PD-0300: NBN gain is predictive for adverse outcome following image-guided radiotherapy for localized prostate cancer

Berlin, A.; Lalonde, Emilie; Zafarana, Gaetano; Sykes, Jenna; Lam, Wwt; Meng, Alice; Milosevic, M.; Kwast, Theodorus van der; Boutros, Paul C.; Bristow, R.G.

doi:10.1016/s0167-8140(15)30405-9

Cited by 8 publications

(11 citation statements)

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“…In a control cohort of 154 localised prostate cancer patients treated with radical prostatectomy, NBN gain was not associated with biochemical relapse-free rate (61% NBN gain versus 77% NBN neutral, P ¼ 0.15). No association was found for any of the other genes assessed [40].…”

Section: Nbnmentioning

confidence: 77%

“…Berlin et al [40] determined copy number variation in the DDR genes MRE11A, RAD50, NBN, ATM, ATR and PRKDC in pre-treatment prostate cancer biopsies. Variation in NBN copy number was the most common abnormality observed and was associated with genomic instability [40].…”

Section: Nbnmentioning

confidence: 99%

“…Other DDR-related biomarkers identified as predictive of outcome exclusively in radiotherapy treated patients were AIMP3 in MIBC [39], NBN in prostate cancer [40] and BRE in breast cancer [41], but these findings have not yet been replicated.…”

Section: Limitations Of Radiotherapy Biomarkers Identifiedmentioning

confidence: 99%

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Biomarkers of Tumour Radiosensitivity and Predicting Benefit from Radiotherapy

2015

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Section: Nbnmentioning

confidence: 77%

Section: Nbnmentioning

confidence: 99%

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Biomarkers of Tumour Radiosensitivity and Predicting Benefit from Radiotherapy

2015

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“…Obviously, in addition to quantitative tumortargeting, accessory factors are influencing response to PSMA-TAT. Preclinical and early clinical studies reported that particular DNA-damage repair associated genemutations (DRMs) can either increase or decrease the radio-sensitivity of prostate cancers (8)(9)(10)(11)(12)(13)(14) and thus might represent one of these cofactors.…”

Section: Introductionmentioning

confidence: 99%

Patients Resistant Against PSMA-Targeting α-Radiation Therapy Often Harbor Mutations in DNA Damage-Repair–Associated Genes

et al. 2019

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Prostate-specific membrane antigen (PSMA) targeting alpha-radiation therapy (TAT) is an emerging treatment modality for metastatic castration-resistant prostate cancer. There is a subgroup of patients with poor response despite sufficient expression of PSMA in their tumors. The aim of this work was to characterize PSMA-TAT nonresponding lesions by targeted next-generation sequencing (tNGS). Methods: Out of 60 patients treated with 225 Ac-PSMA-617, we identified 10 patients that presented with a poor response despite sufficient tumor-uptake in PSMA-PET/CT. We were able to perform CT-guided biopsies with histologic validation of the non-responding lesions in seven of these non-responding patients. Specimens were analyzed by tNGS interrogating 37 DNA damage-repair associated genes. Results: In the seven tumor samples analyzed, we found a total of 15 whole-gene deletions, deleterious or presumably deleterious mutations affecting TP53 (n=3); CHEK2 (n=2), ATM (n=2); BRCA1, BRCA2, PALB2, MSH2, MSH6, NBN, FANCB and PMS1 (n=1 each). The average number of deleterious or presumably deleterious mutations was 2.2 (range, 0-6) per patient. In addition, several variants of unknown significance in ATM, BRCA1, MSH2, SLX4, ERCC-and various FANC-genes were detected. Conclusion: Patients with resistance to PSMA-TAT despite PSMA-positivity frequently harbor mutations in DNA-damage-repair and checkpoint genes. While the causal role of these alterations in the patient outcome remains to be determined, our findings encourage future studies combining PSMA-TAT and DNA-damage-repair targeting agents such as Poly(ADPribose)-Polymerase inhibitors.

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“…Our group recently reported that NBN copy number gain and high percent genome aberration are highly predictive for biochemical relapse following radiotherapy, and such patients may be suitable for intensification with added androgen modulation (11,12). The safety profile of this more intensive treatment, if incorporating androgen stimulation as well, requires detailed evaluation in prospective clinical studies.…”

Section: 2mentioning

confidence: 99%

Testosterone in Androgen Receptor Signaling and DNA Repair: Enemy or Frenemy?

Chua

Bristow

2016

Clinical Cancer Research

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Androgen suppression mediates transcriptional downregulation of DNA repair genes. Stimulation with supraphysiologic levels of dihydrotestosterone induces formation of lethal DNA breaks through recruitment of topoisomerase II enzymes to fragile DNA sites. Bipolar castration and stimulation that contributes to increasing DNA damage represents a novel strategy of sensitizing prostate cancer to cytotoxic therapies, including radiotherapy. Clin Cancer Res; 22(13); 3124-6. Ó2016 AACR.See related article by Hedayati et al., p. 3310 In this issue of Clinical Cancer Research, Hedayati and colleagues (1) report a novel, but possibly counterintuitive, strategy of exploiting sequential androgen suppression and stimulation to increasingly sensitize prostate cancer cells to radiotherapy. They attributed this effect to the induction of transient DNA doublestrand breaks (DSB) following a combination of androgen deprivation and supraphysiologic levels of dihydrotestosterone. This DNA damage response occurs through an exclusive interaction between the androgen receptor (AR) and topoisomerase II beta (TOP2B). This increased accumulation of DSB following irradiation was significant enough to inhibit tumor growth in vivo.The combination of androgen suppression and radiotherapy is a time-honored treatment regime with proven efficacy of advancing cure rates in patients with high-risk and locally advanced prostate cancer. Numerous randomized trials, testing a variety of castration approaches, have conclusively confirmed the synergism between androgen suppression and radiation, reporting better tumor control rates (pooled HR 1.67) and reduction of distant metastases (pooled HR 1.63) when compared with radiotherapy alone (2). On the basis of the documented effects on both local and systemic disease, it is widely perceived that combined modality therapy with suppression of the AR axis simultaneously enhances the cytotoxic effects of radiotherapy on the primary prostate cancer and also targets occult metastases.The mechanistic basis of this clinical observation is starting to mature as increasing evidence indicates that activation of the AR axis exerts an influence on the cellular DNA repair machinery and overall DNA damage response (Fig. 1). In response to genotoxic stress, androgen ligand binding to the AR triggers a cascade of signaling events that promotes the assembly of transcriptional elements leading to the overexpression of DNA repair genes involved in DNA damage sensing, DSB repair, base excision repair (BER), and mismatch repair (MMR; ref.3). The process of ARdependent transcriptional regulation is further modulated by the receptor binding with repair proteins, such as Ku, DNA-dependent protein kinase (catalytic subunit; DNA-PKcs), and PARP1; these proteins also function as AR coactivators (4).Given the positive-feedback circuit linking AR axis stimulation and DNA repair, it would suggest, in principle, that targeting the AR axis represents a very sound and attractive strategy for potentiating the DNA-damaging effects of cyto...

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PD-0300: NBN gain is predictive for adverse outcome following image-guided radiotherapy for localized prostate cancer

Cited by 8 publications

References 0 publications

Biomarkers of Tumour Radiosensitivity and Predicting Benefit from Radiotherapy

Biomarkers of Tumour Radiosensitivity and Predicting Benefit from Radiotherapy

Patients Resistant Against PSMA-Targeting α-Radiation Therapy Often Harbor Mutations in DNA Damage-Repair–Associated Genes

Testosterone in Androgen Receptor Signaling and DNA Repair: Enemy or Frenemy?

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