Circulating Glypican-4 Is a Predictor of 24-Month Overall Survival in Metastatic Breast Cancer

Abstract

Background & objective: Endocrine treatment combined with CDK4/6 inhibitors is the preferred treatment strategy in patients presenting with ER-positive/HER2-negative breast cancer, but the clinical course remains highly variable among individual patients. There is an unmet need for prognostic or predictive biomarkers in this important group of patients. Recently, we have identified circulating glypican-4 (GPC4) as a new biomarker of inferior outcomes in patients with metastatic colorectal cancer. The impact of plasma GPC4 levels on the survival of breast cancer patients is unknown and has been addressed in the present study. Methods: Our study included 47 patients with ER-positive/HER2-negative metastatic breast cancer prior to treatment with CDK4/6 inhibitors combined with endocrine therapy. The endpoint was overall survival (OS) at 24 months. GPC4 levels were measured in plasma using an enzyme-linked immunosorbent assay. Results: Increased circulating GPC4 levels were significantly linked to advanced age, postmenopausal state, visceral metastases, and invasive lobular carcinoma. During the two-year observational follow-up period, 25.5 % of patients died. The area under the receiver operating characteristic curve (ROC-AUC) analysis revealed an AUC of 0.713 [0.555-0.871]; P=0.029 for OS and an optimal cut-off value of GPC4 for predicting OS of 4.77 ng/mL. No patient showing GPC4 values below this cut-off died during the observational period. Cox regression analysis showed a hazard ratio of 2.14 [95% confidence interval: 1.24-3.67]; P=0.006 for one standard deviation change of plasma GPC4. Conclusions: In conclusion, our study suggests circulating GPC4 as a significant predictor of poor survival in metastatic breast cancer patients.

Dichotomous Effects of Glypican-4 on Cancer Progression and Its Crosstalk with Oncogenes

“…The released GPC4, which still exhibits biological activity, is detectable in serum, making it a potential diagnostic and prognostic marker. Two clinical studies have already shown increased plasma levels of GPC4 in metastatic colorectal and breast cancer patients to be associated with poor patient survival, proposing its biomarker potential in these cancers [24,25].…”

“…Also, two comprehensive clinical investigations demonstrate increased levels of plasma GPC4 in colorectal and metastatic breast cancer patients [24,25]. The increased plasma level of GPC4 in these cancers was found to be associated with poor patient survival [24,25].…”

“…Although our understanding of the involvement of GPC4 in cancer is limited, an increasing body of evidence illustrates its essential role in cancer progression. Recent preclinical and clinical reports demonstrate the implications of GPC4 in several cancers, including pancreatic [22], breast [23,24], and colorectal cancer [25]. Further, comprehensive bioinformatic analyses and functional in vitro experiments display a connection between downregulation of GPC4 and the sensitization of pancreatic cancer cells to chemotherapy [22].…”

“…A grand investigation including clinical breast cancer patients, in vivo, ex vivo, and in vitro studies reveals that GPC4 undergoes downregulation in metastatic tumors and that overexpression of GPC4 induces decreased tumorigenicity, i.e., migration and proliferation, in vitro in metastatic cells as well as in vivo in nude mice [23]. Also, two comprehensive clinical investigations demonstrate increased levels of plasma GPC4 in colorectal and metastatic breast cancer patients [24,25]. The increased plasma level of GPC4 in these cancers was found to be associated with poor patient survival [24,25].…”