Phosphorylation of the retinoblastoma protein at Serine 249 and the cadherin switch as clinically informative biomarkers for the discrimination between indolent and aggressive forms of prostate cancer.

Abstract Prostate cancer (PCa) is the second most frequent malignancy in men worldwide. This disease is the cause of most cancer death among Puerto Rican men, representing 18.9% of overall cancer deaths. However, a patient outcome depends on the type of tumor, which can be indolent or aggressive. The indolent PCa is of slow tumor growth and favorable prognosis, whereas the aggressive form is of rapid tumor spread and high mortality. The discrimination between the indolent and aggressive forms of PCa has resulted in a significant problem of overtreating those patients with the indolent form of the disease. Thus, biomarkers that aid in the decision-making process regarding active surveillance in very low-, low-, and favorable intermediate-risk PCa face a large unmet need. For this purpose, we evaluate the expression of phospho-Rb S249 and epithelial to mesenchymal transition markers (E-cadherin, N-cadherin, B-catenin) to create a combination that can help distinguish between the indolent and aggressive forms of PCa. We hypothesize that the biomarkers E-cadherin, and B-catenin could be useful to identify indolence among PCa patients, whereas phospho-Rb S249 and N-cadherin could identify the aggressive form of the disease. As part of our methodology, we have conducted immunohistochemistry (N=182) against the expression of these biomarkers on PCa tumor microarrays (TMA’s). Correlation coefficient analyses were conducted to assess if the expression of these biomarkers could correlate with any of the patient’s clinical parameters (stage, grade, tumor size, lymph nodes metastasis, metastasis to distant sites, Gleason score, and Gleason grade). In addition, we created a linear regression analysis to determine if the combined proteins could precisely predict the staging, grade, or Gleason score of the patients. Results have shown that the combination of phospho-Rb S249, N-cadherin, E-cadherin, and B-catenin had a precision of 68% correctly predicting the staging of the patients, and adding the tumor size, lymph nodes metastasis, and metastasis to distant sites to the equation increased the prediction to a 96%. Additionally, we identified that E-cadherin and B-catenin negatively correlated with the tumor size, grade, stage, Gleason grade, and Gleason score of the patients. Whereas N-cadherin and phospho-Rb S249 positively correlate with the tumor size, stage, and Gleason grade. These results suggest that the expression of phospho-Rb S249, N-cadherin, E-cadherin, and B-catenin could be used as a potential tool to discriminate between the indolent and aggressive forms of PCa. This will contribute to enhancing the clinical decision of which patients should be treated or undergo active surveillance. Citation Format: Sheila M. Valle Cortes, Pedro Santiago Cardona, Carlos Diaz Osterman, Harold Saavedra, Shannalee R. Martinez, Gilberto Ruiz Deya, Jaileene Perez Morales, Adam B. Murphy. Phosphorylation of the retinoblastoma protein at Serine 249 and the cadherin switch as clinically informative biomarkers for the discrimination between indolent and aggressive forms of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6001.