BRCA1 / BRCA2 (HRD)
DNA repair genes. Inheriting a broken copy raises breast and ovarian cancer risk, but tumours that lose them become uniquely vulnerable to PARP inhibitors and platinum. This dossier gathers the 3 products (3 approved), 11 trials, 5 pathways and 9 resistance routes in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
Biology
Homologous recombination repair; loss forces reliance on error-prone pathways.
- Breast (esp. TNBC)
- Ovarian
- Prostate
- Pancreatic
Elsewhere: identifiers and databases
Built from HGNC, Ensembl, UniProt and ChEMBL idsHow common it is, by cancer
Full matrix →| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Triple-negative breast cancer | 15-20% | Germline BRCA1/2 | BRCA1 predominant | Wikipedia |
| Ovarian cancer | 15-20% | Germline BRCA1/2; ~25% including somatic | Wikipedia | |
| Prostate cancer | 8-12% | Germline or somatic BRCA2 (metastatic) | cBioPortal (TCGA) | |
| Pancreatic ductal adenocarcinoma | 5-8% | Germline BRCA1/2 | cBioPortal (TCGA) | |
| HR-positive / HER2-negative breast cancer | 3-5% | Germline BRCA1/2 | BRCA2 predominant | Wikipedia |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Products by modality and phase
Browse products →| Modality | Approved |
|---|---|
| Small molecule 3 |
Trials
Evidence ranking →| Trial | Phase | Status | Setting | Result | Products |
|---|---|---|---|---|---|
| DUO-E / GOG-3041 / ENGOT-EN10 NCT04269200 | 3 | Positive | Newly diagnosed advanced or recurrent endometrial cancer: chemotherapy + durvalumab, then durvalumab ± olaparib maintenance, vs chemotherapy | PFS HR 0.42 (dMMR, durvalumab); 0.57 (pMMR, durvalumab + olaparib). | |
| DUO-O / ENGOT-ov46 NCT03737643 | 3 | Mixed | Newly diagnosed non-BRCA-mutated advanced ovarian cancer: chemotherapy + bevacizumab + durvalumab, then durvalumab + bevacizumab ± olaparib maintenance, vs standard | PFS HR 0.63; interim OS HR 0.95. | |
| TALAPRO-2 NCT03395197 | 3 | Positive | First-line mCRPC: enzalutamide + talazoparib vs enzalutamide + placebo (all-comers and HRR-mutant cohorts) | rPFS HR 0.63 (ITT); OS HR 0.80 (ITT), 0.62 (HRR-mutant). | |
| ATHENA-MONO / GOG-3020 NCT03522246 | 3 | Positive | Newly diagnosed advanced ovarian cancer after response to first-line platinum: rucaparib maintenance vs placebo | PFS 20.2 vs 9.2 months (HR 0.52). | |
| MAGNITUDE NCT03748641 | 3 | Mixed | First-line mCRPC: abiraterone + niraparib vs abiraterone + placebo, HRR-mutant and HRR-negative cohorts | BRCA cohort rPFS HR 0.53; HRR-negative futility. | |
| PROpel NCT03732820 | 3 | Positive | First-line mCRPC, all-comers: abiraterone + olaparib vs abiraterone + placebo | rPFS HR 0.66 (ITT); OS HR 0.81 (NS). | |
| OlympiA NCT02032823 | 3 | Positive | Adjuvant olaparib for one year in germline BRCA-mutated, HER2-negative, high-risk early breast cancer | iDFS HR 0.58; OS HR 0.72. | |
| PROfound NCT02987543 | 3 | Positive | mCRPC with HRR gene alterations after ARPI: olaparib vs enzalutamide/abiraterone switch | rPFS HR 0.34; OS HR 0.69 (cohort A). | |
| PAOLA-1 / ENGOT-ov25 NCT02477644 | 3 | Positive | Newly diagnosed advanced ovarian cancer already on bevacizumab maintenance: adding olaparib vs placebo | PFS HR 0.59 overall, 0.33 HRD-positive; 5-year OS 65.5% vs 48.4% in HRD-positive. | |
| POLO NCT02184195 | 3 | Mixed | Germline BRCA-mutated metastatic PDAC not progressed on ≥16 weeks of platinum: olaparib maintenance vs placebo | PFS HR 0.53; OS HR 0.83 (not significant). | |
| SOLO-1 NCT01844986 | 3 | Positive | Newly diagnosed advanced BRCA-mutated ovarian cancer in response to platinum chemotherapy: olaparib maintenance for 2 years vs placebo | PFS HR 0.30; 7-year OS 67.0% vs 46.5% (HR 0.55). |
Resistance routes that involve this target
Unaddressed routes →Secondary mutations restore the open reading frame and homologous recombination; also confers platinum resistance.
- ctDNA detection of reversions to avoid futile re-challenge; switch to non-DDR agents (ADCs such as mirvetuximab)
Loss of end-protection factors lets BRCA1-deficient cells resect DNA ends and repair by HR.
- ATR inhibitors; POLQ inhibitors (trials)
Stabilised forks tolerate PARP trapping; PARP1 mutations abolish trapping.
- PARP1-selective saruparib for a wider window; PARP PET to confirm target
Olaparib and rucaparib are P-gp substrates.
- Talazoparib and niraparib are weaker substrates
More receptor, or mutations (F877L, T878A) that turn antagonists into agonists.
- AR degraders and N-terminal-domain inhibitors (trials); PSMA radioligand therapy
Truncated receptor lacking the ligand-binding domain is constitutively active and invisible to enzalutamide.
- Taxanes retain activity; N-terminal-domain inhibitors
RB1/TP53 loss enables transdifferentiation; AR-indifferent, DLL3-positive, PSMA-negative.
- Platinum-etoposide; DLL3 engagers (tarlatamab) and B7-H3 ADCs in trials
Reciprocal feedback between AR and PI3K pathways.
- Capivasertib + abiraterone (approved 2026 for PTEN-deficient disease)
GR drives an AR-like transcriptional programme under enzalutamide.
- GR antagonists (relacorilant tested in prostate cancer)
Pathways where it is a node
Pathway-to-drug matrix →- Base excision repair, PARP & alkylation damageNode: HR (BRCA) rescue · 2 druggable nodes
Tens of thousands of times a day a single DNA letter is oxidised or chemically scarred. A small crew snips it out and PARP marks the nick so it gets sealed. PARP inhibitors do not just switch PARP off; they trap it on the DNA, turning a harmless nick into a lethal break when the cell copies its DNA.
Which nodes have drugs → - DNA damage response & homologous recombinationNode: BRCA1/2 – RAD51 (HR) · 3 druggable nodes
The DNA damage response is the cell's set of repair crews. Single-strand breaks are patched by PARP; double-strand breaks by BRCA-dependent homologous recombination. Lose one crew and the cell survives; lose both and it dies. That is how PARP inhibitors work.
Which nodes have drugs → - Double-strand break repair: HR versus end joiningNodes: Resection: BRCA1–CtIP, PALB2–BRCA2 → RAD51 · 4 druggable nodes
A break through both strands of DNA is the most dangerous lesion a cell faces. Two crews compete to fix it: homologous recombination copies the answer from the sister chromosome (accurate, needs BRCA), while end joining simply glues the ends (fast, sloppy). Which crew wins decides whether PARP inhibitors and radiation kill the cell.
Which nodes have drugs → - Mutagenesis & mutational signaturesNode: Repair: MMR, HR, BER, NER · 1 druggable nodes
Every cause of DNA damage leaves its own fingerprint in the genome: sunlight, tobacco, a faulty repair enzyme, a gut bacterium. Reading these fingerprints tells you what caused a cancer and which repair crews it is missing, which in turn predicts which drugs will work.
Which nodes have drugs → - Synthetic lethality: paired dependenciesNode: BRCA / HRD loss · 7 druggable nodes
Two genes are synthetically lethal when losing either alone is fine but losing both kills the cell. Cancers that have already lost one (a tumour suppressor you cannot put back) become uniquely dependent on the other, which you can drug. BRCA and PARP was the first proof; a dozen more pairs are now in trials.
Which nodes have drugs →
Companion diagnostics and assays
Assay registry →| Assay | Platform | Cut-off | Gates |
|---|---|---|---|
| FoundationOne CDx Foundation Medicine (Roche) · FDA CDx 2017 | NGS tissue | Per companion claim: EGFR, ALK, BRAF V600, ERBB2 amplification, KRAS wild-type, BRCA1/2 and HRR genes, PIK3CA, MET exon 14, RET, FGFR2 fusions, IDH1, NTRK fusions; MSI-high; TMB at least 10 mutations per megabase | |
| FoundationOne Liquid CDx Foundation Medicine (Roche) · FDA CDx 2020 | NGS plasma | Per companion claim: EGFR (osimertinib, erlotinib, gefitinib), ALK (alectinib), BRCA1/2 and ATM (olaparib, rucaparib), PIK3CA (alpelisib), FGFR3 (erdafitinib), NTRK and RET; negative plasma results reflex to tissue | |
| BRACAnalysis CDx Myriad Genetics · FDA CDx 2014 | Germline NGS | Deleterious or suspected deleterious germline variant | |
| myChoice CDx Myriad Genetics · FDA CDx 2019 | NGS tissue | Genomic instability score at least 42, or BRCA1/2 mutation, defines HRD-positive (olaparib plus bevacizumab, PAOLA-1; niraparib) | |
| FoundationFocus CDxBRCA Foundation Medicine · FDA CDx 2016 | NGS tissue | Deleterious BRCA1/2 alteration (rucaparib, ovarian cancer) |
Preclinical models
All models →| Cell line | Identifiers | Why it is used |
|---|---|---|
| MDA-MB-436 | CVCL_0623 · ACH-000573 | Breast, BRCA1 5396+1G>A; PARP-inhibitor sensitive. |
| HCC1937 | CVCL_0290 · ACH-000223 | Breast, BRCA1 5382insC; relatively PARP-inhibitor resistant despite BRCA1 loss. |
| SUM149PT | CVCL_3422 · ACH-001390 | Breast, BRCA1 2288delT. |
| Capan-1 | CVCL_0237 · ACH-000354 | Pancreatic, BRCA2 6174delT; olaparib-resistant derivatives carry reversions. |
| PEO1 | CVCL_2686 · ACH-001630 | Ovarian, BRCA2 5193C>G; PEO4 sister line has a reversion. |
| UWB1.289 | CVCL_B079 · ACH-001418 | Ovarian, BRCA1-null; BRCA1-restored isogenic pair available. |
| COV362 | CVCL_2420 · ACH-000278 | Ovarian, BRCA1-mutant. |
| DLD-1 BRCA2-/- | CVCL_HD56 | Isogenic colorectal knock-out pair (Horizon). |
- K14-Cre; Brca1; Trp53 (Mammary Brca1 and Trp53 loss) Liu et al., PNAS 2007
Open questions
All open questions →- 01
Should BRCA reversion mutations detected in ctDNA change treatment before radiographic progression on a PARP inhibitor?
translationalclinicWhy unresolved. Reversions restore homologous recombination and predict PARP-inhibitor and platinum failure, and they are detectable in plasma, but no trial has switched therapy on that signal alone.
What would answer it. A ctDNA-guided switch trial (reversion detected: switch to a non-DDR agent versus continue) with progression-free survival.
Source: SOLO-1 seven-year overall survival, J Clin Oncol 2023
Ideas and companies
Key papers and the live literature
Preprints →- OlympiA: a year of olaparib after surgery for BRCA-mutated, high-risk early breast cancer · New England Journal of Medicine 2021
- PAOLA-1: olaparib added to bevacizumab maintenance in newly diagnosed ovarian cancer, with benefit confined to HRD-positive tumours · New England Journal of Medicine 2019
- SOLO-1: two years of olaparib maintenance after first-line chemotherapy for BRCA-mutated ovarian cancer · New England Journal of Medicine 2018
- PROSE consortium: preventive surgery lowers cancer and death in BRCA1 and BRCA2 carriers · JAMA 2010
Query for this target: (TITLE:"BRCA1 / BRCA2" OR ABSTRACT:"BRCA1 / BRCA2" OR TITLE:"HRD" OR ABSTRACT:"HRD" OR TITLE:"BRCA1" OR ABSTRACT:"BRCA1" OR TITLE:"BRCA2" OR ABSTRACT:"BRCA2") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about BRCA1 / BRCA2 (HRD), not a curated reading list.
Export
The dossier as machine-readable JSON: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/brca.json. Licence CC BY 4.0.