Potential Prognostic NET Biomarker

Identified in published results in NETRF-funded study

A retrospective analysis of neuroendocrine tumor (NET) specimens showed that a novel test for an enzyme secreted by neuroendocrine cells may help predict the course and outcome of neuroendocrine cancers.

Justin Annes, MD, PhD

About the study

As a part of a 2018 NETRF Pilot Award, Justin Annes, MD, PhD, Stanford University, studied the levels of an enzyme called PAM (short for Peptidylglycine α-amidating monooxygenase) in primary NET tissue specimens donated by 109 patients between 1992-2013.

By comparing NET levels of PAM with patient data that included tumor grade, stage, and site of origin, Dr. Annes found the expression of PAM to be associated with disease outcome, which means, if confirmed by additional laboratory and clinical studies, PAM could emerge as a new NET prognostic biomarker that may help predict the likelihood of disease spread, recurrence, and patient treatment response.

PAM is an enzyme found in healthy neuroendocrine cells that is essential for their production of secreted hormones. The lack of this enzyme, according to Dr. Annes, may represent an important new indicator that a tumor has lost its normal behavior and is likely to progress. Given the role of PAM in healthy neuroendocrine cell functions, high levels of PAM “indicate a better prognosis, while reduced PAM levels indicate a worse prognosis, independent of NEN [neuroendocrine neoplasm] stage and, potentially, grade and anatomic origin.”

What the study found

In a July 2, 2020 article in Scientific Reports, an online peer-reviewed journal published by Nature Research, Dr. Annes remarked on the unmet need for prognostic biomarkers in NETs. “Predicting the behavior of individual well-differentiated NENs remains a challenge. Some NENs grow slowly or do not recur after resection, while others behave aggressively and rapidly advance.”

PAM is present in most primary neuroendocrine tumors. Dr. Annes and his colleagues looked at:

  • How much PAM was present.

  • When it was present.

  • Whether PAM was associated with survival.

  • Whether PAM was associated with tumor grade, stage, or site of origin.

The analysis revealed that PAM levels did not associate with either tumor size or disease stage, indicating that it is an independent prognostic indicator of NETs. Importantly, the reduction or lack of PAM was associated with shorter survival and increased risk of death. According to Dr. Annes, the utility of PAM as a potential NET biomarker is further strengthened by its applicability across many different primary sites of tumor origin.

“The role of PAM in neuroendocrine cancers merits much further study,” said John Kanki, PhD, NETRF Director of Research. “These exciting findings serve as a perfect example of how NETRF’s funding of a one-year pilot study can contribute to opening doors to new, meaningful approaches that may improve the diagnosis and treatment of NETs.”


NETRF funds laboratory research to understand the development of neuroendocrine tumors and translational research to explore new concepts in treatment. Research grant descriptions and research updates from NETRF are not intended to serve as medical advice. It can take years for research discoveries to be fully validated and approved for patient care. Always consult your health care providers about your treatment options.