TP53 and Prognosis in Mcrpc Survival: Biology Or Coincidence?

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

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

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.

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

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

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).

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). In

127 light of the variety of treatment and scheduling options for both hormone-sensitive and castration-

128 resistant prostate cancer, there is an unmet medical need for properly validated predictive biomarkers

129 to help guide the rational sequencing of therapies and result in a step-change for outcomes in an

130 otherwise lethal setting.

131

132

133 Figure 1: TP53 Mutation Status for CRPC treatment guidance. Castration-resistant prostate

134 cancer (CRPC) is the result of persistent tumour growth despite sufficient androgen deprivation.

135 Liquid biopsy sampling at this stage allows for risk factor assessment including CTC/ctDNA

136 enumeration, and low coverage whole genome sequencing. TP53 alterations are often found in CRPC

137 predicting for poor outcomes and enabling prediction of response to next-generation antiandrogenic

138 agents. This has the potential for differential treatment planning at this cross-road. ADT=Androgen

139 deprivation therapy, HSPC=Hormone sensitive prostate cancer, CRPC=Castration-resistant prostate

140 cancer, CTCs=circulating tumor cells, ctDNA=circulating tumor DNA, AAP/ENZA = Abiraterone +

141 Prednisone/ Enzalutamide, TP53=tumor protein 53, AR=Androgen receptor, ARV=Androgen

142 receptor variants, BRCA1/2=Breast Cancer susceptibility protein 1/2, ATM=Ataxia telangiectasia-

143 mutated, PI3K/MAPK=phosphoinositol-3-kinase/mitogen activated protein kinase, mt= mutated. Red

144 circle indicates what is addressed in this study.

145

146

147 References

148 1. De Laere B, Oeyen S, Mayrhofer M, Whitington T, van Dam PJ, Van Oyen P, et al. TP53 149 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide 150 outcome in metastatic castration-resistant prostate cancer. Clin Cancer Res 2018 doi 151 10.1158/1078-0432.CCR-18-1943. 152 2. Gillessen S, Attard G, Beer TM, Beltran H, Bossi A, Bristow R, et al. Management of Patients 153 with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus 154 Conference APCCC 2017. Eur Urol 2018;73(2):178-211 doi 10.1016/j.eururo.2017.06.002. 155 3. Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative 156 clinical genomics of advanced prostate cancer. Cell 2015;161(5):1215-28 doi 157 10.1016/j.cell.2015.05.001. 158 4. De Laere B, van Dam PJ, Whitington T, Mayrhofer M, Diaz EH, Van den Eynden G, et al. 159 Comprehensive Profiling of the Androgen Receptor in Liquid Biopsies from Castration- 160 resistant Prostate Cancer Reveals Novel Intra-AR Structural Variation and Splice Variant 161 Expression Patterns. Eur Urol 2017;72(2):192-200 doi 10.1016/j.eururo.2017.01.011. 162 5. Muller PA, Vousden KH. Mutant p53 in cancer: new functions and therapeutic opportunities. 163 Cancer Cell 2014;25(3):304-17 doi 10.1016/j.ccr.2014.01.021.

164

CTCs ctDNA Blood “PCa treatment sequence” Lymphocytes vessel Relapse: (germline DNA) AAP/ENZA Doc Primary Radium 223 ADT Disease burden Liquid biopsy assessment HSPC CRPC mCRPCmCRPC liquidliquid bbiopsyiiopsy

TP53 allelic loss TP53 status delineates mtTP53 GOF prognosis mtTP53 LOF

AR ampliﬁcation Treatment: mtAR (+AR variants) Good AAP/ENZA Germline mtBRCA1/2 & mtATM Intermediate

Aberrant PI3K/MAPK survival and beta-catenin/WNT Treatment: signaling Progression-free Poor alternative ?? (e.g., docetaxel) Time (months) Mutations contributing to CRPC biology

TP53 and prognosis in mCRPC Survival: Biology or Coincidence?

Richard J. Rebello, Christoph Oing, Silke Gillessen, et al.

Clin Cancer Res Published OnlineFirst January 4, 2019.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-18-3401

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