Prognostic Value of Plasma hPG(80) (Circulating Progastrin) in Metastatic Renal Cell Carcinoma

SIMPLE SUMMARY: Metastatic renal cell carcinoma (mRCC) accounts for one-third of all newly diagnosed renal cell cancers. A better understanding of the biology and molecular basis of disease progression has resulted in several drug targets being identified and led to approval of several new drugs for treating mRCC in the past decade. A growing need has emerged for identifying novel molecular tumor biology based and stage-specific prognostic and predictive biomarkers in mRCC reflective of biology beyond the currently available prognostic models which are solely based on clinical characteristics. We investigated hPG80 (circulating progastrin), which is associated with kidney cancer biology and found that hPG80 levels is both an independent prognostic marker in mRCC and also improves current clinical prognostic models. This will help stratify mRCC patients more accurately in future and improve the management of mRCC patients. ABSTRACT: Precise management of kidney cancer requires the identification of prognostic factors. hPG(80) (circulating progastrin) is a tumor promoting peptide present in the blood of patients with various cancers, including renal cell carcinoma (RCC). In this study, we evaluated the prognostic value of plasma hPG(80) in 143 prospectively collected patients with metastatic RCC (mRCC). The prognostic impact of hPG(80) levels on overall survival (OS) in mRCC patients after controlling for hPG(80) levels in non-cancer age matched controls was determined and compared to the International Metastatic Database Consortium (IMDC) risk model (good, intermediate, poor). ROC curves were used to evaluate the diagnostic accuracy of hPG(80) using the area under the curve (AUC). Our results showed that plasma hPG(80) was detected in 94% of mRCC patients. hPG(80) levels displayed high predictive accuracy with an AUC of 0.93 and 0.84 when compared to 18–25 year old controls and 50–80 year old controls, respectively. mRCC patients with high hPG(80) levels (>4.5 pM) had significantly lower OS compared to patients with low hPG(80) levels (<4.5 pM) (12 versus 31.2 months, respectively; p = 0.0031). Adding hPG(80) levels (score of 1 for patients having hPG(80) levels > 4.5 pM) to the six variables of the IMDC risk model showed a greater and significant difference in OS between the newly defined good-, intermediate- and poor-risk groups (p = 0.0003 compared to p = 0.0076). Finally, when patients with IMDC intermediate-risk group were further divided into two groups based on hPG(80) levels within these subgroups, increased OS were observed in patients with low hPG(80) levels (<4.5 pM). In conclusion, our data suggest that hPG(80) could be used for prognosticating survival in mRCC alone or integrated to the IMDC score (by adding a variable to the IMDC score or by substratifying the IMDC risk groups), be a prognostic biomarker in mRCC patients.