TP53 and Prognosis in Mcrpc Survival: Biology Or Coincidence?
Total Page：16
File Type：pdf, Size：1020Kb
Author Manuscript Published OnlineFirst on January 4, 2019; DOI: 10.1158/1078-0432.CCR-18-3401 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 TP53 and prognosis in mCRPC Survival: Biology or Coincidence? 2 Richard J Rebello1*, Christoph Oing1,2*, Silke Gillessen1,3#, Robert G Bristow1# 3 4 5 6 Affiliations 7 1 Translational Oncogenomics Group, Cancer Research UK Manchester Institute, The University of 8 Manchester, Manchester Cancer Research Centre, 555 Wilmslow Road, Manchester M20 4GJ, United 9 Kingdom 10 2 Department of Oncology, Hematology and Bone Marrow Transplantation with Section of 11 Pneumology, University Medical Center Eppendorf, Martinistr. 52, 20246 Hamburg, Germany 12 3 Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, Rorschacher Str. 13 95, 9007 St. Gallen, Switzerland 14 15 16 17 *contributed equally. #co-senior authors 18 19 Running title: TP53 and Prognosis in mCRPC Survival 20 21 Disclosure: No potential conflicts of interest were disclosed. 22 23 24 Correspondance: 25 Robert G. Bristow MD PhD 26 Manchester Cancer Research Centre, 27 University of Manchester 28 555 Wilmslow Road, Manchester, UK, 29 M20 4GJ 30 Email: [email protected] 31 Phone: +44(0)-161-306-3249 32 33 34 35 36 37 38 39 40 41 1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 4, 2019; DOI: 10.1158/1078-0432.CCR-18-3401 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 42 Summary 43 Cell-free circulating tumour DNA (ctDNA) or circulating tumour cell (CTC) assays are potentially 44 powerful in the treatment of metastatic castration-resistant prostate cancer (mCRPC). A new study 45 suggests that mutation of TP53 supercedes AR in predicting mCRPC survival. A role for TP53 46 mutation as a driver for mCRPC remains unexplored. 47 48 49 50 51 52 In this issue of Clinical Cancer Research, De Laere and colleagues (1) report TP53 mutation status as 53 a prognostic indicator for metastatic prostate cancer (PCa) patients who are starting Abiraterone or 54 Enzalutamide systemic therapy. The authors utilised low-pass whole genome sequencing of 55 circulating tumor cells (CTCs) and cell-free circulating tumor DNA (ctDNA) as biomarkers of 56 outcome from 168 patients with metastatic castration-resistant prostate cancer (mCRPC). 57 mCRPC is uniformly lethal as tumor cell proliferation occurs even in the presence of androgen 58 deprivation therapy (ADT) (2). Therefore, despite the resistance to ADT, mCRPC remains dependent 59 on the androgen receptor (AR) signalling axis (2). Over the past decade, randomized Phase III trials 60 have set new standards of care with overall survival benefits observed by selective inhibition of 61 androgen biosynthesis by targeting the enzyme CYP17A1 using Abiraterone acetate plus prednisone 62 (AAP) or by targeting AR more directly with the competitive inhibitor, Enzalutamide (ENZA) (2). 63 Other non-AR targeted systemic treatment options that improve overall survival in mCRPC are 64 Docetaxel and Cabazitaxel chemotherapy, the bone-targeted alpha particle-emitter, Radium-223 as 65 well as the immunotherapy, Sipuleucil-T (2). Of note, sequencing of these novel treatments has been 66 associated with a two-fold prolongation of overall survival in mCRPC patients when compared to 2 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 4, 2019; DOI: 10.1158/1078-0432.CCR-18-3401 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 67 older docetaxel-based regimens (2). The optimal sequencing of systemic therapies remains a matter of 68 debate as tumors can acquire cross-resistance between different agents, and this may associate with 69 inter-patient and inter-tumoral heterogeneity for which there is a paucity of predictive biomarkers (2). 70 Therefore, biomarkers which guide treatment decisions for individual patients in this disease stage are 71 urgently needed to precisely predict the likelihood of a favourable treatment response and to prevent 72 ineffective treatment in poor responders. 73 Alterations in AR and TP53 are among the most frequent mutations in mCRPC, representing more 74 than 60% and 50% of patients respectively (3). AR gene alterations may result in the expression of 75 AR transcript splice variants (AR-Vs) which may be constitutively active AR variants lacking a 76 ligand-binding domain, such as AR-V7 (3). Significantly, the expression of AR-V7 has the potential 77 to enable a clonal selection of castration-resistant cells on a background of “castrate-level” circulating 78 androgen. Several studies have now addressed the importance of AR-V7 detection in tumor tissue, 79 CTCs or in ctDNA and together they support AR-V7 as one factor in acquired resistance towards 80 next-generation AR targeting agents (AAP or ENZA) suggesting the alternate use of up-front 81 Docetaxel chemotherapy in AR-V7 positive patients (2). However, it remains to be seen whether AR- 82 V7 and/or other AR alterations can reliably stratify patients whose tumor burden can be further 83 determined by serial enumeration of CTCs and/or circulating tumor DNA (ctDNA) during therapy 84 progression. 85 Despite the work on AR variants, the additional prognostic role of TP53 mutation in possibly 86 stratifying patients into differential therapy groups remained unknown. To address this question, De 87 Laere and colleagues (1) sequenced whole genomes at low coverage and characterised recurrent gene 88 alterations in mCRPC patients in a multi-centre study to develop prognostic scores in a cohort of 89 responders and non-responders to AAP/ENZA. They detected the presence of somatic alterations in 90 AR and TP53 and correlated this with patient outcome-associated data to derive a stratification model 91 for good, intermediate and poor prognosis (1). Interestingly, only alteration in TP53 status, but not AR 92 alteration, was an independent predictor of poor prognosis when compared to clinical co-variates. A 3 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 4, 2019; DOI: 10.1158/1078-0432.CCR-18-3401 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 93 new risk stratification model using TP53 status and clinical variables was subsequently validated in an 94 independent and tumor burden-matched cohort of men (1). 95 The utility of liquid biopsy in this setting provides a powerful approach to guide clinical decision 96 making as it is now possible to obtain detailed genomic information without employing invasive 97 measures of an individual before the start of systemic treatment for mCRPC and at disease 98 progression. In a previous study, liquid biopsies from 30 CRPC patients beginning next-generation 99 AR-targeted therapy were used to show that the AR gene was frequently and differentially altered 100 giving rise to several potentially pathologic splice variants, including the contentious AR-V7, but no 101 specific AR alteration alone predicted response (4). Importantly, there were many patients even in this 102 smaller cohort of patients who did not possess the AR-V7 variant and still responded poorly. The 103 current study by De Laere and colleagues which included a larger cohort of patients identified instead, 104 alterations in TP53 as an independent and multivariate predictor of treatment outcome. 105 A fundamental role for TP53 in the cell is the control of genetic stability by regulating transcription, 106 DNA repair and progression through G1 and G2 phases of the cell cycle (5). The biological 107 consequence of individual TP53 mutations in these patients was speculated to be loss of gene 108 function, however the complexities of partial or altered TP53 function (i.e. emergence of gain of 109 function mutants or mono-allelic loss) could not be addressed by the assays in the current study. The 110 data proposed by De Laere and colleagues would imply that there may be a biological role for TP53 111 to supersede the importance of AR functional status in men with mCRPC. However, this is occurring 112 in a setting where there are a myriad of other mutations that associate with mCRPC including c-MYC 113 amplification, loss of PTEN, gain of PI3K or MAPK pathway signalling and/or defective DNA repair 114 and cell cycle control (3). In addition, concurrent germline or somatic alterations in DNA repair genes 115 such as BRCA1, BRCA2 or ATM could alter ABI/ENZA responses and were not simultaneously 116 measured. Future studies should determine the functional consequences of functionally variant, TP53 117 mutants in the context of complex background mCRPC mutations, in order to clarify a unique, and 118 possibly targetable, role for TP53 as it relates to differential patient stratification and clinical outcome 119 (5). 4 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 4, 2019; DOI: 10.1158/1078-0432.CCR-18-3401 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 120 The current study positions TP53 status as a potentially powerful prognostic variable which, if 121 validated in subsequent studies which also include the complexity of additional mutation and 122 functional assays, could become a simple test to stratify patients into differential treatment groups. 123 This requires further testing in randomised settings to provide Level I evidence and a ”predictive” 124 assay for improvement of outcome in the mCRPC setting. An additional question is whether this 125 approach will give rise to novel treatments in mCRPC patients with altered TP53 as “poor” 126 responders or whether they will default to a currently available taxane-based therapy (see Figure 1).