The researchers at the Dana-Farber Cancer Institute, MA, and the University of Trento, Italy, developed a new blood test to target the molecular mechanisms used by castration-resistant prostate cancer (CRPC or CRPC-adenocarcinoma [CRPC-adeno]) to transition into the rare and notorious neuroendocrine prostate cancer (CRPC-NE or NEPC).
Cancer cells can evade the immune system by numerous mechanisms, including immunologic and histologic transitions, and sometimes, epigenetic changes like DNA methylation. These changes or “identity switches” are tricky to detect and often result in treatment-resistant or difficult-to-treat cancers.
NEPC is an aggressive subtype of treatment-resistant prostate cancer. Early detection is critical, but current diagnosis relies on metastatic biopsy, which may be unreliable due to high tumor heterogeneity. In a recently published study in Cancer Discovery, the researchers described a targeted DNA methylation assay to detect NEPC using plasma cell-free DNA (cfDNA).
The NEMO test
Co-lead author Himisha Beltran, MD, associate professor of medicine, Lank Center for Genitourinary Oncology and the Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, collaborated with a computational team at the University of Trento, led by Francesca Demichelis, PhD, co-lead author on the study, to create a blood panel test, called NEMO (NEuroendocrine MOnitoring). “The test selectively probes cfDNA in blood plasma for relevant DNA fragments and measures their methylation,” said Demichelis in a recent press release. “Because the number of methylated regions needed to distinguish between normal, CRPC-adeno, and NEPC cells is small, the panel of genes sequenced by the test is minimal and efficient.”
NEMO reports the tumor fraction and tumor phenotype (either CRPC-adeno or NEPC). Tumor fraction is a measure of disease burden based on the ratio of tumor DNA to normal DNA in a blood sample. Tumor phenotype is reported as a score on a continuum using the transcriptional state and regions on the cfDNA. “[NEMO] not only picks up the neuroendocrine phenotype but also can pick up subtypes in the middle, as tumors transition from one subtype to the other,” said Beltran.
Performance and success rate
The team tested the NEMO panel on independent clinical cohorts with known prostate cancer subtypes. The liquid biopsy panel identified CRPC-adeno and NEPC subtypes with a high level of accuracy (AUC > 0.93). NEMO was also cross-verified with clinical outcomes from two progressive trials of patients with aggressive CRPC variants.
“Now that we have robustly shown the accuracy of this panel test, we’re excited to apply it to clinical questions,” said Beltran. “We’d like to determine if this test can help us predict which patients respond to certain prostate cancer treatments, including precise treatments that target neuroendocrine prostate cancer.”