The Lethal Clone in Prostate Cancer: Redefining the Index

Abstract

The heterogeneity of prostate cancer (PCa) represents a major challenge for its study and treatment. This heterogeneity manifests on multiple levels: at the anatomic level, with multiple independent foci often appearing in separate areas of the prostate; at the histologic level, with a variety of pathologic grades; and at the clinical level, where outcomes can range from indolent disease to rapid progression, metastasis, and death from PCa. Recent genomic studies have added molecular heterogeneity to this mix, reinforcing this fundamental feature of the disease and perhaps providing tools to understand the impact on patient care. One of the most pressing questions in research on primary PCa over the past decades has been simple: Which men who present with clinically localized disease have aggressive, lethal PCa? Our growing understanding of the heterogeneity and multifocal nature of PCa adds a new wrinkle to this question: Within an individual patient, which specific PCa focus is the lethal one? This question has critical implications for the emerging practice of focal therapy. In principle, focal therapy applies an organ-sparing approach to clinically localized PCa, eliminating the PCa while sparing surrounding tissues, maximizing cancer control benefit while minimizing morbidity. Application of focal therapy relies on targeting the index lesion, commonly defined as the largest tumor, on the assumption that the largest, highest-grade tumor drives clinical progression [1]. Therefore, clear definition of which tumor focus represents the origin of metastatic lesions is fundamental to the successful application of focal therapy. A report by Haffner and colleagues from Johns Hopkins University, published in the Journal of Clinical Investigation [2], elegantly lays out a framework for this type of molecular investigation. In a patient with lethal, metastatic PCa many years after radical prostatectomy, whole-genome sequencing of multiple metastatic sites defined the genomic characteristics of the lethal disease, followed by targeted analysis of multiple foci from the primary prostatectomy specimen to reconstruct the evolutionary path of the metastatic cancer. Not surprisingly, they found heterogeneity within the primary PCa, with evidence for several different tumor clones, with a single area having the same genomic profile as the distant metastases. The clone giving rise to the metastases harbored mutations in speckle-type POZ protein (SPOP), phosphatase and tensin homolog (PTEN), and tumor protein 53 (TP53) and appeared histologically as ‘‘a single small (2.2 mm 1.3 mm) lesion ... composed solely of Gleason pattern 3 tumor glands’’ [2] within a large volume of high-grade disease. This study [2] raises several questions about the index lesion hypothesis. First, the revelation that the lethal clone appeared as a small area of Gleason pattern 3 provokes the concerning inference that any small, low-grade focus of PCa may harbor an unrecognized killer. Although the report by Haffner and colleagues suggests that more information than size and grade alone is necessary to define the lethal clone, isolated Gleason 6 (3 + 3) cancers have consistently been shown to have low metastatic potential [3,4]. It is dogma that tumors of higher stage and grade are associated with higher risk of biochemical recurrence, clinical metastases, and death from PCa, because an overwhelming preponderance of evidence supports this [5,6]. Closer examination of the case in question shows that the lethal PCa is unlikely to have originated as a small, low-grade tumor. Several areas within the prostate showed the same SPOP mutation, making these very likely to be the same tumor. A quick examination of the prostatectomy sections (which Haffner et al. should be commended for displaying in exquisite detail) revealed that these areas are up to 2 cm apart, with