Prostate cancer
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Researchers from Dana-Farber Cancer Institute and the University of Trento, Italy, report in Cancer Discovery, that they have developed a new blood test differentiates neuroendocrine prostate cancer (NEPC) once it has advanced from adenocarcinoma. Having a non-invasive method to detect this switch has important implications for this hard-to-treat form of the disease.

“As prostate cancer treatments get more effective, we expect the emergence of different types of treatment resistance like neuroendocrine prostate cancer that help them evade treatment,” says co-lead author Himisha Beltran, MD, associate professor of medicine, Dana-Farber Cancer Institute. “We hope this blood test can be used by clinicians to determine if a patient is developing neuroendocrine prostate cancer.”

Currently, NEPC is diagnosed via tumor biopsy from a metastatic tumor. But clinicians are often challenged to determine the right time for an invasive procedure to gather the sample. Further, such tissue-based tests can be inconclusive given metastatic tumors are often heterogeneous. Between 10% to 15% of patients with metastatic prostate cancer will progress to NEPC, characterized by a a shift from cells that are dependent on androgen, to cancer cells that no longer recognize these hormones.

Beltran says that in this transition the cancer cells stop expressing the androgen receptor and shut down the reliance on the hormone for survival to develop a new identity that resists treatment.

To develop the new blood test to identify when this transition has occurred, the international team tapped their previous research of the genetic and epigenetic changes that take place as NEPC develops. Their findings showed that, across the entire genome, methylation changes occur that distinguish castration-resistant prostate cancer adenocarcinoma (CRPC-adeno) from NEPC. The new test, called NEMO (NEuroendocrine MOnitoring panel), can make the distinction between the two subtypes by examining cell-free DNA (cfDNA) shed by the tumors found in the blood.

“The test selectively probes cfDNA in blood plasma for relevant DNA fragments and measures their methylation,” says co-lead author Francesca Demichelis, PhD, of the University of Trento. “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 both the tumor fraction, a measure of disease burden that measures the ratio of tumor DNA to normal DNA, and the tumor type, either CRPC or NEPC. Since a patient’s cancer may be a mix of the two during the transition, NEMO reports this as a score on a continuum. “It 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,” notes Beltran.

The test has been evaluated in both a handful of preclinical models of prostate cancer in blood sample from different cohorts of patients with known subtypes of prostate cancer. NEMO was also evaluated in two clinical trials of patients with aggressive CRPC, with the test panel delivering tumor fraction estimation that was consistent with other measure of disease burden. This points to a future where the test panel could be employed to help monitor how effectively the cancer is being treated by providing data that shows decreased tumor burden—an indication the tumor is shrinking. This information is important as normal measures of disease burden, such as PSA testing become unreliable after the cancer has switched to NEPC.

“Now that we have robustly shown the accuracy of this panel test, we’re excited to apply it to clinical questions,” says 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.”

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