Pulmonary metastasis secondary to abiraterone‐resistant prostate cancer with homozygous deletions of BRCA2: First Japanese case

Introduction Most metastatic prostate cancers acquire the capacity for androgen‐independent growth and become resistant to androgen deprivation therapy. A patient‐focused treatment strategy is needed for aggressive castration‐resistant prostate cancer. Case presentation We report the case of a 62‐year‐old man who presented with prostatic adenocarcinoma who was treated by radiation and combined androgen blockade. After completion of first‐line therapy, he was diagnosed with multiple metastatic castration‐resistant prostate cancer in the lung. Second‐line therapy with abiraterone acetate resulted in partial remission of the lung metastases. Thoracic surgery was performed to remove the single lung metastasis remaining. Next‐generation sequencing of the specimens demonstrated homozygous loss of BRCA2. We note in this case a heterogeneous response to abiraterone acetate may be related to the somatic BRCA2 deletions. Conclusions We present the first Japanese case of a metastatic abiraterone acetate‐resistant castration‐resistant prostate cancer accompanied by BRCA2 mutation.


Introduction
PCa is the second-leading cause of the cancer deaths among men in Western countries. 1 The incidence of PCa is still on the rise in Japan. 2 Most metastatic PCa become both resistant to both castration and androgen deprivation therapy. 3 None of CRPC therapeutic modalities are curative and acquired resistance is inevitable. Precision medicine and a more individual patient focused treatment strategy might be facilitated by the use of NGS.
Genetic aberrations may be directly involved in the development, invasiveness, and metastatic potential of a given cancer. Recently, it has become clear that genetic aberrations involving BRCA1 and BRCA2 genes are heavily involved in the acquisition of resistance to treatment in PCa. 4 We present here the first Japanese case of PCa that was resistant to second-generation antiandrogens and demonstrated homozygous loss of BRCA2.

Case presentation
A 62-year-old man presented for evaluation of an elevated serum PSA (19.8 ng/mL). Needle biopsy led to the diagnosis of prostatic adenocarcinoma with a Gleason score of 4 + 5 = 9. MRI was notable for prostate tumor invading the seminal vesicles, although skeletal scintigraphy revealed no bone metastasis (Fig. 1) and no visceral metastases were detected on abdominal CT. Based on these results, the clinical stage was determined to be cT3bN0M0. First-line treatment included IMRT (total 80 Gy) with combined androgen blockade. Serum PSA decreased to 0.05 ng/mL during the treatment but increased to 2.64 ng/mL at 29 months later. CT scan at that time revealed a metastatic left internal iliac lymph node. The patient was diagnosed with CRPC and treated with local irradiation of 60 Gy to the lymph node. After radiation, serum PSA dropped to its nadir at 0.30 ng/mL. Eight months later, his serum PSA level increased to 4.25 ng/mL in association with multiple lung metastases detected on CT (Fig. 1). The patient was treated with ABI. Nine months after initiating ABI therapy, most of the lung metastases had disappeared, although one lesion remained. This ABI-resistant solitary lung nodule was diagnosed as an oligometastatic lesion; this definition implies that an appropriate surgical procedure may be curative. To remove the remaining lung metastasis, VATS was performed. After the procedure, the PSA level again dropped to 0.04 ng/mL; serum PSA has remained <1.0 ng/mL for 10 months (Fig. 1).
The lung tumor cells proliferated in solid pattern that was consistent with the diagnosis of metastatic PCa (Fig. 2a,b). Immunohistochemically, tumor cells were strongly positive for AR, weakly positive for PSA (Fig. 2c,d) and negative for both thyroid transcription factor 1 and p40 which are markers for adenocarcinoma, and squamous cell carcinoma of the lung, respectively.
We performed a genomic analysis of this resected metastatic tumor using the NGS clinical sequencing system at our hospital (Table S1). 5, 6 We also identified homozygous (biallelic) deletions of BRCA2 and RB1 in the tumor tissue (Fig. 3). CDK12 somatic point mutation (p.Q937*) was detected as a pathogenic variant. All variants detected, including VUS are presented in Table 1.
Oncogene targeted amplification resulted in the detection of IDH2, AR, MYC, ERBB2, ERBB3, ESR1, NRAS, SMO, and AKT2. All relevant copy numbers are presented in Table 2. Tumor mutation burdens were calculated at 4.0 single nucleotide variants per million bp. Copy number variation and variant allele frequency plots (Fig. 3) indicated a high frequency of loss of heterozygosity and scattered allelic imbalance; these findings are detected comparatively frequently in homologous recombination-deficient tumors.

Discussion
The mechanism by which PCa acquires treatment resistance is closely linked to genetic abnormalities of DDR signaling pathways including BRCA1/2 loss. BRCA2 performs homologous recombination-mediated DNA repair and provide critical contributions for the repair of DSBs in genomic DNA. Mutations in these genes lead to the inactivation of homologous DNA repair mechanisms and promote the development of DSBs. BRCA1/2 has been identified as critical therapeutic target for PCa. In recent years, BRCA2 aberrancies have been identified in 12% of metastatic CRPC cases. 7 The loss of function mutations or deletions in BRCA2 has been reported to be associated with the inactivation of homologous DNA repair mechanisms and with the development of double-stranded DNA breaks, rendering these cells more susceptible to PARP inhibitors. Olaparib is a PARP inhibitor that has just been approved for patients with PCa and DDR mutations including BRCA2 loss. 8,9 In the future, PARP inhibitors may be the optimal treatment for PCa with BRCA2 gene alteration in Japan. 10,11 There are various opinions concerning the relationship between BRCA alteration and responsiveness for treatment using ABI or enzalutamide. Annala et al. 12 reported that patients with BRCA2 germline mutation exhibited poor responses to therapies that targeted the AR signaling axis, and in contrast, Antonarakis et al. 13 reported a good response to AR targeting therapies. Mateo et al. 14 have recently published a new analysis that included somatic BRCA2 alteration in addition to germline mutations; these results suggest that BRCA2 alterations are powerful predictors of resistance to AR targeting therapies; these latest data include somatic alterations of DDR-related genes. However, these reports were established in Western patient cohorts; the genomic and biological implications of these findings with respect to Japanese patients remain unclear. In our case, we observed a heterogeneous response to ABI; one lung metastasis remained after treatment. The limitation is that gene profiling of patient's peripheral blood and initial prostate biopsy specimen were not performed. However, homozygous deletion in BRCA2 gene on a wide range of 13q was identified. If the 13q deletion occurred as a germline event, it would cause   Recently, we have reported several cases of somatic and germline mutations in DDR-related genes. 6,11 Collectively, these trials and case reports indicate that the ongoing examination of gene mutations may have a significant impact on future treatments for PCa in addition to the use of PARP inhibitors or platinum-based chemotherapy. Nonetheless, because PCa tends to be heterogeneous within each subtype, genetic testing should be used to develop more specific treatment strategies.

Conclusions
We present the first Japanese case of metastatic ABI-resistant CRPC accompanied by BRCA2 homozygous deletion.