A Case-Based Clinical Approach to the Investigation, Management and Screening of Families with BRCA2 Related Prostate Cancer

Figures & data

Figure 1 Pedigree of a hypothetical family carrying a pathogenic BRCA2 germline variant. Proband (indicated by red arrow) was diagnosed with PC at 54 years, proband’s sister was diagnosed with BC at 41 years and proband’s mother (deceased) was diagnosed with OC at 59 years. A maternal uncle (deceased) was diagnosed with PC at 61 years. Circles indicate females, squares indicate males. A line through a figure indicates that individual is deceased.

Abbreviations: PC, prostate cancer; BC, breast cancer; OC, ovarian cancer; Dx, diagnosis.

Table 1 Summary of Mentioned Poly-ADP Ribose Polymerase (PARP) Inhibitor Clinical Trials Involving Metastatic Castration-Resistant Prostate Cancer Patients

Clinical Trial (Trial No.)	Trial Description	Patient Characteristics	Treatment Given	Primary Trial Endpoint	Main Findings
TOPARP-A (NCT01682772)	Phase II trial	50 mCRPC patients with unknown carrier status for pathogenic DDR gene variants	Olaparib 400mg twice daily	Treatment response rate	NGS identified 16 patients with deleterious DDR gene variants. 14/16 (88%) of this subgroup had a positive treatment response, including all 7 patients with BRCA2-deficient tumours.
TOPARP-B (NCT01682772)	Randomised phase II trial	98 progressing mCRPC patients carrying with pathogenic DDR gene variants	Olaparib 400mg or 300mg twice daily	Treatment response rate	A positive treatment response observed in 54.3% of patients randomised to receive 400mg olaparib compared to 39.1% of patients randomised to receive 300mg olaparib. The most pronounced treatment effect was observed in the BRCA1/2 carrier subgroup, with an overall response rate of 83%.
PROfound (NCT02987543)	Randomised Phase III trial	387 mCRPC patients carrying germline pathogenic variants in BRCA1/2 or ATM (cohort A) or 12 other known DDR genes (cohort B)	Olaparib 300mg twice daily or SOC treatment (enzalutamide or abiraterone) in a 2:1 ratio	Imaging-based PFS	In both study cohorts overall, imaging-based PFS was significantly extended in those on olaparib treatment compared to those receiving SOC (5.8 months vs 3.5 months; hazard ratio for progression or death, 0.49; 95% CI 0.38–0.63; p<0.001). There was a more pronounced treatment effect observed in cohort A (7.4 months vs 3.6 months, hazard ratio, 0.34; 95% CI 0.25–0.47; p<0.001), with hazard ratios of 0.41 and 0.21 calculated for BRCA1 and BRCA2 patients respectively.
TRITON2 (NCT02952534)	Ongoing phase II trial	115 mCRPC patients carrying pathogenic DDR gene variants whose tumours had progressed on 1–2 lines of AR-directed therapy and 1 line of taxane-based chemotherapy	Rucaparib 600mg twice daily	Objective response rate, PSA response rate	Improvements in radiographical and PSA results were demonstrated in the BRCA-deficient mCRPC patient subgroup. Response rates to rucaparib therapy were similar in both patients with somatic BRCA variants and those with germline BRCA variants.
TRITON3 (NCT02975934)	Ongoing phase III trial	mCRPC patients carrying pathogenic variants in BRCA1/2 or ATM whose tumours progressed on one prior AR-directed therapy	Rucaparib 600mg twice daily vs SOC treatment (physician’s choice of second-line AR-directed therapy or docetaxel in chemotherapy-naïve patients)	Radiographic PFS

Abbreviations: mCRPC metastatic castration-resistant prostate cancer; NGS, next generation sequencing; DDR, DNA damage repair; PFS, progression free survival; SOC, standard of care; PSA, prostate specific antigen; AR, androgen receptor.

Table 2 Summary of Mentioned Platinum-Based Chemotherapy Reports Involving Metastatic Castration-Resistant Prostate Cancer Patients

Publication Authors	Publication Type	Patient Characteristics	Treatment Given	Primary Study Endpoint	Main Findings
Pomerantz et al^Citation39	Retrospective cohort study	141 mCRPC patients who were subdivided into carriers and non-carriers of pathogenic germline BRCA2 variants	2 doses of carboplatin and docetaxel	Treatment response rate	6/8 (75%) of BRCA2 carriers exhibited a positive treatment response compared with 23/133 (17%) of non-carriers (p<0.001).
Zafeiriou et al^Citation38	Case report	3 metastatic PC patients, 1 of whom was identified as a germline carrier of a pathogenic BRCA2 variant	BRCA2 carrier received carboplatin and docetaxel following tumour progression on other therapies	Treatment response	44% PSA reduction was observed along with signs of disease regression on MRI following 6 cycles of treatment in the BRCA2 carrier.
Cheng et al^Citation37	Case report	3 mCRPC patients with biallelic BRCA2 loss who had progressed on previous therapy	Carboplatin and docetaxel (patient 1), carboplatin and doxorubicin (patient 2), carboplatin and docetaxel (patient 3)	Treatment response	PSA reductions were observed in all three patients. A positive clinical response was noted in patient 2 and significant radiographical response noted in patient 3.
Slootbeek et al^Citation61	Retrospective cohort study	71 mCRPC patients, of which 14 carried pathogenic DDR gene variants (including 7 BRCA2 carriers)	Carboplatin	PSA response, radiographical response	50% PSA reduction and objective radiographical response observed in all patients with BRCA2 deficient tumours. Median overall survival was significantly longer in BRCA2 deficient patients compared with patients carrying BRCA2 wild type (21 months vs 7 months, p=0.041).
Schmid et al^Citation62	Retrospective cohort study	508 mCRPC patients: 80 DDR gene variant carriers (cohort 1), 98 non-carriers of DDR gene variants (cohort 2) and 300 patients of unknown DDR gene variant carrier status (cohort 3)	Platinum monotherapy (carboplatin/cisplatin) or platinum combination therapy (carboplatin/cisplatin/oxaliplatin + docetaxel/etoposide/paclitaxel)	PSA response, radiographical response	The most profound treatment response was observed in the BRCA2 carrier patient subgroup, of which 23/44 (63.9%) had 50% reduction in PSA value after treatment and soft tissue responses were noted in 17/44 (38.6%).
Mota et al^Citation63	Prospective cohort study	109 mCRPC patients	Carboplatin/cisplatin or carboplatin/cisplatin + taxane chemotherapy/etoposide	Association between DDR variants and response to platinum chemotherapy, response to platinum chemotherapy in patients who had progressed on PARP inhibitor therapy	Patients with DDR variants were more likely to have a 50% reduction in PSA following platinum-based chemotherapy (odds ratio, 7.0; 95% CI 1.9–29.2). Treatment response to platinum-based chemotherapy was only seen in 37% DDR gene variant carriers who had progressed on previous PARP inhibitor therapy.
Simmons et al^Citation64	Case report	1 mCRPC patient with a germline BRCA2 variant	Sequential treatment with carboplatin followed by rucaparib	NGS results following provision of treatment	12 different somatic reversion variants (thought to confer resistance against carboplatin by restoring the C-terminal end of BRCA2) were discovered using NGS after 4 months on carboplatin chemotherapy. As a result of these reversion mutations, rucaparib had little benefit in slowing tumour progression.

Abbreviations: mCRPC, metastatic castration-resistant prostate cancer; PC, prostate cancer; PSA, prostate specific antigen; MRI, magnetic resonance imaging; DDR, DNA damage repair; PARP, poly-ADP ribose polymerase; NGS, next generation sequencing.

Pomerantz MM, Spisák S, Jia L, et al. The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer. 2017;123(18):3532–3539. doi:10.1002/cncr.30808

 PubMed Web of Science ®Google Scholar

Zafeiriou Z, Bianchini D, Chandler R, et al. Genomic analysis of three metastatic prostate cancer patients with exceptional responses to carboplatin indicating different types of DNA repair deficiency. Eur Urol. 2019;75(1):184–192. doi:10.1016/j.eururo.2018.09.048

 PubMed Web of Science ®Google Scholar

Cheng HH, Pritchard CC, Boyd T, Nelson PS, Montgomery B. Biallelic inactivation of BRCA2 in platinum-sensitive metastatic castration-resistant prostate cancer. Eur Urol. 2016;69(6):992–995. doi:10.1016/j.eururo.2015.11.022

 PubMed Web of Science ®Google Scholar

Slootbeek PHJ, Duizer ML, Doelen MJ, et al. Impact of DNA damage repair defects and aggressive variant features on response to carboplatin-based chemotherapy in metastatic castration-resistant prostate cancer. Int J Cancer. 2021;148(2):385–395. doi:10.1002/ijc.33306

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Schmid S, Omlin A, Higano C, et al. Activity of platinum-based chemotherapy in patients with advanced prostate cancer with and without DNA repair gene aberrations. JAMA Netw Open. 2020;3(10):e2021692. doi:10.1001/jamanetworkopen.2020.21692

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Mota JM, Barnett E, Nauseef JT, et al. Platinum-based chemotherapy in metastatic prostate cancer with DNA repair gene alterations. JCO Precis Oncol. 2020;(4):355–366. doi:10.1200/PO.19.00346

 Web of Science ®Google Scholar

Simmons AD, Nguyen M, Pintus E. Polyclonal BRCA2 mutations following carboplatin treatment confer resistance to the PARP inhibitor rucaparib in a patient with mCRPC: a case report. BMC Cancer. 2020;20(1). doi:10.1186/s12885-020-6657-2

 Web of Science ®Google Scholar