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Renal cell carcinoma (RCC) is a prevalent and deadly cancer, with considerable intra-tumor heterogeneity. The 9th most common cancer in men and 14th among women globally. RCC is a “stealth disease”, detected late in its clinical course, with no easy method for screening asymptomatic populations. Even with earlier detection, up to 30% of patients with no noted metastasis at the time of nephrectomy will ultimately have metastatic disease. C-reactive protein (CRP) was found expressed in RCC but not in adjacent normal kidney tissue (Kidney International, Vol. 68 (2005), pp. 2103–2110). Preliminarily, measurable CRP in patient urine correlating with tumor grade was found. Here, we test the hypothesis that urine CRP levels are an indicator of metastatic potential of kidney cancer and can serve as a non-invasive biopsy of the whole tumor to pre-surgically grade tumors by molecular pathology
With IRB approval, informed consent was obtained from all. Urine and plasma was taken from patients pre-operatively undergoing partial nephrectomy with a pre-diagnosis of RCC based on imaging. Post-op pathology reports established 55 with clear cell, 10 with papillary, RCC of 4 cm or less along with tumor grade, 7 with angiomyolipoma, 6 chromophobe and 9 oncocytoma, all 4cm or less. Subsequently, 51 of the RCC patients provided a urine at first post-op follow-up. Urine and plasma samples were obtained from 64 self-described healthy volunteers closely matching age and sex of the RCC cohort. CRP was measured by a sensitive and specific ELISA, the heightened sensitivity of which removed confounding due to urine pH or salt/urea excretion.
If the 65 RCC patients were factored by tumor grade, 41 patients with grades 1/2 tumors cluster below the 24 patients with grade 3/4 tumors, representing 17- and 80-fold increases above 64 healthy controls (both P<0.001, Kruskal-Wallis test, Bonferroni contrast).Two patients in the 1/2 grade group are outliers to the 39 others (Figure). A significant 85% decrease in the post-op urine CRP of those with grade 3/4 tumors was consistent with removal of the biomarker source. If the urine CRP (ng/mg creatinine) was plotted as a function of plasma CRP (ug/ml), one sees that urine levels are low for the normal and those with grade 1/2 tumors, while those with grade 3/4 tumors stratify significantly above all, suggesting urine CRP reflects the tumor and not filtered CRP from blood. The two outliers cluster with grade3/4 tumors. The mean CRP of patients with angiomyolipoma, chromophobe, or oncocytoma are all significantly less than patients with grade 3/4 tumors. The AROC to differentiate grade1/2 from 3/4 tumors was 0.98 (95% CI 0.95-1.00) with sensitivity 1.0 (95% CI, 0.87-1.00) and specificity 0.95 (95% CI,0.84-0.99), based on pre-op plasma CRP, AROC 0.62 (95% CI 0.47-0.76) (P=0.056). Follow-up of all patients (range 182-1266 days), grade 1/2 outliers had noted mets by 563 and 641 days, the other 39 patients had no noted mets, but numerous patients with grade 3/4 tumors developed mets.
Results suggest pre-op urine CRP levels can predict subclinical metastasis. Urine reflects all of the kidney and not prone to sampling errors of needle biopsy. Provocatively, measuring urine CRP is a liquid biopsy of the whole tumor to pre-surgically grade by molecular pathology and inform subsequent patient management.