Prominent response to platinum-based chemotherapy in a patient with BRCA2 mutant-neuroendocrine prostate cancer and MDM2 amplification.
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ABSTRACT: Introduction
Genomic profiling provides useful information for diagnosis, treatment, and prognosis, and detection of certain defects, such as DNA repair gene aberrations or microsatellite instability, can possibly lead to optimal treatment, but this testing has not been widely used to inform prostate cancer treatment.Case presentation
A 55-year-old man sequentially treated for prostate cancer was diagnosed as neuroendocrine prostate cancer from prostate specimens resected because of urinary retention. Subsequently, he received five cycles of platinum-based chemotherapy in total and responded well. We also performed next-generation sequencing of a sample from the prostate specimen and identified a breast cancer susceptibility gene mutation with Murine Double Minute 2 amplification and loss of heterozygosity in retinoblastoma 1.Conclusion
We report a neuroendocrine prostate cancer patient with Murine Double Minute 2 amplification who experienced an aggressive course and for whom platinum-based chemotherapy was effective, and one of the reasons for the good response might be the breast cancer susceptibility gene mutation.
SUBMITTER: Daimon T
PROVIDER: S-EPMC8255288 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionDeoxyribonucleic acid repair gene mutations are now being studied in a variety of solid tumors, with the hope of predicting prognosis, pathogenesis, and treatment outcomes.Case presentationWe report the case of a Japanese patient with advanced castration-resistant prostate cancer who exhibited a prominent response to platinum therapy and had coexisting BRCA2 and PTEN mutations according to retrospective multigene panel analysis.ConclusionThrough a review of clinical outcomes and genetic/pathologic profiling, the presented case provides insights into future management strategies based on the tumor genetic status.
| S-EPMC8720712 | biostudies-literature
Project description: Not available
| S-EPMC7446371 | biostudies-literature
Project description:BackgroundBreast cancer 2 (BRCA2)-associated breast and ovarian cancers are sensitive to platinum-based chemotherapy. It is unknown whether BRCA2-associated prostate cancer responds favorably to such treatment.MethodsA retrospective analysis of a single-institution cohort of men with castration-resistant, metastatic prostate cancer was performed to determine the association between carrier status of pathogenic BRCA2 germline variants and prostate-specific antigen response to carboplatin-based chemotherapy. From 2001 through 2015, 8081 adult men with prostate cancer who had a consultation and/or underwent treatment at Dana-Farber Cancer Institute provided blood samples and consented to analyses of biologic material and clinical records. A subgroup of 141 men received at least 2 doses of carboplatin and docetaxel for castration-resistant disease (94% were also taxane refractory). These patients were categorized according to the absence or presence of pathogenic germline mutations in BRCA2 based on DNA sequencing from whole blood. The primary outcome was the response rate to carboplatin/docetaxel chemotherapy, defined according to a decline in prostate-specific antigen that exceeded 50% within 12 weeks of initiating this regimen. Associations between BRCA2 mutation status and response to carboplatin-based chemotherapy were tested using the Fisher exact test, with a 2-sided P value < .05 as the threshold for significance.ResultsPathogenic germline BRCA2 variants were observed in 8 of 141 men (5.7%; 95% confidence interval, 2.5%-10.9%). Six of 8 BRCA2 carriers (75%) experienced prostate-specific antigen declines >50% within 12 weeks, compared with 23 of 133 noncarriers (17%; absolute difference, 58%; 95% confidence interval, 27%-88%; P < .001). Prostate cancer cell lines functionally corroborated these clinical findings.ConclusionsBRCA2-associated, castration-resistant prostate cancer is associated with a higher likelihood of response to carboplatin-based chemotherapy than non-BRCA2-associated prostate cancer. Cancer 2017;123:3532-9. © 2017 American Cancer Society.
| S-EPMC5802871 | biostudies-literature
Project description:Neuroendocrine prostate cancer (NEPC) is a highly aggressive histologic subtype of prostate cancer associated with a poor prognosis. Its incidence is expected to increase as castration-resistant disease emerges from the widespread use of potent androgen receptor-targeting therapies, such as abiraterone and enzalutamide. Defects in homologous recombination repair genes, such as BRCA1/2, are also being increasingly detected in individuals with advanced prostate cancer. We present the case of a 65-yr-old man with a germline BRCA2 mutation who developed explosive treatment-emergent, small-cell neuroendocrine prostate cancer. He achieved a complete response to platinum-containing chemotherapy, but a limited remission duration with the use of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, as maintenance therapy. Upon relapse, tumor genomic profiling revealed a novel 228-bp deletion in exon 11 of the BRCA2 gene. The addition of the anti-PD1 drug pembrolizumab to olaparib was ineffective. This case highlights the ongoing challenges in treating neuroendocrine prostate cancer, even in the setting of homologous recombination repair deficiency.
| S-EPMC7903888 | biostudies-literature
Project description:PurposeClinical features characteristic of small-cell prostate carcinoma (SCPC), "anaplastic," often emerge during the progression of prostate cancer. We sought to determine the efficacy of platinum-based chemotherapy in patients meeting at least one of seven prospectively defined "anaplastic" clinical criteria, including exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low prostate-specific antigen levels relative to tumor burden, or short response to androgen deprivation therapy.Experimental designA 120-patient phase II trial of first-line carboplatin and docetaxel (CD) and second-line etoposide and cisplatin (EP) was designed to provide reliable clinical response estimates under a Bayesian probability model with early stopping rules in place for futility and toxicity.ResultsSeventy-four of 113 (65.4%) and 24 of 71 (33.8%) were progression free after four cycles of CD and EP, respectively. Median overall survival (OS) was 16 months [95% confidence interval (CI), 13.6-19.0 months]. Of the seven "anaplastic" criteria, bulky tumor mass was significantly associated with poor outcome. Lactic acid dehydrogenase strongly predicted for OS and rapid progression. Serum carcinoembryonic antigen (CEA) concentration strongly predicted OS but not rapid progression. Neuroendocrine markers did not predict outcome or response to therapy.ConclusionOur findings support the hypothesis that patients with "anaplastic" prostate cancer are a recognizable subset characterized by a high response rate of short duration to platinum-containing chemotherapies, similar to SCPC. Our results suggest that CEA is useful for selecting therapy in men with castration-resistant prostate cancer and consolidative therapies to bulky high-grade tumor masses should be considered in this patient population.
| S-EPMC3699964 | biostudies-literature
Project description:Breast cancer gene 2 (BRCA2) deleterious mutations confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition due to its critical role in DNA repair. PARP inhibitor Olaparib is now approved and several other PARP inhibitors are now in different stages of clinical trials. Development of resistance to PARP inhibitors limits their clinical utility. The mechanism of resistance remains not fully understood. Here we show that amplification of mutant BRCA2 confers PARP inhibitor resistance. The amplification of mutant BRCA2 gene copies correlates with an increase in mutant BRCA2 expression and an increase in the levels of its interacting proteins PALB2 and RAD51. In addition, homologous recombination mediated DNA repair is rescued in these cells as evidenced by the formation of RAD51 focus formation. The overexpressed mutant BRCA2 is essential for the observed PARP inhibitor resistance because knockdown of its expression is sufficient to re-sensitize these cells to PARP inhibition. Collectively, our results indicate a new mechanism of resistance to PARP inhibitor in BRCA2 mutant cancer cells
2017-09-02 | GSE86394 | GEO
Project description:Etoposide-platinum (EP) chemotherapy has long been the reference treatment for grade 3 neuroendocrine neoplasms (G3 NEN). However, G3 NEN are heterogeneous, including well-differentiated tumors (NET) and poorly differentiated large (LCNEC) or small (SCNEC) cell carcinomas, whose response to EP chemotherapy varies considerably. Our aim was to evaluate predictive biomarkers for the response to EP chemotherapy in G3 NEN. We retrospectively studied 89 patients with lung (42%) and digestive (58%) G3 NEN treated by EP chemotherapy between 2006 and 2020. All cases were centrally reviewed for cytomorphology/Ki-67 and immunohistochemistry of retinoblastoma protein (Rb)/p53/p16, analyzed using a semi-quantitative score. The absence of Rb staining (Rbinap) or the absence of very intense p53 staining (p53inap) were considered inappropriate. Rb staining was also studied as a quantitative marker, the best threshold being determined by ROC curve. Intense p16 staining (p16high) also suggested cell cycle dysregulation. Our primary endpoint was the objective response rate (ORR). We included 10 G3 NET, 31 LCNEC and 48 SCNEC, which showed ORR of 20%, 32% and 75%, respectively (NET vs. NEC, p = 0.040; LCNEC vs. SCNEC, p < 0.001). The ORR was significantly higher in NEN presenting with Rbinap (63% vs. 42%, p = 0.025) and p16high (66% vs. 35%, p = 0.006). Rb < 150 optimally identified responders (AUC = 0.657, p < 0.001). The ORR was 67% in Rb < 150 (vs. 25%, p = 0.005). On multivariate analysis, only Rb < 150 was independently associated with ORR (OR 4.16, 95% CI 1.11-15.53, p = 0.034). We confirm the heterogeneity of the response to EP treatment in G3 NEN. Rb < 150 was the best predictive biomarker for the response to EP, and p53 immunostaining had no additional value.
| S-EPMC7915900 | biostudies-literature
Project description:The p53 tumor suppressor gene is inactivated in human tumors by several distinct mechanisms. The best characterized inactivation mechanisms are: (i) gene mutation; (ii) p53 protein association with viral proteins; (iii) p53 protein association with the MDM2 cellular oncoprotein. The MDM2 gene has been shown to be abnormally up-regulated in human tumors and tumor cell lines by gene amplification, increased transcript levels and enhanced translation. This communication presents a brief review of the spectrum of MDM2 abnormalities in human tumors and compares the tissue distribution of MDM2 amplification and p53 mutation frequencies. In this study, 3889 samples from tumors or xenografts from 28 tumor types were examined for MDM2 amplification from previously published sources. The overall frequency of MDM2 amplification in these human tumors was 7%. Gene amplification was observed in 19 tumor types, with the highest frequency observed in soft tissue tumors (20%), osteosarcomas (16%) and esophageal carcinomas (13%). Tumors which showed a higher incidence of MDM2 amplification than p53 mutation were soft tissue tumors, testicular germ cell cancers and neuro-blastomas. Data from studies where both MDM2 amplification and p53 mutations were analyzed within the same samples showed that mutations in these two genes do not generally occur within the same tumor. In these studies, 29 out of a total of 33 MDM2 amplification-positive tumors had wild-type p53. We hypothesize that heretofore uncharacterized carcinogens favor MDM2 amplification over p53 mutations in certain tumor types. A database listing the MDM2 gene amplifications is available on the World Wide Web at http://www. infosci.coh.org/mdm2 . Charts of MDM2 amplification frequencies and comparisons with p53 genetic alterations are also available at this Web site.
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Project description:Expression of the DNA/RNA helicase schlafen family member 11 (SLFN11) has been identified as a sensitizer of tumor cells to DNA-damaging agents including platinum chemotherapy. We assessed the impact of SLFN11 expression on response to platinum chemotherapy and outcomes in patients with metastatic castration-resistant prostate cancer (CRPC). Tumor expression of SLFN11 was assessed in 41 patients with CRPC treated with platinum chemotherapy by RNA sequencing (RNA-seq) of metastatic biopsy tissue (n = 27) and/or immunofluorescence in circulating tumor cells (CTC; n = 20). Cox regression and Kaplan-Meier methods were used to evaluate the association of SLFN11 expression with radiographic progression-free survival (rPFS) and overall survival (OS). Multivariate analysis included tumor histology (i.e., adenocarcinoma or neuroendocrine) and the presence or absence of DNA repair aberrations. Patient-derived organoids with SLFN11 expression and after knockout by CRISPR-Cas9 were treated with platinum and assessed for changes in dose response. Patients were treated with platinum combination (N = 38) or platinum monotherapy (N = 3). Median lines of prior therapy for CRPC was two. Median OS was 8.7 months. Overexpression of SLFN11 in metastatic tumors by RNA-seq was associated with longer rPFS compared with those without overexpression (6.9 vs. 2.8 months, HR = 3.72; 95% confidence interval (CI), 1.56-8.87; P < 0.001); similar results were observed for patients with SLFN11-positive versus SLFN11-negative CTCs (rPFS 6.0 vs. 2.2 months, HR = 4.02; 95% CI, 0.77-20.86; P = 0.002). A prostate-specific antigen (PSA) decline of ≥50% was observed in all patients with SLFN11 overexpression. No association was observed between SLFN11 expression and OS. On multivariable analysis, SLFN11 was an independent factor associated with rPFS on platinum therapy. Platinum response of organoids expressing SLFN11 was reduced after SLFN11 knockout. Our data suggest that SLFN11 expression might identify patients with CRPC with a better response to platinum chemotherapy independent of histology or other genomic alterations. Additional studies, also in the context of PARP inhibitors, are warranted.
| S-EPMC7440143 | biostudies-literature
Project description:PurposeAlterations in DNA damage repair (DDR) genes occur in up to 25% of patients with metastatic castration-resistant prostate cancer (mCRPC) and may sensitize to platinum chemotherapy. We aimed to evaluate the efficacy of platinum-based chemotherapy in DDR-mutant (DDRmut) mCRPC.MethodsWe assessed response to platinum chemotherapy based on DDR gene alteration status in men with mCRPC who underwent tumor and germline genomic profiling. Patients with deleterious alterations in a gene panel that included BRCA2, BRCA1, ATM, PALB2, FANCA, and CDK12 were considered DDRmut.ResultsA total of 109 patients with mCRPC received platinum-based chemotherapy between October 2013 and July 2018. Sixty-four of 109 patients were taxane refractory and poly (ADP-ribose) polymerase inhibitor (PARPi) naïve. Within this subset, DDRmut was found in 16/64 patients (25%) and was associated with an increased likelihood of achieving a prostate-specific antigen (PSA) decline of 50% or more from baseline (PSA50; odds ratio, 7.0; 95% CI, 1.9 to 29.2). Time on platinum chemotherapy tended to be longer in the DDRmut group (median, 3.0 v 1.6 months; hazard ratio, 0.55, 95% CI, 0.29 to 1.24). No difference in survival was detected. Of 8 patients with DDRmut disease who received platinum-based therapy after a PARPi, 3/7 evaluable patients had radiographic partial response or stable disease, and 2/7 had a PSA50 response. None of 4 patients with ATM mutations had platinum responses regardless of prior PARPi exposure.ConclusionPatients with DDRmut disease had better response to platinum-based chemotherapy, suggesting that DDR status warrants prospective validation as a potential biomarker for patient selection. Responses to platinum chemotherapy were observed in BRCA-altered prostate cancer after PARPi progression. Additional studies are needed to determine the predictive role of individual genes on platinum sensitivity in the context of other clinical and genomic factors.
| S-EPMC7446522 | biostudies-literature