A novel blood test may accurately detect neuroendocrine prostate cancer and differentiate it from castration-resistant prostate adenocarcinoma, according to a recent study published by Franceschini et al in Cancer Discovery.
Background
Approximately 10% to 15% of patients with metastatic prostate cancer develop neuroendocrine prostate cancer—a difficult cancer type to treat. The transition involves a shift from cancer cells that are dependent on androgens to cancer cells that no longer recognize androgens. Through this process, the cancer cells have been found to take on new “identities.” Detecting such an identity-switch may be particularly challenging when metastatic castration-resistant prostate cancer advances from adenocarcinoma to neuroendocrine prostate cancer.
“They can stop expressing the androgen receptor. They shut down their hormone-driven identity and they turn on a new identity as a way to develop resistance to treatment,” explained co–senior study author Himisha Beltran, MD, Associate Professor of Medicine at the Lank Center for Genitourinary Oncology and the Division of Molecular and Cellular Oncology at Dana-Farber Cancer Institute. “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,” she stressed.
Physicians currently diagnose neuroendocrine prostate cancer using a biopsy of tumor tissue from a metastatic tumor site. However, it isn’t always clear to physicians when to perform a biopsy—which may be unreliable because metastatic tumors are often heterogeneous.
In previous studies, researchers analyzed tissue samples from biopsies to identify the genetic and epigenetic changes related to the transition to more treatment-resistant tumors. They found that across the whole genome, specific epigenetic changes in the form of DNA methylation alterations that switch genes on or off, may help distinguish castration-resistant prostate cancer–adenocarcinoma from neuroendocrine prostate cancer.
These epigenetic changes can be detected in the blood because the body is constantly shedding fragments of dead cells—including tumor cells and cell-free DNA (cfDNA) along with epigenetic tags and structures that were attached to them when the cells died—into the bloodstream.
Study Methods and Results
In the recent study, the researchers developed a novel neuroendocrine monitoring (NEMO) blood panel test. They noted that the NEMO blood test was capable of reporting two measures: the tumor fraction and the tumor type, which was conveyed as a score on a continuum to account for a patient’s tumor being a mix of both castration-resistant prostate cancer–adenocarcinoma and neuroendocrine prostate cancer.
"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," reiterated Dr. Beltran.
The researchers examined the efficacy of the NEMO blood test in several preclinical models of prostate cancer and in blood samples from multiple patient cohorts with known prostate cancer subtypes. The novel test’s tumor type score identified subtypes with a high level of accuracy.
“The test selectively probes cfDNA in blood plasma for relevant DNA fragments and measures their methylation,” emphasized co–senior study author Francesca Demichelis, PhD, of the University of Trento. "Because the number of methylated regions needed to distinguish between normal [castration-resistant prostate cancer–adenocarcinoma] and [neuroendocrine prostate cancer] cells is small, the panel of genes sequenced by the test is minimal and efficient,” she indicated.
The researchers further evaluated the NEMO blood test in two clinical trials involving patients with aggressive castration-resistant prostate cancer. The test’s estimation of tumor fraction was consistent with other accepted measures of disease burden, suggesting that the test may be effective at monitoring response to treatment by revealing if a tumor is shrinking or not. This is especially valuable because measures of disease burden, such as prostate-specific antigen levels, become unreliable when a tumor switches its identity to neuroendocrine prostate cancer.
Additionally, the NEMO blood test successfully identified patients with neuroendocrine prostate cancer in the two clinical trials based on pathology reports. It also identified patients who had not been diagnosed with neuroendocrine prostate cancer despite presenting with signs of a transition to the cancer subtype in their pathology reports.
Conclusions
“We hope this blood test can be used by [physicians] to determine if a patient is developing neuroendocrine prostate cancer,” highlighted Dr. Beltran. “Now that we have robustly shown the accuracy of this panel test, we're excited to apply it to clinical questions. 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,” she added.
The information in a NEMO blood test may help physicians select targeted treatments for patients, help researchers better understand neuroendocrine prostate cancer, or be applied to other types of cancer to distinguish subtypes. The researchers plan to further take steps toward transitioning their NEMO blood test into a clinical test that physicians can order and use in practice.
Disclosure: The research in this study was funded by the Prostate Cancer Foundation, the National Cancer Institute, Fondazione AIRC per la Ricerca sul Cancro ETS, Cancer Research UK, the United States Department of Defense, the Doris Duke Foundation, the Safeway Foundation, the V Foundation, and the Institute for Prostate Cancer Research. For full disclosures of the study authors, visit aacrjournals.org.
