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PIK3CA is the most commonly mutated gene in hormone-driven breast cancer. Drugs against it work, but hitting it cleanly without raising blood sugar took years.
PIK3CA mutations occur in ~40% of HR+ breast cancer. Alpelisib (SOLAR-1), inavolisib (INAVO120, mutant-selective, with palbociclib and fulvestrant), and capivasertib (AKT) are approved. Gedatolisib (pan-PI3K/mTOR, Revtorpyk) was approved in 2026. Mutant-selective and allosteric inhibitors (RLY-2608) aim to avoid hyperglycaemia.
In plain words · PIK3CA is the most commonly mutated gene in hormone-driven breast cancer. Drugs against it work, but hitting it cleanly without raising blood sugar took years.
PIK3CA is the most commonly mutated gene in hormone-driven breast cancer. Drugs against it work, but hitting it cleanly without raising blood sugar took years.
PIK3CA encodes the catalytic subunit of PI3K; H1047R and E545K are the hotspots.
13 products aim at PIK3CA / PI3K-alpha: small molecules, degraders and other agents. Kinases are switched on by binding ATP inside the cell, so most drugs are small molecules shaped to plug that ATP pocket.
Tumour-specific alteration: 1 of 1 label readouts filed under it measure a sequence variant (PIK3CA mutation) absent from normal cells. HPA PIK3CA: RNA low tissue specificity; high antibody staining in 20 normal tissues; highest cancer staining colorectal cancer (11 of 12 high). Distribution: 5 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Breast cancer (all types), Endometrial cancer, Head and neck squamous cell carcinoma, Biliary tract cancer (all types), Colorectal cancer); approvals of single-target medicines aimed at it also list Lymphoma, Leukaemia, not counted; Open Targets associates it with 23 specific cancer types at or above 0.5 (CLOVES syndrome, breast cancer, ovarian cancer, breast adenocarcinoma, hepatocellular carcinoma, non-small cell lung carcinoma and more). (Rule 3 of scripts/fetch-target-specificity.ts.)
Sources: PIK3CA mutation label threshold; Human Protein Atlas PIK3CA tissue; Open Targets ENSG00000121879 associations
First described 1994. Earliest sequence paper UniProt cites for the protein: Volinia et al, Genomics, 1994, "Molecular cloning, cDNA sequence, and chromosomal localization of the human phosphatidylinositol 3-kinase p110 alpha (PIK3CA) gene". Source.
What a pathology or genomic report can say about this target, each with the thresholds approvals use.
PIK3CA encodes the catalytic subunit of PI3K; H1047R and E545K are the hotspots.
RNA: low tissue specificity, detected in all normal tissues.
Medium: Cerebral cortex, Cervix, Epididymis, Esophagus, Hippocampus, Liver, Lung, Lymph node.
Medium only: renal cancer, skin cancer.
HPA PIK3CA tissue · HPA PIK3CA pathology · HPA protein class: Essential proteins, FDA approved drug targets
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Endometrial cancer | 45-55% | Activating mutation | cBioPortal (TCGA) | |
| HR-positive / HER2-negative breast cancer | 35-40% | Activating mutation | cBioPortal (TCGA) | |
| Non-small-cell lung cancer | 11-38% | Hotspot mutation and high-level amplification | cBioPortal: mutation in 53 of 484, 11.0%, plus high-level amplification in 184 of 487, 37.8%, in lusc_tcga_pan_can_atlas_2018; mutation 28 of 178, 15.7%, plus amplification 68 of 178, 38.2%, in lusc_tcga_pub; mutation 11 of 108, 10.2%, in lusc_cptac_2021; amplification 208 of 1,144, 18.2%, in nsclc_tcga_broad_2016. E545K (13 records) and E542K (13) lead, with H1047R (5) behind, the reverse of the breast cancer pattern. PTEN is mutated in 51 of 484, 10.5%, with deep deletion in 48 of 487, 9.9%. The founding paper counted the phosphatidylinositol-3-kinase pathway altered in 47% of tumours (Cancer Genome Atlas Research Network 2012). | cBioPortal (TCGA) |
| Colorectal cancer | 20-28% | Hotspot mutation (E542K, E545K, H1047R) | cBioPortal: 1,486 of 7,237, 20.5%, in crc_msk_2026 (E545K 331, H1047R 232, E542K 216 samples); 229 of 1,134, 20.2%, in crc_msk_2017; 298 of 1,516, 19.7%, in crc_eo_2020; 147 of 534, 27.5%, in coadread_tcga_pan_can_atlas_2018; 45 of 224, 20.1%, in coadread_tcga_pub; 132 of 619, 21.3%, in coadread_dfci_2016; 130 of 1,015, 12.8%, in crc_sysucc_2022. | cBioPortal (TCGA) |
| Head and neck squamous cell carcinoma | 15-20% | Activating mutation | HPV+ enriched | cBioPortal (TCGA) |
| Colorectal cancer | 15-20% | Activating mutation | cBioPortal (TCGA) | |
| Triple-negative breast cancer | 10-18% | Mutation (amplification in a further tenth) | 9% of basal-like tumours (Cancer Genome Atlas 2012); 20% of 447 sequenced TNBCs, 55% within the LAR subtype (Bareche 2018); cBioPortal: 9 of 84, 10.7%, in brca_tcga_pub and 14 of 123, 11.4%, on the 2018 calls; 53 of 299, 17.7%, in brca_metabric; 23 of 176, 13.1%, in breast_msk_2018. PIK3CA amplification in 10 of 119, 8.4%, (brca_tcga_pan_can_atlas_2018) and 34 of 320, 10.6%, (brca_metabric). | doi.org |
| Gallbladder cancer | 11% | Mutation | Mutation in 26 of 244 samples, 10.7%, in cBioPortal gbc_mskcc_2022 and 11 of 103, 10.7%, in gbc_msk_2018; 6.2% of 32 exomes in gbc_shanghai_2014; absent from the 11 Japanese tumours in Narayan 2019; named among the actionable variants in 35% of patients (Giraldo 2022). | cBioPortal (TCGA) |
| Non-small-cell lung cancer | 5-7% | Hotspot mutation (E545K, E542K, H1047R) | cBioPortal: 159 of 2,653, 6.0%, in luad_mskcc_2023_met_organotropism (E545K 53, E542K 20, H1047R 16 records); 65 of 915, 7.1%, in lung_msk_2017; 28 of 566, 4.9%, in luad_tcga_pan_can_atlas_2018; 12 of 302, 4.0%, in luad_oncosg_2020. It was the driver in 6 of 733 fully genotyped adenocarcinomas, under 1% (Kris 2014). | cBioPortal (TCGA) |
| Prostate cancer | 2-9% | Activating mutation, plus amplification of PIK3CA or PIK3CB | cBioPortal mutation: PIK3CA 110 of 2,260, 4.9%, in prostate_msk_2024; 24 of 424, 5.7%, in prad_mcspc_mskcc_2020; 14 of 444, 3.2%, in prad_su2c_2019; 10 of 494, 2.0%, in prad_tcga_pan_can_atlas_2018. PIK3CB mutation 31 of 2,260, 1.4%, with amplification 17; AKT1 mutation 42 of 2,260, 1.9%. PIK3CA hotspot records in prostate_msk_2024: E545K 18, E542K 16, H1047R 12 of 116 records. The TCGA taxonomy paper counted a presumed actionable lesion in the PI3K or MAPK pathways in 25% of 333 primary tumours once PTEN was included (Cancer Genome Atlas Research Network 2015). | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Alpelisib was the first PI3K drug for PIK3CA-mutant breast cancer (2019). It is effective, but high blood sugar and rash limited its use, and newer drugs are displacing it.
Capivasertib (Truqap) is the first AKT inhibitor, for breast cancer with PI3K-pathway mutations and, since 2026, for prostate cancer with PTEN loss.
Copanlisib is an intravenous PI3K inhibitor for relapsed follicular lymphoma, approved in 2017 and withdrawn in 2023 when its confirmatory trial failed.
A dual PI3K inhibitor for relapsed CLL whose survival data raised FDA concern; use is now limited to late lines.
An mTOR-blocking pill that doubled progression-free time with exemestane in 2012 and is now paired with the oral SERD giredestrant.
An intravenous drug that blocks the whole PI3K/mTOR pathway, approved in July 2026 for hormone-positive breast cancer.
Idelalisib was the first PI3K inhibitor for blood cancers; it is effective in CLL with rituximab but so toxic (colitis, hepatitis, pneumonitis, infections) that the class has largely been abandoned.
Inavolisib is a PI3K drug that also destroys the mutant protein, approved in 2024 with palbociclib and fulvestrant for PIK3CA-mutant breast cancer.
Serabelisib is an experimental small-molecule drug from Faeth Therapeutics in phase 2 trials for HR-positive / HER2-negative breast cancer and endometrial cancer, aimed at PIK3CA / PI3K-alpha.
Tersolisib is an experimental small-molecule drug from Eli Lilly and in phase 3 trials for HR-positive / HER2-negative breast cancer, aimed at PIK3CA / PI3K-alpha.
A family of quick single-gene tests that decide who can have several bowel, lung, breast and bladder cancer drugs.
A PI3K inhibitor for marginal zone and follicular lymphoma approved in 2021 and withdrawn in 2022 after the UNITY-CLL trial suggested more deaths.
Zovegalisib is an experimental small-molecule drug from Relay Therapeutics in phase 3 trials for HR-positive / HER2-negative breast cancer, aimed at PIK3CA / PI3K-alpha.
Evidence that the immune environment of gallbladder cancer differs by population even when the mutations do not; a reason to report gallbladder cancer and its regions separately in immunotherapy trials rather than as one biliary subgroup.
The reference Western cohort for gallbladder cancer frequencies, deposited on cBioPortal as gbc_mskcc_2022, where the per-gene sample counts on OnCo were read. It supports panel testing at diagnosis: one patient in three has a targetable finding.
PAKT gives the trial-based prevalence of PI3K-pathway alteration in first-line metastatic TNBC (one in five) and the strongest signal for AKT inhibition in that subgroup; the phase 3 CAPItello-290 did not confirm it.
It is the practical guide to what to do after transformation: treat it as small-cell lung cancer with platinum and etoposide, expect central nervous system disease, and do not expect a checkpoint inhibitor to help.
The FUSCC cohort is the East Asian reference and the basis of the FUTURE subtype-guided umbrella trial; its LAR findings point to CDK4/6 and HER2-mutant strategies rather than PARP inhibitors for that subtype.
What a prostate cancer sequencing report looks like in practice, and the numerical basis for two clinical rules: do not expect checkpoint immunotherapy to work unless the tumour is mismatch repair deficient, and do not treat a CDK12 alteration as if it were a BRCA alteration.
Regional biology is real but partial: exposures and age differ, some genes differ, and SMAD4 loss emerges as the shared bad-prognosis marker. It is the paper behind the MSK 2018 gallbladder study on cBioPortal (gbc_msk_2018).
It is the caution attached to the sidedness rule: a tumour at the hepatic flexure and one at the caecum are both called right-sided and are not the same disease.
Query for this target: (TITLE:"PIK3CA / PI3K-alpha" OR ABSTRACT:"PIK3CA / PI3K-alpha" OR TITLE:"PIK3CA" OR ABSTRACT:"PIK3CA") 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 PIK3CA / PI3K-alpha, not a curated reading list.
Shares Relay Therapeutics, Cogent Biosciences, Comprehensive molecular characterization of gallbladder carcinoma and potential targets for intervention, FGF / FGFR signalling and the tags driver, kinase.
Shares Classifying colorectal cancer by tumor location rather than sidedness highlights a continuum in mutation profiles and consensus molecular subtypes, Oncogene, Hallmark: sustaining proliferative signalling, Clinical sequencing defines the genomic landscape of metastatic colorectal cancer and the tags driver, kinase.
Shares Oncogene, Hallmark: sustaining proliferative signalling, Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs, Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms and the tags driver, kinase.
Shares Comprehensive molecular portraits of human breast tumours, Oncogene, Vanderbilt-Ingram Cancer Center, Hallmark: sustaining proliferative signalling and the tags driver, kinase.
Shares Cogent Biosciences, PI3K / AKT / mTOR, Receptor tyrosine kinase activation, Small-molecule kinase inhibitors and the tags driver, kinase.
Shares PI3K / AKT / mTOR, Receptor tyrosine kinase activation, Non-small-cell lung cancer and the tags driver, kinase.
Shares Receptor tyrosine kinase activation, Small-molecule kinase inhibitors, Colorectal cancer, Non-small-cell lung cancer and the tags driver, kinase.
Shares Receptor tyrosine kinase activation, Small-molecule kinase inhibitors and the tags driver, kinase.