DNA‐repair status should be assessed in treatment‐emergent neuroendocrine prostate cancer before platinum‐based therapy

Abstract

Objectives This study sought to provide contemporary data from a multi‐institution with respect to DNA‐repair genes (DRGs) status and its impact on effects of platinum‐based chemotherapy in treatment‐emergent neuroendocrine prostate cancer (t‐NEPC), for which little data exist. Patients and Methods All patients were retrospectively collected with eligible biopsied tissues for targeted next generation sequencing (NGS). The main outcomes were radiologic progression‐free survival and overall survival according to Response Evaluation Criteria in Solid Tumors, version 1.1. Results Among the 43 NEPC patients, 13/43 (30%) harbored homozygous deletions, deleterious mutations, or both in DRGs. Eleven patients (11/13, 85%) with DRGs aberrations had effective response, including 7 patients with BRCA1/2 defects and 2 with mismatch repair‐deficient caused by MSH2 alterations. While significantly fewer responders (30%) were detected in patients without DRGs aberrations (odds ratio = 12.83, p = 0.003). Compared with patients without genomic DRGs aberrations, the hazard ratio (HR) for radiologic progression in those with DRGs defects was 0.42 (95% confidence interval [CI]: 0.19–0.93), and the HR for death was 0.65 (95% CI: 0.24–1.72). The most common adverse event of Grade 3 or 4 was anemia, as noted in 7 patients (16%). Conclusion The DRGs status is therapeutically meaningful in t‐NEPC. Given the potential responses to platinum‐based chemotherapy, our findings support the clinical use of NGS in t‐NEPC patients to identify DRGs aberrations.

Genomic alterations in neuroendocrine prostate cancer: A systematic review and meta‐analysis

“…The main characteristics of the eligible studies are shown in Table 1. Overall, 14 studies with 449 patients were included in the meta‐analysis 3,8–10,16–25 . The median number of patients enrolled in each study was 17 (range: 5–218), and the median age ranged from 65 to 77 years.…”

“…Overall, 14 studies with 449 patients were included in the meta‐analysis. 3 , 8 , 9 , 10 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 The median number of patients enrolled in each study was 17 (range: 5–218), and the median age ranged from 65 to 77 years. Eleven studies performed gene sequencing on tumour tissues, two studies conducted liquid biopsies (circulating tumour cells and cell‐free DNA), and one study did not report the source of tumour DNA.…”

“…Recently, several large clinical trials have demonstrated the effectiveness of PARP inhibitors in mCRPC patients with HRR defects, especially in those harbouring deleterious ATM or BRCA1/2 mutations 27–29 . In addition, a retrospective study showed that DNA‐repair genes status was associated with treatment response and progression‐free survival in t‐NEPC patients receiving platinum‐based chemotherapy 25 . In our study, we focused on the deleterious mutations in ATM and BRCA1/2 because of their strong therapeutic predictive value in PCa.…”

“… 27 , 28 , 29 In addition, a retrospective study showed that DNA‐repair genes status was associated with treatment response and progression‐free survival in t‐NEPC patients receiving platinum‐based chemotherapy. 25 In our study, we focused on the deleterious mutations in ATM and BRCA1/2 because of their strong therapeutic predictive value in PCa. The overall pooled prevalence of deleterious ATM/BRCA mutations in NEPC was 16.8%, with BRCA2 mutations being the most frequent at 10.6%.…”

“…Overall, 14 studies with 449 patients were included in the meta-analysis. 3,[8][9][10][16][17][18][19][20][21][22][23][24][25] The median number of patients enrolled in each study Quality assessments were performed on the included studies (details summarized in Table S1). Seven studies were considered good quality, five studies were of moderate quality, and two studies were of poor quality.…”