12 2.83 10.43 35 no amniocentesis performed no congenital disease normal no abnormalities mass in anterior mediastinum; adenopathies near thoracic outlet and incisura jugularis classical Hodgkin lymphoma, nodular sclerosis Hodgkin lymphoma (NSHL); Ann-Arbor stage IIA 57 cfDNA aberrations confirmed in tumor DNA (FISH; Suppl.…”

Non‐invasive prenatal testing suggesting a maternal malignancy: What do we tell the prospective parents in Belgium?

“…When using a subchromosomal analysis pipeline, they found an aberrant plasma DNA profile in 41% of the ovarian cancers, including 38% of early stage cases 22 . For breast cancer an overall GIPSeq sensitivity of 26% was reported by our group 23 . So, while early stage cancers are detectable on NIPT, there is not sufficient sensitivity to consider NIPT a screening test for cancer.…”