The great strength of the PCWG3 is the recognition that second- , third- , and fourth-line treatments offer new possibilities for extending overall survival.
“The future is already here-it is just not evenly distributed”
For 21st-century oncologists and prostate cancer patients, the emerging molecular classification of actionable targets for precision oncology is inevitable and exciting. The question is not when, but how, to implement the findings of our new disease taxonomy in practice and what else we will need to learn about the different lethal clonotypes that make up the heterogeneity of clinical outcomes from this disease.[1,2]
The review by Ramakrishnan Geethakumari and colleagues is a scholarly contribution that updates oncologists on the management of advanced prostate cancer and the new relevant guidelines set forth by the Prostate Cancer Clinical Trials Working Group 3 (PCWG3). The integration of urology and medical oncology perspectives in their piece reflects the multidisciplinary approach needed for prostate cancer oncology at every point of management, much like in breast cancer oncology. The great strength of the PCWG3, as outlined in the review, is the recognition that second- , third- , and fourth-line treatments offer new possibilities for extending overall survival. Notably, treatment decisions in the future will not rely on the “clinical states” charted in Figure 2 of the review, but rather on the full integration of anatomic, clinical, and genomic information alluded to in the article.[4,5] Working groups plan on their recommendations becoming obsolete with new discoveries that further improve the care of patients; so, the speed of this obsolescence is to be celebrated as the median overall survival of castration-resistant prostate cancer (CRPC) is extended.
The Prostate Cancer Foundation (PCF) funded the initial discoveries of androgen receptor (AR) splice variants and a genome-wide search for actionable and treatable driver mutations in 750 patients. However, these data are only the beginning. The molecular classification of recurrent disease, which is then treated precisely and in real time, will require cohorts numbering in the thousands in order to be validated. In a new era of patient engagement, oncologists should expect to have read the articles by Antonarakis et al and Mateo et al in the New England Journal of Medicine and to subsequently ask whether their patients’ circulating tumor cells (CTCs) test positive for AR splice variant 7 (AR-V7) or, if their metastatic sites have been biopsied, whether any DNA damage repair genes confer sensitivity to olaparib. Collecting the genomic patterns of resistance and response to therapy and correlating this knowledge to the course of clinical care-not unlike an Oslerian with genomic biocomputing prowess-is the academic work that lies immediately ahead. Aggregated “N of 1” extreme response molecular case reports will also be an invaluable resource for further hypothesis testing. We predict that the next working group’s treatment recommendations will draw on the genomics data commons now being populated.
Prostate cancer is rapidly changing from a histopathologic and anatomic description to a molecular taxonomy, much like diffuse large B-cell lymphoma (DLBCL). The molecular classification of DLBCL is a critical biologic, prognostic, and predictive activity. Both lymphoma oncology and prostate cancer oncology now mandate molecular biomarker precision when making treatment choices. Since the genomic discovery of two molecular types of DLBCL in otherwise morphologically indistinguishable cases, lymphoma drug developers have never looked back. Furthermore, the pace of progress in lymphoma has been unprecedented, with “double-hit” lymphomas generating their own treatment science agenda less than 5 years after original discovery. Prostate cancer, with different driver mutations, chromosomal translocations, and transcription alterations, requires the same approach beyond morphology as B-cell lymphomas. The “cartography” for the treatment of prostate cancer has been completely redrawn using DNA and RNA sequencing biotechnology, replacing a purely histopathologic and anatomic understanding. By early 2016, we know that approximately 90% of metastatic CRPC patients harbor clinically actionable molecular mutations and targets, including AR, phosphoinositide-3-kinase (PIK3), DNA repair defects, BRAF/RAF gene fusion, cell cyclin kinase inhibition, and WNT. Prostate cancer pathology will have to evolve accordingly. Pathologists may also soon have to address the seven discrete forms of primary cancer in its molecular taxonomy (ERG, ETV1, ETV4, FLI1, SPOP, FOXA1, IDH1), independent of Gleason grade, as drug discovery targeting many of these gene targets is already well underway.
We manage DLBCL with repeated biopsies and “omic” analyses at the time of recurrence. The same paradigm can be envisaged as the new future for advanced prostate cancer management. PCF studies have demonstrated that tumor biopsies can be performed safely in men with metastatic CRPC and yield useful new information in most patients. For example, in a remarkable yet-to-be-published study of more than 100 patients conducted by Kunju et al, it was found that over 80% of soft-tissue and bone biopsies in prostate cancer can be successfully sequenced for exomes and transcription patterns. Thus, we believe that the 21st-century paradigm of diagnosis and treatment for advanced prostate cancer should not turn away from histopathologic evaluation, but should reinforce current practice by understanding clonal heterogeneity, with comprehensive genomic analysis of each patient. The fact that bone and soft-tissue biopsies are used in routine clinical research practice by the PCF East and West Coast international “dream team” to inform an actionable next treatment in advanced prostate cancer makes “re-interrogation” of the treatment-resistant clonotype a potentially vital component of the next working group’s framework. Therefore, the interventional radiologist can be predicted to join the multidisciplinary team that cares for patients with advanced prostate cancer.
Finally, the PCWG3 identifies CTC biomarker biotechnologies and regulatory sciences as an emerging area in prostate cancer oncology. Liquid biopsies may soon be implemented in routine practice for optimal precision medicine decision making. For example, elimination of high CTC counts predicts overall survival improvement with abiraterone and enzalutamide. Prostate cancer kills because it becomes a hematopoietic stem-cell niche occupying epithelial stem cell disease that secretes prostate-specific antigen in the bone marrow. Clones then depart the bone marrow and create multiple secondary metastases in more bone marrow sites and secondary sites that favor a monoclonal dominant clonotype’s survival via mechanisms that are yet to be fully understood. In this way, prostate cancer is also like B-cell lymphomas: a hematogenous menace without clonal eradication. Controlling what we have termed “prostate cancer carcinemia”Â (PCC; in-transit hematogenous spreading of prostate cancer out of established bone, lymph node, lung, and liver metastases)-like controlling B-cell lymphoma as a systemic neoplasm-is going to be essential in greatly extending overall survival. Precision medicine for PCC is a new, welcomed, rapidly growing area in the field of prostate cancer oncology.
Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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