Breast cancer (KEGG map)
KEGG's breast cancer map lays out the three clinical subtypes as signalling routes: oestrogen receptor driving cyclin D and CDK4/6 in hormone-receptor-positive disease, HER2 driving PI3K/AKT and MAPK in HER2-positive disease, and EGFR, Notch, Wnt and BRCA defects in triple-negative disease. Each route has its own drug class.
Overview
The KEGG breast cancer map (hsa05224) is organised by molecular subtype. Hormone-receptor-positive tumours (luminal A and B) are driven by oestrogen binding ESR1, which with co-activators (NCOA1, NCOA3) switches on cyclin D1, MYC and the progesterone receptor; cyclin D1 partners CDK4/6 to phosphorylate RB and release E2F, and CCND1 amplification is a recurrent event. HER2-positive tumours overexpress ERBB2, which dimerises with EGFR or HER3 and activates both PI3K to AKT to mTOR and RAS to RAF to MEK to ERK for growth, survival and differentiation, with PIK3CA mutation or amplification and PTEN loss adding to the PI3K arm. Triple-negative and basal-like tumours show EGFR overexpression, deregulated Notch (NOTCH1 to 4, JAG and DLL ligands driving HES and HEY genes) and Wnt/beta-catenin signalling (FZD7 and LRP6 overexpression), and about 8% of all breast cancers are hereditary through germline BRCA1 or BRCA2 mutations that disable homologous recombination repair. TP53, PIK3CA and GATA3 are the only genes mutated in more than 10% of all breast cancers. The map also includes FGF/FGFR1 amplification, IGF1R, KIT and RANKL (TNFSF11). Harbeck et al., Nat Rev Dis Primers, 2019 (doi:10.1038/s41572-019-0111-2) review how these subtypes translate into treatment, with endocrine therapy plus CDK4/6 inhibition, HER2-directed antibodies and small molecules, and chemotherapy plus immunotherapy or PARP inhibition for triple-negative disease.
What drugs do about it: for ER-positive disease, aromatase inhibitors (letrozole), tamoxifen, fulvestrant and oral SERDs such as elacestrant, imlunestrant and camizestrant remove or degrade the receptor while palbociclib, ribociclib and abemaciclib block CDK4/6; alpelisib, inavolisib and capivasertib target PIK3CA, PI3K and AKT alterations. For HER2-positive disease, trastuzumab and pertuzumab, the antibody-drug conjugates trastuzumab emtansine and trastuzumab deruxtecan, and the kinase inhibitors tucatinib, neratinib and lapatinib shut down HER2. For triple-negative disease, pembrolizumab with chemotherapy, the TROP2 antibody-drug conjugates sacituzumab govitecan and datopotamab deruxtecan, and the PARP inhibitors olaparib and talazoparib for germline BRCA carriers are the mainstays.
In one picture
Three engines that can power a breast cancer. Hormone-receptor-positive tumours run on oestrogen, so endocrine drugs cut the fuel and CDK4/6 inhibitors put a chock under the wheel. HER2-positive tumours have an oversized growth-signal antenna, so anti-HER2 antibodies cap it. Triple-negative tumours have neither, so treatment goes after their broken DNA repair (PARP inhibitors), their surface markers (TROP2 conjugates) and their visibility to the immune system.
Diagram
top- HR-positive disease: endocrine therapy (letrozole, tamoxifen, fulvestrant, oral SERDs elacestrant, imlunestrant, camizestrant) with a CDK4/6 inhibitor (palbociclib, ribociclib, abemaciclib), then alpelisib, inavolisib or capivasertib for PIK3CA, AKT1 or PTEN alterations
- HER2-positive disease: trastuzumab plus pertuzumab, trastuzumab emtansine, trastuzumab deruxtecan, and the HER2 kinase inhibitors tucatinib, neratinib and lapatinib
- Triple-negative disease: pembrolizumab with chemotherapy, TROP2 antibody-drug conjugates sacituzumab govitecan and datopotamab deruxtecan
- PARP inhibitors olaparib and talazoparib for germline BRCA1/2-mutated breast cancer
- Trastuzumab deruxtecan for HER2-low tumours across subtypes
Pages like this
not linked directly; found by shared links- PathwayEndometrial cancer (KEGG map)
Shares Letrozole (and other aromatase inhibitors), Oestrogen receptor signalling, Wnt / β-catenin, PIK3CA / PI3K-alpha.
- CancerMale breast cancer
Shares Fulvestrant, Ribociclib, Talazoparib, Letrozole (and other aromatase inhibitors).
- PathwayChemical carcinogenesis - receptor activation
Shares Alpelisib, Fulvestrant, Elacestrant, Capivasertib.
- PairingPI3K/AKT-pathway inhibitor + endocrine therapy (± CDK4/6)
Shares Inavolisib, Alpelisib, Fulvestrant, Capivasertib.
- PathwayPancreatic cancer (KEGG map)
Shares DNA damage response & homologous recombination, PIK3CA / PI3K-alpha, CDK4/6, Receptor tyrosine kinase activation.
- PathwayGastric cancer (KEGG map)
Shares Wnt / β-catenin, PIK3CA / PI3K-alpha, Receptor tyrosine kinase activation, p53 / RB / cell-cycle checkpoint.
- PathwayColorectal cancer (KEGG map)
Shares Tucatinib, Wnt / β-catenin, PIK3CA / PI3K-alpha, p53 / RB / cell-cycle checkpoint.
- TermOral SERD
Shares Imlunestrant, Camizestrant, Fulvestrant, Elacestrant.