Diagnostic and Prognostic Molecular Markers for Renal Cell Carcinoma: A Critical Appraisal of the Current State of Research and Clinical Applicability

Abstract

Context

Earlier detection of renal cell carcinoma (RCC) and the recent expansion of treatment possibilities have positively influenced the outlook for patients with this disease. However, progression and treatment response are still not sufficiently predictable. Molecular markers could help to refine individual risk stratification and treatment planning, although they have not yet become clinically routine.

Objective

This review presents an overview of diagnostic and prognostic molecular markers for RCC and a subgrouping of these markers for different clinical issues.

Evidence acquisition

Literature and recent meeting abstracts were searched using these terms: renal (cell) carcinoma, molecular/tumor markers, biopsy, blood, urine, disease progression/prognosis, immunohistochemistry, risk factors, and survival.

Due to the resulting large number of articles, studies were subjectively selected according to the importance of a study on the field, number of investigated patients, originality, multivariate analyses performed, contrast with previously published data, actuality, and assumed clinical applicability of the described results. More then 90% of the selected studies originated from the past 10 yr; >50% of the articles were written in 2006 or later.

Evidence synthesis

These data were predominantly obtained via nonrandomized, retrospective, but often controlled studies. Thereby, the resulting level of evidence is 2A/2B. The broad spectrum of described molecular markers (MMs) for RCC consists of markers already extensively studied in other malignancies (eg, p53), as well as MMs typically associated with specific RCC-altered gene functions and pathways (eg, von Hippel–Lindau [VHL]). The main goal of using MMs is to refine the prediction of clinical end points like tumor progression, treatment response, and cancer-specific and/or overall survival. Further, MMs might facilitate the clinical work-up of undefined renal masses and prove to be more convenient tools for screening and follow-up in blood and urine.

Conclusions

Presently, there are a number of promising MMs for diverse clinical questions, but the available data are not yet valid enough for routine, clinical application. We should comply with the demand for large multicenter prospective investigations, stratified for RCC type and treatment modalities, to lift the use of molecular markers in RCC to a practical level, thereby providing a better consultation for our patients regarding diagnosis, treatment, and follow-up.

Introduction

Despite a stage migration to a higher proportion of localized renal cell carcinomas (RCC) [1], the demand for an individual aftercare of these patients is still foiled by the unpredictable course of localized RCC. Consequently, a suggested risk-stratification for follow-up schemes still has not yet achieved universal acceptance [2]. Simultaneously, the role of ablative treatments for small tumors is increasing, and there are a growing number of advocates of an “active surveillance” strategy for small renal masses. With even small tumors having metastatic potential and the fact that the overall RCC mortality has not yet dropped [3], markers for the individual aggressiveness of a tumor are desired.

The base of all prognostic models, the TNM system [4], is not yet optimal in predicting the long-term course of the disease: The overall concordance rate has been described to be 58–73% [5], [6], and it seems to be not significant for e.g. papillary RCC (papRCC) [6]. Further, many authors demand a reclassification, especially for the overly global pT3–4 groups [5], [7], [8]. Integrated prognostic models seem to perform slightly better, but they are also based on the TNM system and have concordance rates between 60% and 85% [9], [10], [11].

For metastatic diseases, new therapeutic agents—so-called targeted therapies—have brought about a revolution in treatment strategies. However, unlike therapies in other cancers (eg, human epidermal growth factor receptor 2 [HER-2] in breast cancer [12]), the question of whether a tumor does have the target at which the therapy is aimed has not been raised. Moreover, with a lack of markers for response, we are unable to detect progress or to treat refractory cancer earlier than with radiologic evaluation. And finally, with the new drugs again posing the question of potential benefit of adjuvant therapies, an improved grouping is necessary to better determine the patients who are at high risk.

A broad variety of markers are described in literature. This review summarizes (pre-) clinically tested molecular markers (MMs) that might be applicable for above surrogates.