Prioritizing precision medicine for prostate cancer.

Prostate cancer is the most commonly diagnosed cancer in men and the third most common cause of male-cancer-related mortality in Europe [1]. Overtreatment of prostate cancer in men who have indolent disease but that would not become clinically manifest in their life-time is a significant health burden with only one life saved for every 33 men treated in a PSA-screened population [2]. A reduction in overtreatment must however not sacrifice current cure rates. To achieve this, improvements in tumor risk stratification require multimodality approaches including better imaging and molecular subtyping. At the other end of the disease spectrum, patients with metastatic disease invariably become resistant to castration, hormonal manipulations and chemotherapy. The successful development of new drugs and improved sequencing of currently approved agents will probably require biomarker-driven strategies to select patients for the next line of treatment based on their underlying molecular aberrations. To achieve these aims for prostate cancer as for several other cancer types, Annals of Oncology is prioritizing precision medicine studies that contribute to treatment optimization through improved characterization of tumors [3]. A significant clinical impact will only become reality with approaches that are broadly applicable to clinical samples (of widely variable quality) and using high-throughput, affordable and rapid turnaround technology. Assays will have to work on formalin-fixed samples, bone biopsies or circulating biomarkers such as circulating tumor cells or circulating cell-free DNA. In this issue of Annals of Oncology, the Tomlins lab describes MiPC that uses targeted next-generation sequencing and RT-PCR to study DNA and mRNA in 53 formalin-fixed and clinically representative prostate cancer samples [4]. Our understanding of the molecular aberrations and drivers that underlie prostate cancer has increased significantly over the past decade so this report is timely. A number of mutually exclusive aberrations have been described that split the disease into the distinct molecular subtypes used in this study (Figure 1 and reviewed in [5]). The most commonly occurring molecular subtype is characterized by fusion of ERG, a member of the ETS family of transcription factors, with a hormone-driven promoter most commonly TMPRSS2. Other subtypes are less common and characterized by fusions involving other ETS or RAF family members or (often co-occurring) overexpression of SPINK1, loss of CHD1 and point mutations in SPOP. Up to a quarter of prostate cancers do not fit into any of these subtypes, as also observed in this current series. Additionally, multiple molecular aberrations span these subtypes, can occur at various stages of disease progression to the lethal phenotype and some have been associated with a worse prognosis or drug resistance, including for example loss of PTEN or gain of aurora kinase A [6, 7]. There are a number of commercially available assays and companies that have optimized assays for performing targeted exome-sequencing on formalin-fixed tissue with a rapid turnaround (∼2–3 weeks). MiPC improves on these by simultaneously integrating RNA-based data to detect gene fusions and evaluate androgen receptor (AR) signaling and proliferation. This will allow stratification of prostate cancer into the abovedescribed molecular subtypes (Figure 1) and identification of other molecular signatures that could inform on best treatment selection. These could for example lead to selection of patients for AR targeting treatments based on activation of AR signaling with or without increased levels of splice variants lacking the ligand-binding domain [8], for taxanes based on loss of RB1 [9] or for DNA damaging agents such as platinum and PARP inhibitors based on aberrations in BRCA genes [10]. Nucleic acids from decalcified bone marrow biopsies were not amenable to characterization in the current study. In the majority of patients with advanced prostate cancer, the sole metastatic site that tumor tissue can be obtained from is bone and approaches for processing bone biopsies that avoid decalcification are required for MiPC. The one qualification to the imminent broad introduction of MiPC is that none of the defined markers of molecular subtypes have been validated for risk stratification of prostate cancer at diagnosis and prostate cancer does not yet have a biomarker indication that predicts treatment response. The recent approval of several new agents has been achieved in molecularly unselected populations. In the multicenter COU-AA-302 abiraterone phase III clinical trial in chemotherapy-naïve CRPC patients, formalin-fixed paraffin embedded (FFPE) archival samples were collected for evaluation of ERG gene fusions from close to half of the 1088 accrued patients [11]. A subclass detected by fluorescence in situ hybridization (FISH) characterized by an ERG gene fusion with a deletion and duplication or triplication of ERG gene fusion sequences appeared to have a greater benefit than other molecular subtypes but the improvement in benefit was not sufficiently great to warrant evaluation of ERG in isolation. Nonetheless, the study emphasized the feasibility and potential utility of characterizing archival prostate cancer FFPE tissue in large multicenter trials and suggested that multiplex approaches such as MiPC may be required to improve patient selection for AR-targeting therapies. Also, samples collected immediately before treatment initiation will probably be required to identify AR aberrations that associate with resistance and this may require evaluation of both tissues using an adapted MiPC panel and circulating biomarkers [8, 12]. Moreover, several ed ito ria ls editorials Annals of Oncology 26: 1041–1042, 2015 doi:10.1093/annonc/mdv179 Published online 10 April 2015