Real-world data on the prevalence of BRCA1/2 and HRR gene mutations in patients with primary and metastatic castration resistant prostate cancer

Abstract

Purpose: This study seeks to contribute real-world data on the prevalence of BRCA1/2 and HRR gene mutations in prostate cancer.

Methods: We compiled sequencing data of 197 cases of primary and metastatic prostate cancer, in which HRR mutation analysis was performed upon clinical request within the last 5 years. All cases were analyzed using a targeted NGS BRCAness multigene panel, including 8 HRR genes (ATM, BRCA1, BRCA2, CDK12, CHEK2, FANCA, HDAC2, PALB2).

Results: Our findings reveal a prevalence of potentially targetable mutations based on FDA criteria of 20.8%, which is comparable to the literature. However, the frequency of targetable BRCA2 mutations within our cohort was lower than reported for mCRPC and ATM and CHEK2 mutations were more prevalent instead. Thus, while 20.8% (n = 38) of the cases meet the criteria for olaparib treatment per FDA approval, only 4.9% (n = 9) align with the eligibility criteria according to the EMA approval.

Conclusion: This study offers valuable real-world insights into the landscape of BRCA1/2 and HRR gene mutations and the practical clinical management of HRR gene testing in prostate cancer, contributing to a better understanding of patient eligibility for PARPi treatment.

Keywords: BRCA2; HRR; Olaparib; PARPi; Prostate cancer.

Fig. 1

The distribution of tumor samples tested for HRR alterations. (A) Primary tumor samples were the preferred type of tumor tissue tested for HRR alterations (n = 111), followed by metastatic tumor tissue (n = 76) and tumor tissue from local recurrences (n = 10). (B) Needle core biopsies (NCB) from the initial diagnosis of prostate cancer were the preferred material tested for HRR alteration (n = 68), followed by radical prostatectomy specimen (RPE) (n = 23) and transurethral resection specimen (TUR-P) (n = 20). (C) Bone metastases were the most common material tested for HRR alterations (n = 55), followed by distant lymph node metastases (n = 9), liver metastases (n = 5), soft tissue metastases (n = 3), pleural metastases (n = 2). Lastly, one lung metastasis and one gastrointestinal metastasis were analyzed

Fig. 2

The distribution of HRR gene mutations. (A) Depiction of all HRR mutations found, including suspected benign variants, variants of unknown significance, suspected pathogenic and pathogenic mutations. ATM (n = 26) mutations were most prevalent, followed by mutation in BRCA2 (n = 21), CHEK2 (n = 21), CDK12 (n = 13), FANCA (n = 8), PALB2 (n = 4), BRCA1 (n = 3) and HDAC2 (n = 1). (B) Depiction of suspected pathogenic and pathogenic HRR mutations. ATM (n = 11) mutations were most prevalent, followed by mutation in CHEK2 (n = 10), BRCA2 (n = 8), CDK12 (n = 8), PALB2 (n = 2), BRCA1 (n = 1) and FANCA (n = 1). No suspected pathogenic or pathogenic mutations in HDAC2 were found