Subtypes of minimal residual disease, association with Gleason score, risk and time to biochemical failure in pT2 prostate cancer treated with radical prostatectomy

Abstract

Introduction The Gleason score is a strong prognostic factor for treatment failure in pathologically organ-confined prostate cancer (pT2) treated by radical prostatectomy (RP). However, within each Gleason score, there is clinical heterogeneity with respect to treatment outcome, even in patients with the same pathological stage and prostate-specific antigen (PSA) at diagnosis. This may be due to minimal residual disease (MRD) remaining after surgery. We hypothesise that the sub-type of MRD determines the risk of and timing of treatment failure, is a biological classification, and may explain in part clinical heterogeneity. We present a study of pT2 patients treated with RP, the subtypes of MRD for each Gleason score and clinical outcomes. Patients and methods Patients with Gleason ≤6 (G6) or Gleason 7 (G7) pT2 cancer participated in the study. One month after surgery, blood was taken for circulating prostate cell (CPCs); mononuclear cells were obtained by differential gel centrifugation and identified using immunocytochemistry with anti-PSA. The detection of one CPC/sample was defined as a positive test. Touch-preparations from bone-marrow biopsies were used to detect micro-metastasis using immunocytochemistry with anti-PSA. Biochemical failure was defined as a PSA >0.2 ng/mL. Patients were classified as: Group A MRD negative (CPC and micro-metastasis negative), Group B (only micro-metastasis positive) and Group C (CPC positive). Biochemical failure-free survival (BFFS) using Kaplan–Meier and time to failure using Restricted Mean Survival Time (RMST) after 10 years of follow-up were calculated for each group based on the Gleason score. Results Of a cohort of 253 men, four were excluded for having Gleason 8 or 9 prostate cancer, leaving a study group of 249 men of whom 52 had G7 prostate cancer. G7 patients had a higher frequency of MRD (69% versus 36%) and worse prognosis. G6 and G7 patients negative for MRD had similar BBFS rates, 98% at 10 years, time to failure 9.9 years. Group C, G6 patients had a higher BFFS and longer time to failure compared to G7 patients (19% versus 5% and 7 versus 3 years). Group B showed similar results up to 5 years, thereafter G6 had a lower BFFS 63% versus 90%. Conclusions G7 and G6 pT2 patients have different patterns of MRD and relapse. Risk stratification using MRD sub-types may help to define the need for adjuvant therapy. This needs confirmation with large randomised long-term trials.

The CAPRA-S score versus subtypes of minimal residual disease to predict biochemical failure after radical prostatectomy

“…Recently, a single PSM of >3 mm or multifocal PSM was associated with an increased risk of metastasis [30], whereas a single focus of PSM was not associated with biochemical failure [31]. Interestingly, the frequency of MRD subtypes detected was not significantly different between patients with pT3a PSM negative and positive prostate cancer although there were a limited number of pT3a-positive PSMs in the study [29].…”

“…The presence of CPCs, even in patients with pT2 disease, Gleason 6 and negative surgical margins is associated with early treatment failure. However, the frequency of such patients is significantly lower than patients with pT3a margins negative and pT3a margins positive, 20% versus 58% and 65%, respectively [29]. The significantly higher frequency of MRD negative disease in pT2 margin negative patients is one explication for the better prognosis.…”

“…The significantly higher frequency of MRD negative disease in pT2 margin negative patients is one explication for the better prognosis. Interestingly, the frequency of patients with only bone marrow micrometastasis was similar in the three groups [29]. Positive surgical margins (PSM) have been associated with an increased risk of biochemical failure.…”

Metastatic Spread in Prostate Cancer Patients Influencing Radiotherapy Response

“…The authors found that CTC positivity correlates with early relapse while DTC positivity is associated with late failure. Therefore, they propose the existence of two forms of MRD representing different clinical characteristics ( 264 , 265 ). This leads to the hypothesis that the dynamics of MRD determines therapy response and patient outcome.…”

The CAPRA score versus sub-types of minimal residual disease to predict biochemical failure after external beam radiotherapy

“…Treatment failure arises from the proliferation of tumour cells not eradication by curative therapy, these micro-metastasis not detected by conventional studies are termed minimal residual disease. We have recently described two sub-types of minimal residual disease (MRD), those patients with circulating prostate cells detected in blood (independent of whether there are micro-metastasis detected in the bone marrow or not) have a high risk of early treatment failure, while patients only positive for bone marrow micro-metastasis are at risk for late failure and have a similar outcome to MRD negative patients for the first 5 years [9,10].…”