Analysis of the Clinical Advancements for BRCA-Related Malignancies Highlights the Lack of Treatment Evidence for BRCA-Positive Male Breast Cancer
Abstract
Simple Summary
Abstract
1. Introduction
2. The Genetic Landscape of MBC
2.1. BRCA1 and BRCA2
2.2. Moderate to Low Penetrance Germline Mutations
3. Clinical Management of BRCA-Related MBC
4. BRCA-Related MBC Studies
5. BRCA Mutations in Transgender Patients
6. Clinical Trial Led Advancements in Other BRCA-Related Cancers
6.1. Female Breast Cancer (FBC)
6.2. Prostate Cancer
7. Future Directions in BRCA-Related MBC
7.1. National Registry and Combining Efforts
7.2. Translational Research
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Author (Year) | Study Population | No. of Patients | Study Objective |
---|---|---|---|
Tirkkonen et al. (1999) [94] | MBC patients | 25 | Somatic genetic alterations in BRCA2-associated and sporadic MBC |
BRCA2-mutated | 5 | ||
Basham et al. (2002) [75] | MBC patients | 94 | BRCA1/2-mutation status and risk of breast cancer in female relatives |
BRCA1-mutated | 0 | ||
BRCA2-mutated | 5 | ||
Ottini et al. (2003) [48] | MBC patients | 25 | The Characterisation of BRCA1 and BRCA2 MBC |
BRCA1-mutated | 1 | ||
BRCA2-mutated | 3 | ||
Kwiatkowska et al. (2003) [76] | MBC patients | 43 | Investigation of the prognostic value of BRCA2 status in MBC |
BRCA2-mutated | 12 | ||
Palli et al. (2007) [93] | MBC patients | 99 | The association between the BRCA2 N732H variant and MBC risk |
Ottini et al. (2009) [49] | MBC patients | 108 | Characterisation the clinic-pathological features of BRCA1/2- positive MBC |
BRCA1-mutated | 2 | ||
BRCA2-mutated | 8 | ||
Ding et al. (2011) [78] | MBC patients | 115 | To determine the frequency of pathogenic mutations in BRCA2 and PALB2 in MBC cases and to investigate the correlations between mutation status and cancer phenotype |
BRCA2-mutated | 18 | ||
Ottini et al. (2012) [50] | MBC patients | 382 | Investigation of the clinical–pathologic features of MBC in association with BRCA mutations |
BRCA1-mutated | 4 | ||
BRCA2-mutated | 6 | ||
de Juan et al. (2015) [92] | MBC patients | 312 | BRCA1/2 mutations in males with familial breast and ovarian cancer syndrome |
BRCA1-mutated | 20 | ||
BRCA2-mutated | 49 | ||
Gargiulo et al. (2016) [53] | MBC patients | 47 | Characterisation of MBC, including BRCA1/2-mutated patients, and the impact on long-term survival |
BRCA1-mutated | 1 | ||
BRCA2-mutated | 5 | ||
Silvestri et al. (2016) [74] | MBC patients | 366 * | To determine if BRCA1/2 mutation carriers display specific pathologic features and if these differ from FBCs |
BRCA1-mutated | 40 | ||
BRCA2-mutated | 326 | ||
Deb et al. (2017) [90] | MBC patients | 60 | Investigation of a panel of commonly methylated breast cancer genes in familial MBCs |
BRCA1-mutated | 3 | ||
BRCA2-mutated | 25 | ||
Rizzolo et al. (2018) [77] | MBC patients | 69 | Gene-specific methylation profiles in BRCA-mutation positive and negative MBC |
BRCA1-mutated | 2 | ||
BRCA2-mutated | 8 | ||
Ibrahim et al. (2018) [18] | MBC patients | 102 | Evaluation of clinical characteristics, pathology findings, treatment selection and survival in BRCA-positive males |
BRCA1-mutated | 0 | ||
BRCA2-mutated | 9 | ||
André et al. (2019) [52] | MBC patients | 196 | Specific biological characteristics and survival in MBC |
BRCA1-mutated | 0 | ||
BRCA2-mutated | 13 | ||
Vietri et al. (2020) [72] | MBC patients | 28 | Characterisation of BRCA1/BRCA2 and PALB2 mutations in MBC patients |
BRCA1-mutated | 2 | ||
BRCA2-mutated | 8 |
Author (Year) | Study Population | No. of Patients | Study Objective |
---|---|---|---|
Savelyeva et al. (1998) [84] | BRCA2-mutated MBC | 3 | Case report describing three brothers with BRCA2 mutation, two of which developed infiltrating ductal breast cancer |
Scheidbach et al. (2000) [87] | BRCA2-mutated MBC | 1 | Describe a case of BRCA2-mutation positive MBC |
Kwiatkowska et al. (2002) [89] | BRCA2-mutated MBC | 2 | Novel BRCA2 mutation (frameshift mutation 6621del4 in exon 11) in two male breast cancer cases (father and son) in a Polish family. |
Brenner et al. (2004) [86] | BRCA2-mutated MBC | 1 | Highlight a case of BRCA2-mutation positive MBC and the implications for screening |
Karamanakos et al. (2004) [83] | BRCA1-mutated MBC | 1 | A case of male breast adenocarcinoma in a prostate cancer patient following prolonged anti-androgen monotherapy |
Azzouzi et al. (2007) [88] | BRCA2-mutated MBC | 3 | To highlight three BRCA2-positive MBC patients who were identified following positive prostate cancer screening |
Panchal et al. (2009) [85] | BRCA2-mutated MBC | 1 | A case of BRCA2-mutation positive MBC case with a history of prostate cancer |
Guaoua et al. (2014) [82] | BRCA2-mutated MBC | 1 | An account of a novel BRCA2c.6428C>A p.Ser2143Ter nonsense mutation in a man with familial breast cancer |
Benjamin & Riker (2015) [73] | BRCA1/HER2-positive MBC | 1 | To describe a case of a BRCA1/HER2 positive MBC |
Singer et al. (2015) [80] | BRCA2-mutated MBC | 1 | Highlight the risk of BRCA2 on multiple cancer risk through a case of prostate and MBC. |
Saha et al. (2017) [81] | BRCA1-mutated MBC | 1 | Describe the treatment of MBC by dual HER2 blockade and response prediction using novel optical tomography imaging. |
Cheng et al. (2019) [79] | BRCA2-mutated MBC | 1 | To describe an account of metachronous MBC that progressed following radio and chemotherapy which responded to palbociclib, fulvestrant and leuprolide. |
Huszno et al. (2019) [91] | BRCA2-mutated MBC | 1 | Clinicopathological analysis of BRCA2 gene variant, c. 2808_2811delACAA (p. Ala938Profs) in MBC |
Phase III Trial (Year) | Trial Arms | Study Population | No. of Patients | Study Result | ||
---|---|---|---|---|---|---|
PARPi (F/M) | PFS HR (95%CI) | mPFS (Months) | ORR (%) | |||
Advanced breast cancer | ||||||
OlympiAD (2017) [38] | Olaparib vs. standard chemotherapy | Patients with <2 lines of previous chemotherapy | 205 (200/5) | 0.58 (0.43–0.80); p < 0.001 | 7.0 vs. 4.2 | 59.9 vs. 28.8 |
EMBRACA (2018) [40] | Talazoparib vs. standard single agent of a clinician’s choice * | gBRCA-mutated | 287 (283/4) | 0.54 (0.41–0.71); p < 0.001 | 8.6 vs. 5.6 | 62.2 vs. 27.2 |
BROCADE (2020) [103] | Veliparib with carboplatin/paclitaxel vs. carboplatin/paclitaxel alone | gBRCA-mutated | 337 (333/4) | 0.71 (0.57–0.88); p = 0.0016 | 14.5 vs. 12.6 | |
Early breast cancer | DD or death (99.5%CI) | ID or death (99.5%CI) | ||||
OlympiA (2021) [67] | Olaparib vs. placebo | gBRCA-mutated with local treatment and neoadjuvant or adjuvant chemotherapy | 921 (919/2) | 0.57 (0.39–0.83); p < 0.001 | 0.58 (0.41–0.82); p < 0.001 |
Trial (Year) | Phase | Trial Arms | Study Population | No. of Patients | Study Result |
---|---|---|---|---|---|
PARPi | |||||
PROfound (2020) [41] | III | Olaparib versus standard anti-androgen therapy | Cohort A (BRCA1, BRCA2, or ATM mutation) | 162 | rPFS 7.4 m vs. 3.6 m; HR 0.34 (95% CI 0.25–0.47); p < 0.001 |
Cohort A+ B (Other DDR alterations *) | 256 | rPFS 5.8 m vs. 3.5 m; HR 0.49 (0.38–0.63); p < 0.001 | |||
TRITON2 (2020) [105] | II | Rucaparib | gBRCA-mutated mCRPC patients progressing after previous androgen hormonal therapy and a taxane chemotherapy | 177 | rORRa BRCA-mutated 43.5% (95% CI, 31.0–56.7) and independent investigator ORR 50.8% (95% CI 38.1–63.4) rORR a for other HRD-mutation 28.6%; CHEK2-mutation 11.1%; ATM-mutation 10.5%; CDK2-mutation 0% |
GALAHAD (2019) [106] | II | Niraparib | mCRPC and biallelic DRD mutated mCRPC patients with disease progression on taxane and androgen receptor-targeted therapy. | 81 | rORR a BRCA-mutated 41% (95% CI 23.5–61.6); rPFS 8.2 (95% CI 5.2–11.1) rORR a BRCA1/2-WT HRD-mutation 9% (95% CI 1.1–29.2); rPFS 5.3 (95% CI 1.9–5.7) |
TALAPRO-1 (2020) [107] | II | Talazoparib | BRCA- mutated mCRPC patients with disease progression on taxane and androgen receptor-targeted therapy | 46 | ORR 43.9%; rPFS 9.3 (95% CI 8.1–13.7) |
BRCA-WT mCRPC patients | 40 | ORR PALB2-mutated 33%; rPFS 7.4 (95% CI 2–7.4); ATM-mutated 11.8%; rPFS 5.5 95% CI (1.7–8.2) |
Trial | Phase | PARPi | Combined Agent |
---|---|---|---|
Anti-androgen therapy | |||
PROpel [113] | III | Olaparib | Abiraterone |
MAGNITUDE [114] | III | Niraparib | Abiraterone |
TALAPRO-2 [115] | III | Talazoparib | Enzalutamide |
Immunotherapy | |||
NCT02484404 [116] | I/II | Olaparib | Durvalumab |
ATRi | |||
NCT03787680 [119] | II | Olaparib | Ceralasertib |
High dose testosterone | |||
NCT03516812 [120] | II | Olaparib | Testosterone enanthate or cypionate |
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McClurg, D.P.; Urquhart, G.; McGoldrick, T.; Chatterji, S.; Miedzybrodzka, Z.; Speirs, V.; Elsberger, B. Analysis of the Clinical Advancements for BRCA-Related Malignancies Highlights the Lack of Treatment Evidence for BRCA-Positive Male Breast Cancer. Cancers 2022, 14, 3175. https://doi.org/10.3390/cancers14133175
McClurg DP, Urquhart G, McGoldrick T, Chatterji S, Miedzybrodzka Z, Speirs V, Elsberger B. Analysis of the Clinical Advancements for BRCA-Related Malignancies Highlights the Lack of Treatment Evidence for BRCA-Positive Male Breast Cancer. Cancers. 2022; 14(13):3175. https://doi.org/10.3390/cancers14133175
Chicago/Turabian StyleMcClurg, Dylan P., Gordan Urquhart, Trevor McGoldrick, Subarnarekha Chatterji, Zosia Miedzybrodzka, Valerie Speirs, and Beatrix Elsberger. 2022. "Analysis of the Clinical Advancements for BRCA-Related Malignancies Highlights the Lack of Treatment Evidence for BRCA-Positive Male Breast Cancer" Cancers 14, no. 13: 3175. https://doi.org/10.3390/cancers14133175
APA StyleMcClurg, D. P., Urquhart, G., McGoldrick, T., Chatterji, S., Miedzybrodzka, Z., Speirs, V., & Elsberger, B. (2022). Analysis of the Clinical Advancements for BRCA-Related Malignancies Highlights the Lack of Treatment Evidence for BRCA-Positive Male Breast Cancer. Cancers, 14(13), 3175. https://doi.org/10.3390/cancers14133175