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The resounding effect of DNA repair deficiency in prostate cancer.

ABSTRACT: An estimated one-fifth or more of metastatic castration-resistant prostate cancer (mCRPC) harbor defects in genes involved in DNA repair pathway (e.g., BRCA2, BRCA1, and others). Early evidence suggests these alterations may be predictive of therapeutic response to PARP inhibitors and platinum chemotherapy, thought to reflect principles of synthetic lethality and are currently being investigated in an increasing number of prospective clinical trials. Other studies have examined these alterations as prognostic biomarkers and in association with response to currently available treatments. A smaller fraction of men (5%-10%) with mCRPC have evidence of microsatellite instability and defects in the DNA mismatch repair pathway, which may predict therapeutic response to immune checkpoint inhibitors. Loss of function of these 2 critical DNA repair pathways serves as new candidate predictive biomarkers for treatment strategies that represent net gains in the treatment toolbox for prostate cancer. Additionally, more than one-tenth of men with mCRPC carry genetic alterations of DNA repair in their germline DNA, which may indicate high- to moderate-penetrance heritable cancer risk and have important implications for family members. Cascade genetic testing of family can, in some cases, direct modified strategies for screening and prevention of multiple cancers. Further study in each of these arenas is ongoing, although the potential for resounding effect is clear.

SUBMITTER: Cheng HH

PROVIDER: S-EPMC6746340 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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The resounding effect of DNA repair deficiency in prostate cancer.

Cheng Heather H HH

Urologic oncology 20180317 8

An estimated one-fifth or more of metastatic castration-resistant prostate cancer (mCRPC) harbor defects in genes involved in DNA repair pathway (e.g., BRCA2, BRCA1, and others). Early evidence suggests these alterations may be predictive of therapeutic response to PARP inhibitors and platinum chemotherapy, thought to reflect principles of synthetic lethality and are currently being investigated in an increasing number of prospective clinical trials. Other studies have examined these alterations ...[more]

PMID: 29555412

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Project description:BACKGROUND:Prostate-specific membrane antigen (PSMA; folate hydrolase) prostate cancer (PC) expression has theranostic utility. OBJECTIVE:To elucidate PC PSMA expression and associate this with defective DNA damage repair (DDR). DESIGN, SETTING, AND PARTICIPANTS:Membranous PSMA (mPSMA) expression was scored immunohistochemically from metastatic castration-resistant PC (mCRPC) and matching, same-patient, diagnostic biopsies, and correlated with next-generation sequencing (NGS) and clinical outcome data. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Expression of mPSMA was quantitated by modified H-score. Patient DNA was tested by NGS. Gene expression and activity scores were determined from mCRPC transcriptomes. Statistical correlations utilised Wilcoxon signed rank tests, survival was estimated by Kaplan-Meier test, and sample heterogeneity was quantified by Shannon's diversity index. RESULTS AND LIMITATIONS:Expression of mPSMA at diagnosis was associated with higher Gleason grade (p=0.04) and worse overall survival (p=0.006). Overall, mPSMA expression levels increased at mCRPC (median H-score [interquartile range]: castration-sensitive prostate cancer [CSPC] 17.5 [0.0-60.0] vs mCRPC 55.0 [2.8-117.5]). Surprisingly, 42% (n=16) of CSPC and 27% (n=16) of mCRPC tissues sampled had no detectable mPSMA (H-score <10). Marked intratumour heterogeneity of mPSMA expression, with foci containing no detectable PSMA, was observed in all mPSMA expressing CSPC (100%) and 37 (84%) mCRPC biopsies. Heterogeneous intrapatient mPSMA expression between metastases was also observed, with the lowest expression in liver metastases. Tumours with DDR had higher mPSMA expression (p=0.016; 87.5 [25.0-247.5] vs 20 [0.3-98.8]; difference in medians 60 [5.0-95.0]); validation cohort studies confirmed higher mPSMA expression in patients with deleterious aberrations in BRCA2 (p<0.001; median H-score: 300 [165-300]; difference in medians 195.0 [100.0-270.0]) and ATM (p=0.005; 212.5 [136.3-300]; difference in medians 140.0 [55.0-200]) than in molecularly unselected mCRPC biopsies (55.0 [2.75-117.5]). Validation studies using mCRPC transcriptomes corroborated these findings, also indicating that SOX2 high tumours have low PSMA expression. CONCLUSIONS:Membranous PSMA expression is upregulated in some but not all PCs, with mPSMA expression demonstrating marked inter- and intrapatient heterogeneity. DDR aberrations are associated with higher mPSMA expression and merit further evaluation as predictive biomarkers of response for PSMA-targeted therapies in larger, prospective cohorts. PATIENT SUMMARY:Through analysis of prostate cancer samples, we report that the presence of prostate-specific membrane antigen (PSMA) is extremely variable both within one patient and between different patients. This may limit the usefulness of PSMA scans and PSMA-targeted therapies. We show for the first time that prostate cancers with defective DNA repair produce more PSMA and so may respond better to PSMA-targeting treatments.

Project description:BACKGROUND:Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib. METHODS:We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies. RESULTS:Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib. CONCLUSIONS:Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).

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The resounding effect of DNA repair deficiency in prostate cancer.

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The resounding effect of DNA repair deficiency in prostate cancer.

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