Abstract
BackgroundLymph-node (LN) metastasis in prostate cancer (PC) is a main risk factor for tumor recurrence after radical prostatectomy (RP). Molecular analysis facilitates detection of small-volume LN metastases with higher sensitivity than histopathology. We aimed to prospectively evaluate six candidate gene markers for detection of pelvic LN metastases and to determine their ability to predict biochemical recurrence-free survival (bRFS) in patients treated with RP.MethodsThe expression of kallikrein 2, 3, and 4 (KLK2, KLK3, and KLK4), prostate-specific membrane antigen (PSMA), transmembrane serine protease 2 (TMPRSS2) and transient receptor potential cation channel subfamily M member 8 (TRPM8) was assessed using qPCR. We analyzed LNs from 111 patients (intermediate PC, n = 32 (29%); high-risk PC, n = 79 (71%)) who underwent RP and extended pelvic lymph-node dissection without neoadjuvant treatment.ResultsOverall, 2411 LNs were examined by molecular and histopathologic examination. Histopathology detected 69 LN metastases in 28 (25%) patients. KLK2 and KLK3 diagnostically performed best and classified all pN1-patients correctly as molecular node-positive (molN1/pN1). The concordance on LN level was best for KLK3 (96%). KLK2, KLK3, KLK4, PSMA, TMPRSS2, and TRPM8 reclassified 27 (24%), 32 (29%), 29 (26%), 8 (7%), 13 (12%), and 23 (21%) pN0-patients, respectively, as node-positive (pN0/molN1). On multivariable cox regression analysis molecular LN status (molN1 vs. molN0) using KLK3 (HR 4.0, p = 0.04) and TMPRSS2 (HR 5.1, p = 0.02) were independent predictors of bRFS. Median bRFS was shorter in patients with only molecular positive LNs (molN1/pN0) for KLK3 (24 months, p = 0.001) and for TMPRSS2 (12 months, p < 0.001) compared to patients with negative nodes (molN0/pN0) (median bRFS not reached).ConclusionsFor diagnostic purposes, KLK3 showed highest concordance with histopathology for detection of LN metastases in PC patients undergoing RP. For prognostic purposes, KLK3 and TMPRSS2 expression were superior to histopathologic LN status and other transcripts tested for molecular LN status. We suggest a combined KLK3/TMPRSS2 panel as a valuable diagnostic and prognostic tool for molecular LN analysis.
Highlights
Prostate cancer (PC) remains the most common cancer among men both in Europe and the US and the second to third leading cancer-specific cause of death [1]
Following a literature review and subsequent preclinical evaluation of candidate genes we identified six genes (kallikrein 2, 3, and 4 (KLK2, KLK3, and KLK4), prostatespecific membrane antigen (PSMA), transmembrane serine protease 2 (TMPRSS2), and transient receptor potential cation channel subfamily M member 8 (TRPM8)) suitable for molecular LN analysis with high expression in prostate cancer (PC) and low expression in peripheral blood mononuclear cells (PBMCs), which can be used as a model for detection of disseminated tumor cells in LNs [22]
In this study we prospectively compared the candidate transcripts KLK2, KLK3, KLK4, prostate-specific membrane antigen (PSMA), TMPRSS2, and TRPM8 for molecular LN staging, which were identified from a systematic literature review and were selected based on systematic preclinical evaluation [22]
Summary
Prostate cancer (PC) remains the most common cancer among men both in Europe and the US and the second to third leading cancer-specific cause of death [1]. Cancer recurrence occurs in about 20% of patients with postoperative node-negative status following RP and is even more frequently observed in patients with high-risk features [10,11,12] This might be explained by LNunderstaging due to insufficient extent of LN dissection or localization of LN metastases outside of the dissection template, leading to false node-negative results. An extended pelvic LN dissection (ePLND) respecting the lymphatic draining sites of the prostate including the obturatoric fossa, internal, external, and common iliac field has been recommended by the European Association of Urology guidelines [13]. Another reason might be the presence of small-volume metastases within the dissected tissue that remain undetected by standard histopathology. We aimed to prospectively evaluate six candidate gene markers for detection of pelvic LN metastases and to determine their ability to predict biochemical recurrence-free survival (bRFS) in patients treated with RP
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