BRCA mutation in Vietnamese prostate cancer patients: a mixed cross-sectional study and case series

Study design

This mixed cross-sectional study and case series report were conducted at Bach Mai Hospital between 2021 and 2022. The flow chart of the study is presented in Figure 1.

Figure 1:

Flow chart of this study.

Study process

The genetic analysis techniques used in the research were as follows.

Participants

The patients had been diagnosed with prostate cancer and underwent biopsy or surgery for the primary tumor, whose specimen was FFPE. Peripheral blood samples required for further analyses of germline gene mutations, complete medical record information, and consent for participation in the study were obtained from patients with somatic gene mutations in FFPE tissues.

The exclusion criteria were as follows: Patients whose specimens did not qualify for NGS (specifically, samples with low post-extraction DNA concentration and/or quality) were excluded.

In this study, we eliminated 38 cases due to insufficient concentration and quality of input DNA and sequencing library. We also eliminated eight cases without enough information in the medical record (the rate of exclusion from the study was 46/106 cases, accounting for 43.4 %).

Measures

The outcome variables included age, patient history, disease stage, metastatic status, serum total PSA level at diagnosis, Gleason score, and BRCA1 and BRCA2 variants [24]. Data on the medical records, pathology results, genetic test results, and patient statements (family history) were obtained (Table 1).

Sample size

The samples were collected using the entire sampling method. After collecting and eliminating patients with insufficient data on research indicators and tissue samples that did not meet the standards for conducting NGS, only 60 patients were included in the study.

Statistical analysis

Statistical analyses were performed using SPSS Statistics (version 20.0; IBM Corp., Armonk, NY). Continuous variables were expressed as the medians and interquartile ranges, while categorical variables were expressed as frequencies and percentages. Using Fisher’s exact test for categorical variables and the Mann-Whitney U test for continuous variables, we examined the between-group differences and the prevalence of related indicators. p-Values less than 0.05 were regarded as significant.

Ethics statement

This study was approved by the Ethics Committee of Bach Mai Hospital (approval number: 5362/BM-HĐĐĐ). Data on all research variables and indicators were collected accurately and scientifically. The patients consented to the research participation agreement and the research information statement. All personal patient information was kept confidential and used only for research purposes.

Rate of detection of BRCA variants in the study group

After assessing the BRCA1 and BRCA2 gene mutation status in paraffin-embedded tumor tissue samples, we discovered that 5 of 60 patients (8.3 %) carried BRCA2 pathogenic variants. None of the patients had pathogenic variants in the BRCA1 gene. Moreover, 55 patients (91.7 %) did not carry mutations in the BRCA1 or BRCA2 gene (see Table S1).

In five patients who exhibited mutations in the BRCA2 gene, five different gene variations were discovered at the mutation location. Two patients had nonsense mutations, one had a missense mutation, one had a deletion mutation, and one had an insertion mutation with variant allele frequencies (VAF) of 3.1–69.6 %.

We continued to investigate the germline mutation status in patients with BRCA2 gene mutations in the tumor tissue samples. Currently, two patients showed germline mutations, two patients did not detect germline mutations on blood samples and one scheduled for blood sampling was inaccessible (Table 2).

Some clinical characteristics and BRCA gene mutation status

The average age of the study group was 71.7 ± 8.1; ranging from 54 to 90 years. Most patients were aged between 60 and 79 years (see Table S2).

The median PSA level at initial diagnosis was 202.10 ng/mL; the highest PSA level was 5,000.00 ng/mL, while the lowest level was 1.80 ng/mL. Most patients had a PSA level of >100 ng/mL at diagnosis (see Figure S1).

The average age at the time of diagnosis in the five patients with BRCA mutations was 66.2, which tended to be lower than that of patients without BRCA mutations (72.1). Five patients with BRCA mutations tended to have a higher Gleason grade group (80 % had Gleason grade group 4–5) than those of patients without mutations (78.5 %). The rates of regional lymph node metastasis and distant metastasis in patients who carried BRCA mutations were higher (60 and 80 % compared with 45.5 and 72.7 %, respectively) (Table 3).

Cases series report

Case 1

Case presentation

Patient #1 is a 66-year-old male with no remarkable medical history. In April 2021, the patient presented with lower back pain, inadvertent weight loss, and prolonged fever over several weeks. Clinical examination revealed symptoms of bone metastasis and no suspicious infection. Computed tomography (CT) examination indicated multiple osteolytic bone metastases in the axial skeleton, no visceral metastases were observed (Figure 2).

Figure 2:

CT scans showed multiple lytic bone metastases in vertebral and pelvis bone in April 2021.

Figure 3:

Prostate MRI demonstrated a convex contour of the prostate capsule lesion in T2-weighted (arrow).

Bone biopsy revealed adenocarcinoma metastasis originating from the prostate (Gleason score: 4 + 5 = 9). Further workup disclosed a serum total PSA level measuring 296.30 ng/mL. Prostate magnetic resonance imaging (MRI) delineated a lesion characterized by a Prostate Imaging-Reporting and Data System (PI-RADS) score of 5 within the left peripheral zone, accompanied by an absence of regional lymphadenopathy (Figure 3). In a patient diagnosed with high-risk, high-volume metastatic prostate cancer, a therapeutic regimen consisting of androgen deprivation therapy using goserelin, abiraterone acetate, prednisone, and bisphosphonate was administered. The patient responded favorably to the therapy, with notable improvement in bone pain and fever. The PSA level initially declined from 296.30 to 4.67 ng/mL in the first 4 months. However, subsequent evaluations revealed a progressive escalation in PSA levels, from 4.67 to 414.10 ng/mL by January 2022. The patient experienced a recurrence of skeletal discomfort. CT examination revealed a combination of osteolytic and osteoblastic metastases instead of the previously prevalent osteolytic lesions (Figure 4). Disease progression was also confirmed.

Figure 4:

CT scans showed multiple combinations of osteolytic and osteoblastic metastasis in January 2022.

The patient underwent a therapeutic regimen involving docetaxel, goserelin, and bisphosphonates. However, the patient exhibited intolerance to the treatment, resulting in grade 2 fatigue and anemia. Concurrently, the PSA level marginally decreased from 414.20 to 392.80 ng/mL within 2 months of treatment. However, it subsequently increased to 866.50 ng/mL by August 2022. This substantial elevation in PSA level strongly indicated an early progression of the disease. Subsequently, the patient received two cycles of ¹⁷⁷Lu-PSMA-617. BRCA testing for prostate was approved in our center in January 2023. NGS was performed on the patient’s bone biopsy samples, revealing a mutation in the BRCA2 gene at position 8364G>A. Nevertheless, the VAF index was less than 5 %. Further examination of blood samples confirmed the presence of a similar genetic mutation identified in the previous tissue sample. Unfortunately, several liver lesions were detected, and the patient’s clinical status deteriorated within 1 month with liver failure, precluding the administration of PARPi. Consequently, the patient’s overall survival duration was limited to 24 months.

Investigation exhibited a family history marked by a younger sister (III.4) diagnosed with breast cancer at the age of 48. However, she died before the research timeframe rendering her sample unavailable. The patient’s father (II.3) died from an unidentified disease at the age of 60. Additionally, the patient had a cousin (III.1) with gastric cancer and an uncle with lung cancer (age at diagnosis unknown) (Figure 5). Genetic counseling was conducted on the patient’s relatives, while genetic testing was performed on the patient’s children. Fortunately, the patient’s children (IV.1 and IV.2) did not harbor the pathogenic variant.

Figure 5:

Pedigree chart of patient #1 (III.2) (PC, prostate cancer; BC, breast cancer; GC, gastric cancer; LC, lung cancer).

Discussion

The patient had a germline mutation and a family history of breast cancer indicated hereditary breast and ovarian cancer syndrome. Having a younger sister (a first-degree relative) who was diagnosed with breast cancer before the age of 50 constituted a high-risk factor for being a germline mutation carrier in this patient. The occurrence of stomach cancer in a cousin and lung cancer in an uncle did not significantly contribute to the genetic predisposition. Simultaneously, the patient exhibited clinical features resistant early to non-PARP inhibitor treatment. Genetic counseling was conducted among the family members of the patient.

Additionally, in the presented case, the patient’s tissue was obtained from a bone. Analysis of this sample may not provide sufficient information to diagnose the patient’s genetic status. On the other hand, patients with a family history of cancer diagnosis at an early age, coupled with pathological features like treatment resistance, metastasis, and a high Gleason score, are more likely to harbor germline mutations. Therefore, a genetic mutation identification test in this patient was necessary.

Patient’s perspective

Patient #1’s wife, “If we had known about BRCA mutation sooner, maybe he could have lived longer. Fortunately, my children do not have these mutations, but we will screen them early for cancer.”

Learning point

1. BRCA2 mutations can drive aggressive forms of prostate cancer.

2. A detailed family history is crucial as it can provide clues to potential genetic predispositions.

3. Genetic counseling and testing can offer valuable insights into disease management and prognosis.

Case 2

Case presentation

Patient #2, a 64-year-old man, presented with lower urinary tract symptoms. His medical and family histories were unremarkable. Further investigation with prostate MRI showed a direct extra-glandular tumor extension into the seminal vesicles and multiple common iliac lymph nodes (Figure 6).

Figure 6:

A prostate MRI showed a T2 hypointense lesions which invasion to seminal vesical (yellow arrow) and left common iliac lymph node (red arrow).

A 12‐core transrectal ultrasound‐guided prostate needle biopsy revealed the presence of prostatic adenocarcinoma (Gleason score: 4+3=7). Genetic analysis was performed using the NGS technique and Sanger sequencing. BRCA2 gene mutations were identified in tumor tissue samples (7879A>T) with a mutation frequency of 3.10 % (VAF). A blood test was performed, indicating the absence of germline mutations.

No evidence of distant metastasis was detected on both the 99mTc-MDP bone scan and whole-body CT scan; leading to the diagnosis of cT3bN1M0 (Gleason 4+3=7) prostate adenocarcinoma.

The patient subsequently underwent definitive radiotherapy and goserelin combined with bicalutamide. His PSA level reached a nadir of 0.03 ng/mL and maintained stability during the last assessment in October 2023.

Discussion

BRCA2 mutations were found in tumor tissue samples with a mutation frequency (VAF) of 3.1 %. It is noteworthy that in patients solely carrying mutations in the tumor tissues, the variant allele frequency may be relatively low.

Patients were screened, resulting in the detection of the disease at an early stage, and received early treatment. PARPi could be a potential therapy when resistance to alternative regimens emerges.

Patient’s perspective

Patient, “I hope that when my cancer progresses, I can access targeted therapy”.

Learning points

Testing for BRCA gene mutations should be conducted in prostate cancer patients (irrespective of the absence of a family history) to predict disease prognosis and to provide additional treatment methods (PARPi) in advanced-stage disease.

Rate of detection of BRCA gene mutations in the study group

BRCA1 and BRCA2 genes are the two most mentioned and researched genes related to breast and ovarian cancers. The role of BRCA gene mutations is not only being further studied in breast and ovarian cancers but is also expanding in other cancers, such as pancreatic and prostate cancers. A previous study reported a BRCA1 gene mutation incidence of 3–9 % in prostate cancer patients, of which the rate of BRCA2 mutations was 15–34 % [25]. In our study, 8.3 % of the patients had BRCA2 mutations, while none had BRCA1 mutations. Thus, BRCA2 is closely associated with prostate cancer. Indeed, two recent studies by Silvestri et al., and colleagues showed that people carrying BRCA2 mutations have a high risk of developing prostate cancer, especially in invasive and metastatic cases; the risk varies depending on family history and location of gene mutation [26]. Most studies have shown a stronger association between BRCA2 mutations and prostate cancer than that with BRCA1 mutations [27, 28].

Point and frameshift mutations frequently occur in the coding regions of the BRCA1 and BRCA2 genes [29]. A given population will circulate specific mutations within that population at a higher rate than in other populations [30]. In a study about heredity and Spain male breast cancer [31], mutations included 5530T>A in the BRCA1 gene and 6860delA, 5374-5375del, and 03 cases have 9382C>T in the BRCA2 gene. In our study, three patients demonstrated point mutations leading to nonsense and missense mutations: one patient had deletion, one had insertion, and none had frameshift mutation (Table 1). More research with a bigger sample size is required to determine the features of the mutations in the Vietnamese population.

Some clinical characteristics and BRCA gene mutation status

The average age of the research group was 71.7 ± 8.2; ranging from 54 to 90. Most patients were aged between 60 and 79 years. The median PSA level at diagnosis was 202.10 ng/mL, and the highest level was 5,000.00 ng/mL. The lowest level was 1.80 ng/mL. Most of the patients had a PSA level of >100 ng/mL at diagnosis.

The average initial diagnosis age in the five patients with BRCA mutations was 66.2, tending to be lower than that of patients without BRCA mutations (72.2). The Gleason grade group in five patients with BRCA mutations also tended to be higher (80 %, Gleason scores: 4–5) compared with those in patients without mutations (78.5 %). The results of this study also demonstrated that the rates of lymph node metastasis and distant metastasis in patients with BRCA mutations were higher (60 and 80 % compared with 45.5 and 72.7 %, respectively) (Table 3).

These differences were not significant because of the low number of patients with BRCA mutations; however, this study also showed that BRCA2 carriers tend to have a worse prognosis. In a large retrospective study on 2019 prostate cancer patients, there were 18 patients had BRCA1 mutations, and 61 patients had BRCA2 mutations. The BRCA carriers were more frequently associated with a higher Gleason score and more advanced stage at initial diagnosis than the frequency of non-carriers. Tryggvadottir et al. analyzed 89 prostate cancer patients in Iceland from 1955 to 2004. BRCA mutation carriers were diagnosed at a younger age (69 years) compared to non-carriers (74 years). Additionally, mutation carriers were admitted with a more advanced tumor stage and had poorer differentiated histology than non-carriers [32]. However, Thorne et al. showed no difference in the age of diagnosis or the initial serum PSA level between patients with and without mutation. However, BRCA2 mutation patients presented with poorer differentiated and more advanced tumor stages compared to those observed in BCRA wild-type patients [18].

To our knowledge, this study is the first to report the gene carrier status of Vietnamese patients with prostate cancer as well as the accompanying clinical characteristics. However, due to the small sample size and low mutation detection rate, statistical analysis is not meaningful for assessing the relationship between gene carrier status and the pathological features of prostate cancer.