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.
Germline BRCA1/2 mutations account for ~5-10% of breast and ~15% of ovarian cancers; ~10-20% of TNBC. Homologous recombination deficiency (HRD) extends the phenotype to BRCA-wild-type tumours and is measured by genomic scars (myChoice CDx). Predicts benefit from PARP inhibitors and platinum.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
In plain words · 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.
- 1 · What it is
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.
- 2 · What goes wrong in cancer
Homologous recombination repair; loss forces reliance on error-prone pathways.
- 3 · How drugs use it
3 products aim at BRCA1 / BRCA2 (HRD): small molecules. Because the protein is lost rather than overactive, drugs either restore its function or exploit the weakness its loss leaves (synthetic lethality).
Biology
Homologous recombination repair; loss forces reliance on error-prone pathways.
- Breast (esp. TNBC)
- Ovarian
- Prostate
- Pancreatic
How common it is, by cancer
| 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.
Olaparib was the first PARP inhibitor, and turned an inherited BRCA mutation from a risk factor into a drug target, including after surgery in breast cancer.
A PARP inhibitor for BRCA-mutated ovarian and prostate cancer whose original maker went bankrupt; still available, with a narrowed label.
Talazoparib is the most potent PARP trapper, approved in BRCA breast cancer and with enzalutamide in prostate cancer.
Everyone with HER2-negative early breast cancer that meets high-risk criteria should be offered germline BRCA testing, because a positive result now changes treatment: a year of olaparib after chemotherapy reduces relapse and death. It does not apply to low-risk tumours, HER2-positive disease, or somatic-only BRCA mutations.
Women with newly diagnosed advanced ovarian cancer should have their tumour tested for BRCA mutations and homologous recombination deficiency, because those who are HRD-positive gain years of additional disease control and better survival from adding olaparib to bevacizumab maintenance. Those who are HRD-negative gain nothing from olaparib in this combination and should not be exposed to its toxicity and cost. HRD testing has become a routine part of ovarian cancer care as a result.
Every woman diagnosed with advanced high-grade ovarian cancer should be tested for BRCA mutations at diagnosis, because those who carry one should receive two years of olaparib after chemotherapy, which greatly extends the time in remission and improves long-term survival. The plateau in the survival curves suggests some patients are cured by this approach. Toxicity is mostly anaemia, fatigue and nausea, and the two-year limit appears sufficient.
For women who carry a BRCA mutation, preventive removal of the ovaries and tubes saves lives, and preventive mastectomy almost eliminates breast cancer. These are the strongest prevention effects in oncology, which is why finding carriers before they develop cancer matters so much.
Latest papers
topQuery 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.