# Clinical Implications of Molecular and Genetic Biomarkers in Cushing’s Disease: A Literature Review

## TL;DR

This review explores how molecular and genetic markers can help predict tumor behavior and treatment response in Cushing’s disease, aiming to improve personalized care.

## Contribution

The paper highlights novel molecular biomarkers like USP8 mutations and Ki-67 index for predicting tumor aggressiveness and treatment outcomes in Cushing’s disease.

## Key findings

- Immunohistochemical markers like Ki-67 and E-cadherin correlate with tumor invasiveness and surgical outcomes.
- Genetic alterations such as USP8 mutations influence tumor growth and response to targeted therapies.
- Biomarkers like CABLES1 and TP53 are linked to more aggressive tumor behavior.

## Abstract

Cushing’s disease (CD) is a rare disorder caused by adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumors, which lead to chronic hypercortisolism and significant complications with increased mortality. These tumors are characterized by a substantial heterogeneity in their biological behavior, prognosis, and therapeutic response, making their management challenging. While transsphenoidal surgery remains the first-line treatment, recurrence rates remain high, and alternative therapeutic approaches, such as pharmacological therapy and radiotherapy, have a variable efficacy and are frequently limited due to side effects. Increasing evidence suggests that molecular biomarkers, both immunohistochemical and genetic, may play an important role in predicting a tumor’s aggressiveness, recurrence risk, and response to targeted therapies. The immunohistochemical evaluation of its granulation pattern, Ki-67 proliferation index, and E-cadherin expressions have been linked to a tumor’s invasiveness and surgical outcomes, while somatostatin and dopamine receptor expressions may influence its response to Pasireotide and cabergoline therapy. Genetic alterations such as USP8 mutations impact tumor growth and its response to targeted therapies, whereas CABLES1 and TP53 alterations may contribute to more aggressive tumor behavior. Despite these findings, the clinical applicability of many of these markers remains limited by inconsistent validation and lack of standardized cutoff values. This narrative review provides an update on the latest evidence regarding the roles of molecular biomarkers in corticotropinomas, emphasizing their role in prognosis, recurrence risk, and the response to different treatment options. A better understanding and integration of these biomarkers into clinical practice could lead to a better patient stratification, more efficient therapeutic strategies, and personalized treatment approaches for patients with CD.