Immunohistochemical Expression Profile of Cdk4 in Carcinoma Breast and Correlation to Clinicopathological Parameters- A Cross-Sectional Study

Abstract

Breast carcinoma stands as the most commonly diagnosed cancer among women and is a leading contributor to cancer-related deaths in females. It is increasingly being identified at younger ages, with tumors that are often biologically aggressive and diagnosed at more advanced stages, thereby resulting in elevated mortality rates. In the context of personalized medicine, there is a pressing need to discover novel, effective prognostic and predictive biomarkers that are involved in the development and progression of breast cancer, as well as serve as potential therapeutic targets—particularly when considering the genetic variability among patients.

Among the many molecules and biomarkers implicated in the molecular pathogenesis of breast cancer, disruption of the cyclin D–cyclin-dependent kinase (CDK) regulatory axis may shift cells away from senescence and promote a more proliferative behavior. Cancer cells may exploit multiple pathways to enhance cyclin D-associated CDK activity. CDKs, through their interaction with cyclin D proteins, play a crucial role in advancing the cell cycle and are considered promising targets for cancer treatment, including in breast tumors.

Despite this, previous research has shown mixed findings regarding the role of CDK4 in breast cancer, and only a limited number of studies have been conducted in the Indian population. Therefore, the current study was designed to investigate the immunohistochemical (IHC) expression of CDK4 in breast carcinoma and examine its association with various clinicopathological parameters and molecular subtypes. The objective is to evaluate its potential prognostic and predictive significance, which could support better patient classification and contribute to more personalized treatment approaches.

Methods

Seventy cases of invasive breast carcinoma in which 66 cases w ere mastectomy specimens and four cases of lumpectomy specimens received in the Department of Pathology between January 2021 to December 2024 were included in our cross-sectional study (retrospective and prospective). Immunohistochemical staining was done on these cases using Cyclin-dependent kinase 4 (CDK 4). IHC expression profiles (with specific staining scoring system) were correlated with clinicopathological parameters like age, tumor size, histopathological grading, lymph node metastasis, lymphovascular invasion, perineural invasion and adjacent ductal carcinoma in situ, estrogen- receptor (ER), Progesterone-receptor (PR) and Human-epidermal growth factor receptor-2 ( HER-2) expression and Ki-67 and molecular subtyping based on St. Gallen 2017 recommendation were done.

Results

CDK4 overexpression showed a statistically significant association with adverse prognostic parameters like patient group having lymph node metastasis (p=0.023) and perineural invasion (p=0.027). CDK4 overexpression also showed a statistically

significant association with ER (p=0.047), PR (p=0.034), Her/2 neu (p<0.001) and also association with four molecular subtypes with p =0. 05. Based on intensity of staining parameters, significant association noted between perineural invasion and ER, PR and HER2neu receptor expression status with more strong association with Her- 2neu group compared to ER, PR group.

Conclusion

Significant association of CDK- 4 expression, which belongs to cyclin- dependent kinase family, regulating cell cycle, noted with lymph node metastasis, peri neural invasion and hormone receptor expression along with molecular sub typed breast carcinomas. These findings significantly correlate CDK-4 expression with higher risk of metastasis and hence associated with aggressive prognosis. Therefore CDK- 4 can be used as a potential anti- cancer drug target for better prognosis of the patients specially in hormone receptor sensitive patients.