Aggressive prostate cancer with somatic loss of the homologous recombination repair gene FANCA: a case report
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Precision medicine based on genomic analysis of germline or tumor tissue is attracting attention. However, there is no consensus on how to apply the results of genomic analysis to treatment.
A 59-year-old man diagnosed with metastatic prostate cancer was diagnosed with castration-resistant prostate cancer. Although he was sequentially treated with enzalutamide and abiraterone, bone metastasis progression was identified by skeletal scintigraphy. Therefore, we sequentially performed docetaxel therapy followed by cabazitaxel. After the third cycle of cabazitaxel, his prostate-specific antigen level was stable at < 10 ng/mL, and no radiological progression was detected.
The patient’s formalin-fixed paraffin-embedded tumor biopsy specimen underwent multiple-gene testing by next-generation sequencing, which identified a FANCA homodeletion. No significant germline mutation was observed.
We describe a case of aggressive, castration-resistant prostate cancer with FANCA homodeletion. Genomic analysis of prostate cancer tissue can be useful to determine optimal treatment of such cancers.
KeywordsFANCA Homologous recombination repair Castration-resistant prostate cancer Next-generation sequencing Genomic analysis
DNA integrity number
Magnetic resonance imaging
Poly (ADP)-ribose polymerase
Various drugs, such as second-generation antiandrogens, radium-223, and cabazitaxel, have been approved for treatment of castration-resistant prostate cancer (CRPC) in many countries, including Japan. However, the duration of response to these drugs is limited to several months. Although precision medicine based on genomic analysis of germline or tumor tissue is attracting attention, there is no consensus on how to apply the results of genomic analysis to treatment.
Allelic imbalance of 16q, which includes FANCA gene, is a known risk factor for cancer development or progression [1, 2, 3]. Recent studies have shown that DNA damage repair gene variants are biomarkers for the response to poly (ADP)-ribose polymerase (PARP) inhibitors  but are poor prognostic factors for prostate cancer .
We present a case of prostate cancer that was resistant to second-generation antiandrogens and taxanes and showed somatic loss of the homologous recombination repair gene FANCA.
DNA double-strand breaks are a serious threat to cell survival because they lead to a loss of chromosomal content. There are two main repair pathways for double-strand breaks: nonhomologous end joining and homologous recombination. FANCA belongs to the Fanconi anemia complementation group (FANC) family and is known as one of the genes responsible for Fanconi anemia . It plays an important role in DNA interstrand crosslinking in homologous recombination repair .
Loss of FANCA function is associated with hereditary breast and ovarian cancer [9, 10]. FANCA variants are a significant risk factor for breast cancer among the population without BRCA1/2 loss . Furthermore, loss of FANCA is associated with a familial history of prostate cancer [11, 12]. The National Comprehensive Cancer Network prostate cancer guideline recommends genetic counseling for patients with prostate cancer and having BRCA1/2, ATM, PALB2, or FANCA mutation .
Recently, the Gleason grade groups based on pathological findings has been considered as a prognostic factor for prostate cancer . The World Health Organization has accepted this grading system since 2016 . In our case, the Gleason grade group was 5, with an expected poor prognosis. A previous study reported that the prevalence of DNA repair mutation involving FANCA was higher in prostate cancer cases with high Gleason grade groups than in cases with low Gleason grade groups .
While germline loss of FANCA function is known as a causative variant for prostate cancer development, it has also been reported that somatic variants in DNA repair genes, including FANCA, are increased in metastatic CRPC tissue [17, 18]. Our patient had no pathogenic variants in the germline genome, and FANCA loss was considered an acquired variant. In light of these facts, we should investigate the genome not only of white blood cells but also of primary and recurrent tumors, because genes for homologous recombination repair pathways can be mutated independently of the germline.
Ovarian cancer cells with disruption of the FANC-BRCA2 pathway are highly sensitive to cisplati n. In prostate cancer cells, FANCA knockout is associated with hypersensitivity to cisplatin . In a phase 2 trial, CRPC cases with FANCA homodeletion tended to respond well to the PARP inhibitor olapari b. Based on these findings, although we performed cabazitaxel therapy for bone metastasis progression, cisplatin-based chemotherapy or PARP inhibitors may be more effective for our patient.
This report focuses on a case of aggressive CRPC with FANCA homodeletion. Cisplatin-based chemotherapy or PARP inhibitors can be an optimal treatment for CRPC with deficiency in the homologous recombination pathway.
Yoko Suzuki, Emmy Yanagida, and Hiroshi Yamada provided technical assistance.
Conception and design: TK, HN, MO. Provision of study material or patients: TK, HN. Collection and assembly of data: TK, EA, HH. Data analysis and interpretation: TK, EA, HN. Manuscript writing: TK, HH, EA. Final approval of manuscript: KT, HH, EZ, HN, MO.
This study was supported in part by Grants-in-Aid for Scientific Research (#17 K11158 to T. Kosaka) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and by a research grant to T. Kosaka from the Takeda Science Foundation, Japan.
Ethics approval and consent to participate
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
The authors declare that they have no competing interests.
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