Editorial Comment to Prominent response to platinum‐based chemotherapy in a patient with BRCA2 mutant‐neuroendocrine prostate cancer and MDM2 amplification

platinum-based chemotherapy. Recently, some studies have shown that DNA repair gene aberrations, such as mutations of BRCA1/2 and ataxia telangiectasia mutated, are biomarkers for the higher likelihood response of platinum chemotherapy and poly(adenosine diphosphate-ribose) polymerase inhibitor. Those genetic mutations are present in 20% of metastatic CRPCs. In this case, a BRCA2 mutation was identified, and VAF plots (Fig. 2b) indicated the potential of a high LOH frequency and scattered allelic imbalance. Recently, three independent DNA-based measures of genomic instability reflecting underlying tumor HRR deficiency have been developed on the basis of LOH, telomeric allelic imbalance, and large-scale state transitions. However, we could not determine the homologous recombination deficiency score because the relevant test did not undergo, and therefore, could not prove this. However, we can hypothesize that the BRCA2 mutation results in an HRR deficiency subsequently causes a high LOH frequency and scattered allelic imbalance, which potentially results in a good response to platinum chemotherapy. Furthermore, some reports have indicated that genetic features of NEPC are inactivation of the RB and p53, and some researchers have reported MDM2 as one of the regulators of p53. Overexpression of MDM2 inhibits p53 activity thorough p53 ubiquitination and inhibition of p53 interaction with DNA and leads to tumor progression. MDM2 is upregulated in almost 30% of prostate cancer patients and associated with distant metastasis. However, the association between NEPC and MDM2 has rarely been reported to date. In this NEPC case, next-generation sequencing identified a BRCA2 mutation, MDM2 amplification, and LOH in the RB1 gene, although there was no tumor protein p53 mutation. In this case, LOH was observed in the RB1 gene. Thus, we believe that the other allele may be inactivated by RB1 promoter methylation or epigenetic change, which induced the loss of RB1 functionality. Genetic analysis suggested that RB1 inactivation and p53 inactivation due to MDM2 amplification after sequential treatment could have led to the NEPC of this patient. Testing DNA alterations and checking those DNA repair gene aberrations might be beneficial to patients with aggressive CRPC from the point of view of precision oncology. In this case, a BRCA2 mutation had already been detected by genetic testing; therefore, we planned to use a poly(adenosine diphosphate-ribose) polymerase inhibitor after platinum-based chemotherapy. Here, we report an NEPC patient with MDM2 amplification who experienced an aggressive course and for whom platinum-based chemotherapy was effective because of a BRCA2 mutation.

consensus on what kind of CRPC patients can benefit from platinum-based chemotherapy.
Recently, some studies have shown that DNA repair gene aberrations, such as mutations of BRCA1/2 and ataxia telangiectasia mutated, are biomarkers for the higher likelihood response of platinum chemotherapy and poly(adenosine diphosphate-ribose) polymerase inhibitor. Those genetic mutations are present in 20% of metastatic CRPCs. 5 In this case, a BRCA2 mutation was identified, and VAF plots (Fig. 2b) indicated the potential of a high LOH frequency and scattered allelic imbalance. Recently, three independent DNA-based measures of genomic instability reflecting underlying tumor HRR deficiency have been developed on the basis of LOH, telomeric allelic imbalance, and large-scale state transitions. However, we could not determine the homologous recombination deficiency score because the relevant test did not undergo, and therefore, could not prove this. However, we can hypothesize that the BRCA2 mutation results in an HRR deficiency subsequently causes a high LOH frequency and scattered allelic imbalance, which potentially results in a good response to platinum chemotherapy.
Furthermore, some reports have indicated that genetic features of NEPC are inactivation of the RB and p53, 6,7 and some researchers have reported MDM2 as one of the regulators of p53. Overexpression of MDM2 inhibits p53 activity thorough p53 ubiquitination and inhibition of p53 interaction with DNA and leads to tumor progression. 8 MDM2 is upregulated in almost 30% of prostate cancer patients and associated with distant metastasis. 9 However, the association between NEPC and MDM2 has rarely been reported to date. In this NEPC case, next-generation sequencing identified a BRCA2 mutation, MDM2 amplification, and LOH in the RB1 gene, although there was no tumor protein p53 mutation. In this case, LOH was observed in the RB1 gene. Thus, we believe that the other allele may be inactivated by RB1 promoter methylation or epigenetic change, which induced the loss of RB1 functionality. Genetic analysis suggested that RB1 inactivation and p53 inactivation due to MDM2 amplification after sequential treatment could have led to the NEPC of this patient.
Testing DNA alterations and checking those DNA repair gene aberrations might be beneficial to patients with aggressive CRPC from the point of view of precision oncology. In this case, a BRCA2 mutation had already been detected by genetic testing; therefore, we planned to use a poly(adenosine diphosphate-ribose) polymerase inhibitor after platinum-based chemotherapy. Here, we report an NEPC patient with MDM2 amplification who experienced an aggressive course and for whom platinum-based chemotherapy was effective because of a BRCA2 mutation.

Supporting information
Additional Supporting Information may be found in the online version of this article at the publisher's web-site: Table S1. 160 genes examined in the PleSSision-Rapid test. Appendix S1. Materials and methods.

Editorial Comment
Editorial Comment to Prominent response to platinum-based chemotherapy in a patient with BRCA2 mutant-neuroendocrine prostate cancer and MDM2 amplification In this issue, Daimon et al. 1 reported on the efficacy of platinum-based chemotherapy in patients with neuroendocrine prostate cancer harboring BRCA2 mutations. Docetaxel administered after progression to castration-resistant prostate cancer (CRPC) initially suppressed disease progression, but prostatespecific antigen (PSA) levels remained constantly elevated during the subsequent administration of enzalutamide and cabazitaxel. Eventually, the patient was pathologically diagnosed as adenocarcinoma with neuroendocrine differentiation. After This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
BRCA2 mutation with MDM2 amplification and loss of heterozygosity of RB1 were identified by targeted next-generation sequencing, the patient is currently undergoing platinumbased chemotherapy, decreasing PSA level.
The patient was diagnosed with prostate cancer with a high Gleason score at the relatively young age of 55 years with no family history, although it is unknown whether this patient has germline or somatic mutation in BRCA2 gene. Because BRCA2 is essential to maintain genomic integrity by homologous recombination of double-strand breaks, BRCA2 mutations accumulate genomic errors and increase the risk of carcinogenesis. Recently, Nyberg et al. 2 reported an increased incidence of prostate cancer among BRCA2 mutation carriers in a prospective cohort study (EMBRACE trial).
It has been reported that carriers of BRCA2 mutations respond well to platinum-based chemotherapy. 3 Here, the patient carried BRCA2 mutation (p.N2345Qfs*20), which involves the DNA-binding domain, and suggested pathogenic by causing the homologous recombination deficiency. 4 Poly (ADP-ribose) polymerase (PARP) inhibitor was developed for metastatic CRPC with BRCA1 or BRCA2 mutation. PARP inhibitors are expected to be effective in this case. However, there have been no reports on the efficacy of PARP inhibitors in patients treated with platinum drugs. Recently, BRCA reversion mutations restoring its function were reported as a mechanism obtaining resistance to PARP inhibitor as well as platinum-based chemotherapy. 5 Therefore, subsequent report on this case after the use of PARP inhibitor would be important with sequential genomic analysis on BRCA2.