Comments for:
Abstract
Primary prostate cancer lesions are clonally heterogeneous and often arise independently. In contrast, metastases were reported to share a monoclonal background. Because prostate cancer mortality is the consequence of distant metastases, prevention of metastatic outgrowth by primary tumor ablation is the main focus of treatment for localized disease. Focal therapy is targeted ablation of the primary index lesion, but it is unclear whether remaining primary lesions metastasize at a later stage. In this study, we compared copy number aberration profiles of primary prostate cancer lesions with matching pelvic lymph node metastases of 30 patients to establish clonality between a lymph node metastasis and multiple primary lesions within the same patient. Interestingly, in 23.3% of the cases, the regional metastasis was not clonally linked to the index primary lesion. These findings suggest that focal ablation of only the index lesion is potentially an undertreatment of a significant proportion of prostate cancer patients.
Authors
Jeroen Kneppers, Oscar Krijgsman, Monique Melis, Jeroen de Jong, Daniel S. Peeper, Elise Bekers, Henk G. van der Poel, Wilbert Zwart, Andries M. Bergman
Focal therapy for some selected patients but not for everyone
Submitter: Armando Stabile | armando.stabile88@gmail.com
Authors: Armando Stabile, Marco Moschini, Francesco Montorsi, Xavier Cathelineau, and Rafael Sanchez-Salas
Department of Urology and Division of Experimental Oncology, URI, Urological Research Institute, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
Published April 4, 2019
We read with great interest the article by Kneppers and collegues (1) who attempted to address the complex topic of prostate cancer (PCa) multifocality and its relationship with the biological behavior of this disease which so far still represents the second most common cancer related cause of death in men (2). The authors aimed at defining the clonal origin of PCa metastasis comparing the copy number of alteration of primary PCa lesions with pelvic lymph node (LN) metastasis in a cohort of thirty me affected by node positive PCa (1). Interestingly it was demonstrated as in 23% of patients the LN metastasis was not clonally related to the index lesion (IL) defined as the largest primary tumour with the highest grade found within the prostate. According to these findings the Authors concluded that tissue preserving therapies, as focal therapy (FT), that aim at treating the IL while preserving the rest of the prostatic gland, may represent an undertreatment for those men whose LN metastasis are likely caused by satellite smaller PCa foci surrounding the IL. Kneppers and collegues (1) should be commended for their attempt in providing these pre-clinical evidences in an effort to better understand PCa biology and consequently supporting or rather undermine the increasing interest regarding the potential role of FT in an era where several efforts are being made to reduce overtreatment and radical treatment related side-effects (3–5).
Nonetheless, considering the clinical implications derived from this interesting study, some points deserve discussion.
First, according to our knowledge this is the first study showing the genomic relationship between PCa metastasis and IL, making one step forward compared to previous studies demonstrating the mono-clonal origin of PCa distant localizations (6) and rising some doubts regarding the biological role of the IL in determining PCa progression (7). Still, the authors showed as in 77% of cases LNs tumour cells were clonal with IL (1). Even though being this an extremely interesting result, the clinical implication seem to be that in most of cases LNs metastasis originated from the IL with this supporting previous reports describing as the natural history of the disease is predominantly driven by the largest lesion with the highest grade, namely the IL (8–10). This result should be encouraging in supporting the theory that some men affected by PCa might be cured with the use of FT, bearing in mind that some others may experience clinical progression.
Second, in order to address the aim of the study, Kneppers and collegues relied on a population of node positive PCa men. More specifically, looking at the population characteristics, 87% (26/30) and 63% (19/30) had ISUP grade>2 and clinical stage based on digital examination ≥T2c (1). Considering that the most accepted eligibility criteria for FT include disease up to Gleason score 3+4 and clinical stage up to T2b (11–13), it is hard to translate the results of this study on FT effectiveness, notwithstanding their clinical impact.
Third, always in the context of patient selection, multiparametric MRI of the prostate has gained a cornerstone role in FT patient’s selection pathway in order to clearly identify the IL and rule out the presence of others clinically significant PCa foci (11–14) Interestingly, it has been demonstrated as using MRI in addition to targeted biopsy and intermediate risk eligibility criteria, more than one third of patient would be eligible for FT defined as hemiablation (13). Since no information in this regard was provided by the study in subject, the results of this rely on a population of men who would have not been considered suitable for FT.
Lastly, taking into account LN metastasis is probably not the most accurate method to address feasibility of FT, given the well-known heterogeneity of node positive patients characterized by different outcomes and the current still controversial therapeutic role of pelvic lymph node dissection (15,16).
In conclusion, Kneppers and collegues provided extremely novel and translational evidences regarding PCa biological behavior which underline, together with the points previously discussed, the importance of patient selection when proposing a therapeutic strategy as FT in order to give patients the best tailored approach. Furthermore their results, for a proportion of patients (77%), support the “index lesion theory” underlying the rationale of FT effectiveness. This novel therapeutic approach does not want to replace radical treatments but rather being an alternative for a proportion of patients highly selected through a process that still need to be refined but in which the use of MRI and targeted biopsy will have a crucial role (13). Indeed FT has already shown promising medium term oncological results in the treatment of PCa providing even more promising functional outcomes (4,5). To date, the management of localized PCa remains a controversial topic (17,18). In a recent trial was shown as the presence of ISUP grade 2 was not associated with an increased risk of death after twenty-nine years of follow-up (18). Much still need to be understood regarding PCa. Having in mind the concept that the optimal treatment is the one with best oncological outcome at the cost of less side-effects, the field of FT must be furtherly studied. Only future prospective trials with strong outcomes and accurately selected patients providing long-term results (oncological and functional) will explain the potential role of FT and eventually re-define the treatment approach for localized PCa.
References
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