Urologic Oncology: Seminars and Original Investigations ] (]]]]) ]]]–]]]
Seminar Section Introduction
Predictive medicine: Using circulating biomarkers to guide management of patients with genitourinary cancers Take a moment to envision how patients with advanced genitourinary (GU) cancers could receive treatment 10 years from now. The current movement toward accurate, precise, and predictive oncology with individually tailored personalized molecularly targeted therapies based on genomically defined biomarkers such as tumorspecific mutations is presently facing a more broadly encompassing movement toward immuno-oncology, with its own set of personalized biomarkers. With immunotherapy, such tumor-specific mutations may be important, such as in the case of DNA mismatch repair defects and programmed death 1 (PD-1) blockade [1], but novel predictive biomarkers of immunotherapy benefit may range from tumor and latent viral neoantigens as well as immune regulatory molecules in the tumor microenvironment or even in the host macroenvironment, such as the microbiome [2–6]. Such advances on these 2 fronts in the war on cancer leads to the conclusion that the days of empiric broad spectrum chemotherapies and unselected clinical trials in many cancer types are moving in the past. Whether a targeted therapy or an immune checkpoint inhibitor, trials designed to optimize benefit and minimize the harms, and costs to individuals and society are becoming of paramount importance. In this special edition of Urologic Oncology: Seminars and Original Investigations, multiple experts in the field of GU oncology and biomarker development address this unmet need and the present state of science. For example, would a man in the year 2020 with metastatic prostate cancer and androgen receptor (AR)-V7 splice variant driven disease be offered a novel immunotherapy cocktail or a novel N-terminal AR inhibitor based on circulating tumor RNA measurements in the blood. And, perhaps his cell-free DNA analysis would help to decide whether to add an fibroblast growth factor receptor or WNT pathway inhibitor as part of a multiagent cocktail, much like the paradigm of highly active antiretroviral therapy cocktails used for human immunodeficiency virus induction and maintenance therapy. Drs. David Miyamoto and Richard Lee at Massachusetts General Hospital provide a concise, but expert review http://dx.doi.org/10.1016/j.urolonc.2016.09.009 1078-1439/r 2016 Elsevier Inc. All rights reserved.
of the ever-changing field of circulating biomarkers in prostate cancer. Would a woman with metastatic clear-cell renal cell carcinoma be offered adjuvant anti-angiogenic or immunotherapy or combinations of these therapies based on her circulating angiokine profile, or would her tumor's immune signature dictate such therapy to prevent ultimate relapse and metastasis? Drs. Tian Zhang, Dan George, and Andy Nixon from the Duke Cancer Institute provide an expert review of the state of science in this disease and look forward toward precision approaches. Would a patient with muscle-invasive urothelial carcinoma undergo cell-free DNA or urine DNA or miRNA biomarker analysis for decision-making around the benefits of platinum chemotherapy vs. PD-ligand 1 (PDL-1) blockade in the adjuvant setting? Drs. Philip Abbosh, Jonathan Rosenberg, and Elizabeth Plimack at Fox Chase Cancer Center and Memorial Sloan Kettering Cancer Center provide a seminar piece on current potential predictive biomarkers in urothelial cancers and paths forward for personalized medicine in this disease. These 3 articles highlight both the challenges and the promise of predictive GU oncology using circulating biomarkers, where pitfalls range from assay analytic validation and reproducibility to interpatient and intrapatient tumor heterogeneity and the need for large scale prospective and ideally controlled clinical validation studies. In prostate cancer, recent studies highlight the power of circulating biomarkers to examine RNA splice variants, whole genomic DNA analysis, and RNA sequencing approaches to discover and predict treatment benefit [7–10]. However, the recent failure of the ARMOUR-3 trial of galeterone vs. enzalutamide in men with V7-positive CRPC illustrates the major challenges in biomarker and companion diagnostic development and the dependence on actionable findings and active therapeutic alternatives for patients (Tokai press release July 26, 2016). Prospective biomarker comparison trials, such as NCT02269982 funded by the Prostate Cancer Foundation and Movember, should provide valuable data around the predictive value of such CTC, DNA, RNA, and protein biomarkers as well as ctDNA
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A.J. Armstrong / Urologic Oncology: Seminars and Original Investigations ] (]]]]) ]]]–]]]
based biomarkers in the context of enzalutamide and abiraterone therapy, particularly AR-V7, AR amplification, and genomic lesions beyond AR [11]. The ever-changing treatment and biomarker landscape as well as both the within and between patient genomic heterogeneity in all GU cancers challenge us to develop therapeutic trials in molecularly defined subsets of patients, and recent clinical trial guidance (PCWG3) emphasizes methods to address this unmet need going forward in prostate cancer[12]. Innovative trial designs that evaluate both systemic agents and biomarkers prospectively in molecularly defined GU cancers, such as GU-specific MATCH trials, are needed. Disease heterogeneity in both space and time limits the use of a single-metastatic biopsy at a single point in time, but an important question is whether CTC assays or cell-free DNA, RNA, miRNA, or angiome analyses overcome this by assessing the disseminating or drug resistant tumor clones at a given time point in a patient's treatment history? The predictive biomarkers of the past, such as serum LDH for mTOR inhibitor benefit in poor-risk renal cell carcinoma [13], or clear cell histology for high-dose IL-2, or PDL-1 tumor expression, may need to give way toward more innovative approaches to examining the use of novel immunotherapies across histologic subtypes and treatment settings in kidney cancer. In many GU cancers, novel approaches examining host immune and microbiome biomarkers integrated with genomic data and treatment outcomes may provide a path forward in deciphering the net benefits with immune checkpoint blockade, but such strategies need to be incorporated into industry and academic collaborative trials with federal support. This exciting seminar series encompasses these concepts and provides a basis for translational predictive medicine studies to bring these biomarkers into the clinic. Andrew J. Armstrong, M.D., ScM, FACP Duke Cancer Institute, Durham, NC E-mail address:
[email protected] References [1] Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509–20. Available at: https://www.ncbi. nlm.nih.gov/pubmed/26028255.
[2] Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 2016;164:1073. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27064190. [3] McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351:1463– 9. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26940869. [4] Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, et al. Commensal bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015;350:1084–9. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26541606. [5] Kataoka K, Shiraishi Y, Takeda Y, Sakata S, Matsumoto M, Nagano S, et al. Aberrant PD-L1 expression through 30 -UTR disruption in multiple cancers. Nature 2016;534:402–6. Available at: https://www. ncbi.nlm.nih.gov/pubmed/27281199. [6] Mak MP, Tong P, Diao L, Cardnell RJ, Gibbons DL, William WN, et al. A patient-derived, pan-cancer emt signature identifies global molecular alterations and immune target enrichment following epithelial-tomesenchymal transition. Clin Cancer Res 2016;22:609–20. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26420858. [7] Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014;371(11):1028–38. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25184630. [8] Gupta S, Li J, Kemeny G, Bitting RL, Beaver J, Somarelli J, et al. Whole genomic copy number alterations in circulating tumor cells from men with abiraterone or enzalutamide resistant metastatic castration-resistant prostate cancer. Clin Cancer Res 2016. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27601596. [9] Scher HI, Lu D, Schreiber NA, Louw J, Graf RP, Vargas HA, et al. Association of AR-V7 on circulating tumor cells as a treatmentspecific biomarker with outcomes and survival in castration-resistant prostate cancer. JAMA Oncol 2016. Available at: http://www.ncbi. nlm.nih.gov/pubmed/27262168. [10] Miyamoto DT, Zheng Y, Wittner BS, Lee RJ, Zhu H, Broderick KT, et al. RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science 2015;349:1351–6. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26383955. [11] Antonarakis ES, Armstrong AJ, Dehm SM, Luo J. Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting. Prostate Cancer Prostatic Dis 2016;19:231–41. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27184811. [12] Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the prostate cancer clinical trials working group 3. J Clin Oncol 2016;34:1402–18. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26903579. [13] Armstrong AJ, George DJ, Halabi S. Serum lactate dehydrogenase predicts for overall survival benefit in patients with metastatic renal cell carcinoma treated with inhibition of mammalian target of rapamycin. J ClinOncol 2012;30:3402–7. Available at: http://www. ncbi.nlm.nih.gov/pubmed/22891270.