Role of BRCA Mutations in Cancer Treatment with Poly(ADP-ribose) Polymerase (PARP) Inhibitors
Abstract
:1. Introduction
2. BRCA Genes and Cancer Susceptibility
3. Role of PARP Enzymes and BRCA Proteins in DNA Repair
4. PARP Inhibitors Enter the Clinic
5. Germline and Somatic BRCA Mutation Carriers Equally Respond to PARPi
6. Deleterious BRCA Mutations and Sensitivity to Platinum-Based Drugs or PARPi
7. Sensitivity to PARP Inhibitors beyond BRCA Mutations
8. Recent Approval of PARPi for Breast Cancer
9. Conclusions
Funding
Conflicts of Interest
Abbreviations
APEX1 | apurinic/apyrimidinic endodeoxyribonuclease 1 |
ATM | ATM serine/threonine kinase |
ATR | ATR serine/threonine kinase |
BARD1 | BRCA1 associated RING domain 1 |
BRCA1 | BRCA1, DNA repair associated |
BRCA2 | BRCA2, DNA repair associated |
BRIP1 | BRCA1 interacting protein C-terminal helicase 1 |
CCNE1 | cyclin E1 |
CDK12 | cyclin dependent kinase 12 |
CHK1 | checkpoint kinase 1 |
CHK2 | checkpoint kinase 2 |
CtIP | official name: RBBP8, RB binding protein 8, endonuclease |
DSS1 | SEM1, 26S proteasome complex subunit |
DR5 | official name: TNFRSF10B, TNF receptor superfamily member 10b |
EMSY | EMSY, BRCA2 interacting transcriptional repressor |
FANCA | FA complementation group A |
FANCC | FA complementation group C |
FANCD2 | FA complementation group D2 |
FANCM | FA complementation group M |
FAS | Fas cell surface death receptor |
H2AX | official name: H2AFX, H2A histone family member X |
γH2AX | phospho-H2AFX |
IDH1 | isocitrate dehydrogenase (NADP+) 1, cytosolic |
IDH2 | isocitrate dehydrogenase (NADP(+)) 2, mitochondrial |
KU70 | official name: XRCC6, X-ray repair cross complementing 6 |
KU80 | official name: XRCC5, X-ray repair cross complementing 5 |
LIG3 | DNA ligase 3 |
LIG4 | DNA ligase 4 |
MRE11 | MRE11 homolog, double strand break repair nuclease |
NBN | nibrin (also known as NBS1) |
NF-kB | official name: REL proto-oncogene, NF-kB subunit |
PALB2 | partner and localizer of BRCA2 |
PARG | poly(ADP-ribose) glycohydrolase |
PARP1 | poly(ADP-ribose) polymerase 1 |
PARP2 | poly(ADP-ribose) polymerase 2 |
PARP3 | poly(ADP-ribose) polymerase family member 3 |
POLB | DNA polymerase β |
POLD POLL POLM | DNA polymerase δ DNA polymerase λ DNA polymerase µ |
POLQ | DNA polymerase θ |
PTEN | phosphatase and tensin homolog |
RAD50 | RAD50 double strand break repair protein |
RAD51 | RAD51 recombinase |
RAD51C | RAD51 paralog C |
RAD51D | RAD51 paralog D |
RAD52 | RAD52 homolog, DNA repair protein |
RAD54 | RAD54 homolog B |
RB1 | RB transcriptional corepressor 1 |
RIF1 | replication timing regulatory factor 1 |
RPA1 | replication protein A1 |
SP1 | Sp1 transcription factor |
TP53 | tumor protein p53 |
TP53BP1 | tumor protein p53 binding protein 1 |
PCAT1 | prostate cancer associated transcript 1 (non-protein coding) |
XLF | official name: NHEJ1, non-homologous end joining factor 1 |
XRCC1 | X-ray repair cross-complementing 1 |
XRCC4 | X-ray repair cross complementing 4 |
Alt-EJ | alternative Non-homologous End Joining (also known as alt-NHEJ, a-NHEJ, back-up NHEJ, B-NHEJ, MMEJ) |
BER | base excision repair |
DSB | DNA double-strand breaks |
HR | homologous recombination |
NGS | Next-Generation Sequencing |
NHEJ | Non-homologous End Joining |
SSB | single strand break |
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PARPi | Approved Indications | Registration Clinical Trial | Deleterious Germline or Somatic BRCA Mutations | Dose | |
---|---|---|---|---|---|
FDA | EMA | ||||
Olaparib (Lynparza®, AstraZeneca, Cambridge, UK) | 19 December 2014 Treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. | 24 October 2014 Maintenance treatment of adult patients with relapsed, platinum-sensitive high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer with mutations (germline or somatic) in BRCA genes, and who are in response to platinum-based chemotherapy | FDA: Study 42, Phase II (NCT01078662) | Required | FDA: 400 mg PO bid (sixteen 50 mg hard capsules); in 2017: 300 mg PO bid (four 150 mg tablets) |
EMA: Study 19, Phase II (NCT00753545) | EMA: 400 mg PO bid (sixteen 50 mg hard capsules) | ||||
17 August 2017 Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy | 8 May 2018 Maintenance therapy for patients with platinum-sensitive relapsed high-grade, epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete response or partial response to platinum-based chemotherapy, regardless of BRCA status | SOLO2, Phase III (NCT01874353) Study 19, Phase II (NCT00753545) | Not required | 300 mg PO bid (four 150 mg tablets) | |
12 January 2018 Treatment of patients with deleterious or suspected deleterious germline BRCA-mutated, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. | OlympiAD, Phase III (NCT02000622) | Required | 300 mg PO bid (four 150 mg tablets) | ||
Rucaparib (Rubraca®, Clovis Oncology, Boulder, CO, USA) | 19 December 2016 Treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. | 24 May 2018 Treatment of adult patients with platinum sensitive, relapsed or progressive, BRCA-mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with two or more prior lines of platinum based chemotherapy, and who are unable to tolerate further platinum based chemotherapy. | ARIEL 2, Phase II (NCT01891344); Study 10, Phase I/II (NCT01482715) | Required | 600 mg PO bid (four 300 mg film/coated tablets) |
6 April 2018 Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy | ARIEL3, Phase III (NCT01968213) | Not required | |||
Niraparib (Zejula®, Tesaro, Waltham, MA, USA) | 27 March 2017 Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy | 16 November 2017 Maintenance treatment of adult patients with platinum-sensitive relapsed high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy | NOVA study, phase III (NCT01847274) | Not required | 300 mg PO qd (three 100 mg hard capsules) |
Talazoparib (Talzenna®, Pfizer Inc., New York, NY, USA) | 16 October 2018 Treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer. | EMBRACA, phase III (NCT01945775) | Required | 1 mg PO qd (1 hard capsule) |
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Faraoni, I.; Graziani, G. Role of BRCA Mutations in Cancer Treatment with Poly(ADP-ribose) Polymerase (PARP) Inhibitors. Cancers 2018, 10, 487. https://doi.org/10.3390/cancers10120487
Faraoni I, Graziani G. Role of BRCA Mutations in Cancer Treatment with Poly(ADP-ribose) Polymerase (PARP) Inhibitors. Cancers. 2018; 10(12):487. https://doi.org/10.3390/cancers10120487
Chicago/Turabian StyleFaraoni, Isabella, and Grazia Graziani. 2018. "Role of BRCA Mutations in Cancer Treatment with Poly(ADP-ribose) Polymerase (PARP) Inhibitors" Cancers 10, no. 12: 487. https://doi.org/10.3390/cancers10120487
APA StyleFaraoni, I., & Graziani, G. (2018). Role of BRCA Mutations in Cancer Treatment with Poly(ADP-ribose) Polymerase (PARP) Inhibitors. Cancers, 10(12), 487. https://doi.org/10.3390/cancers10120487