Endometrial cancer (KEGG map)
KEGG's endometrial cancer map shows oestrogen-related type I tumours with PTEN loss, KRAS and beta-catenin mutations and faulty mismatch repair, and type II tumours with TP53 mutation and HER2 amplification. Immunotherapy for mismatch-repair-deficient tumours and HER2-directed therapy follow directly from this split.
Overview
The KEGG endometrial cancer map (hsa05213) separates the two classical types. Type I (endometrioid) carcinoma follows unopposed oestrogen exposure and endometrial hyperplasia and shows loss of PTEN, the most frequent event, releasing PI3K to AKT signalling (with PIK3CA and PIK3R1 mutations adding to it), activating KRAS mutations feeding RAF to MEK to ERK, stabilising CTNNB1 (beta-catenin) mutations that escape the APC/AXIN/GSK3B destruction complex and drive TCF/LEF and MYC transcription, and defects in DNA mismatch repair (MLH1 promoter methylation, or germline Lynch syndrome mutations) that produce microsatellite instability. Type II (serous and other non-endometrioid) carcinoma arises in atrophic endometrium, lacks hormone receptors and shows TP53 mutation, aneuploidy and ERBB2 (HER2) amplification with downstream EGFR/ERBB2 to RAS and PI3K signalling. Crosbie et al., Lancet, 2022 (doi:10.1016/S0140-6736(22)00323-3) update this into the four molecular classes now used clinically: POLE ultramutated, mismatch repair deficient, p53 abnormal, and no specific molecular profile, which predict outcome and guide adjuvant therapy.
What drugs do about it: PD-1 antibodies (dostarlimab, pembrolizumab, durvalumab) added to carboplatin and paclitaxel are now first-line for advanced or recurrent disease, with the largest benefit in mismatch-repair-deficient tumours; pembrolizumab with lenvatinib treats mismatch-repair-proficient tumours after chemotherapy; trastuzumab and trastuzumab deruxtecan target HER2-positive serous tumours; and hormonal therapy (progestins, aromatase inhibitors such as letrozole, sometimes with the mTOR inhibitor everolimus) exploits the oestrogen dependence of low-grade type I disease.
In one picture
Two different break-ins. In type I the alarm system (PTEN, mismatch repair) is disabled and oestrogen keeps the doors open; the intruders leave so many fingerprints (mutations) that the immune police can recognise them once PD-1 antibodies unmask them. In type II a single master key (TP53 loss, HER2 amplification) does the damage, so HER2-targeted drugs are the tool.
Diagram
top- PD-1 antibodies dostarlimab, pembrolizumab or durvalumab with carboplatin and paclitaxel for advanced or recurrent disease, especially mismatch-repair-deficient tumours
- Pembrolizumab plus lenvatinib for mismatch-repair-proficient disease after platinum chemotherapy
- HER2-directed therapy (trastuzumab with chemotherapy, trastuzumab deruxtecan) for HER2-positive serous carcinoma
- Hormonal therapy (progestins, letrozole, with or without everolimus) for low-grade oestrogen-receptor-positive disease
- Molecular classification (POLE, mismatch repair, p53) to de-escalate or intensify adjuvant treatment after surgery
Pages like this
not linked directly; found by shared links- PathwayGastric cancer (KEGG map)
Shares Mismatch repair & microsatellite instability, Wnt / β-catenin, PIK3CA / PI3K-alpha, p53 / RB / cell-cycle checkpoint.
- PathwayColorectal cancer (KEGG map)
Shares Mismatch repair & microsatellite instability, Wnt / β-catenin, PIK3CA / PI3K-alpha, p53 / RB / cell-cycle checkpoint.
- PathwayBreast cancer (KEGG map)
Shares Letrozole (and other aromatase inhibitors), Oestrogen receptor signalling, Wnt / β-catenin, PIK3CA / PI3K-alpha.
- PathwayChemical carcinogenesis - receptor activation
Shares Letrozole (and other aromatase inhibitors), PIK3CA / PI3K-alpha, Estrogen receptor (ERα), p53 / RB / cell-cycle checkpoint.
- PathwayHepatocellular carcinoma (KEGG map)
Shares Wnt / β-catenin, Lenvatinib, Durvalumab, p53 / RB / cell-cycle checkpoint.
- IdeaHER2 ADCs as standard for HER2-positive serous endometrial cancer
Shares Trastuzumab, Trastuzumab deruxtecan, TP53, Endometrial cancer.
- PathwayRenal cell carcinoma (KEGG map)
Shares Everolimus, Lenvatinib, PD-1 / PD-L1 immune checkpoint & T-cell activation, PI3K / AKT / mTOR.
- PathwayPancreatic cancer (KEGG map)
Shares PIK3CA / PI3K-alpha, p53 / RB / cell-cycle checkpoint, PI3K / AKT / mTOR, TP53.