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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. This dossier gathers the 13 products (8 approved), 66 trials, 14 pathways and 6 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.
PIK3CA encodes the catalytic subunit of PI3K; H1047R and E545K are the hotspots.
| 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.
| Residue | Kind | How common | What it does | Addressed by | Defeats | Source |
|---|---|---|---|---|---|---|
| E542K / E545K 545 | Activating | Helical hotspots; with H1047R they account for about 80% of PIK3CA mutations | Relieve inhibition by the p85 regulatory subunit. Drug response is similar across hotspots with alpelisib and inavolisib; mutant-selective inhibitors that spare wild-type p110alpha are in trials. | - | Samuels et al., Science 2004 | |
| H1047R / H1047L 1047 | Activating | The single most common PIK3CA allele | Kinase-domain hotspot that increases membrane association; the allele most mutant-selective programmes target first. | - | Samuels et al., Science 2004 |
Frequencies are quoted from the source on each row; a blank means no figure was sourced, not that it is rare. Domain boundaries are approximate. Sources for the map: Cancer Hotspots (MSK) · COSMIC: PIK3CA.
| Modality | Approved | Phase 3 | Phase 2 | Withdrawn or failed |
|---|---|---|---|---|
| Small molecule 11 | ||||
| Degrader 1 | - | - | - | |
| Test or device 1 | - | - | - |
| Trial | Setting | Result | Products | ||
|---|---|---|---|---|---|
| 3 | Active | A Phase III Double-blind Randomised Study Assessing the Efficacy and Safety of Capivasertib/+Paclitaxel vs Placebo+Paclitaxel as First-line Treatment for Patients With Locally Advanced (Inoperable) or Metastatic TNBC. | Overall survival 17.7 vs 18.0 months (HR 0.92, p 0.32) overall and 20.4 vs 20.4 months (HR 1.05) in PIK3CA/AKT1/PTEN-altered tumours; PFS 5.6 vs 5.1 months (HR 0.72). | ||
ALASCCA NCT02647099 | 3 | Positive | Resected stage I-III rectal or stage II-III colon cancer with somatic PIK3CA (exon 9/20) or other PI3K-pathway alterations: aspirin 160 mg/day for 3 years vs placebo | 3-year recurrence HR 0.49 (PIK3CA hotspot) and 0.42 (other PI3K alterations). | |
CAPItello-281 NCT04493853 | 3 | Positive | De novo metastatic hormone-sensitive prostate cancer with PTEN deficiency: abiraterone + capivasertib vs abiraterone + placebo | Median rPFS 33.2 against 25.7 months, HR 0.81 (95% CI 0.66 to 0.98, p=0.034); OS HR 0.90 at 26.4% maturity; approved 2026. | |
COMPETE NCT03049189 | 3 | Positive | Progressive grade 1-2 SSTR-positive GEP-NETs: 177Lu-edotreotide vs everolimus | PFS 23.9 vs 14.1 months, HR 0.67. | |
evERA NCT05306340 | 3 | Positive | ER+/HER2- advanced breast cancer after CDK4/6 inhibitor: giredestrant + everolimus vs standard endocrine therapy + everolimus | PFS HR 0.56 (ITT); HR 0.38 (ESR1-mutant). | |
IPATunity130 NCT03337724 | 3 | Negative | PIK3CA, AKT1 or PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer, no prior chemotherapy for advanced disease: first-line paclitaxel with ipatasertib or placebo (cohort A), 30 countries including the United Kingdom | PFS 7.4 vs 6.1 months (HR 1.02, 0.71 to 1.45); OS 24.4 vs 24.9 months (HR 1.08). Negative. | |
| 3 | Active | A Randomized, Multicenter, Open-Label, Phase 3 Study of Acalabrutinib (ACP-196) Versus Investigator's Choice of Either Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Subjects With R/R Chronic Lymphocytic Leukemia | - | ||
LITESPARK-005 NCT04195750 | 3 | Positive | Advanced clear-cell RCC after PD-1/PD-L1 and VEGF-TKI: belzutifan vs everolimus | PFS HR 0.75; ORR 22.7% vs 3.5%; OS not significant. | |
CAPItello-291 NCT04305496 | 3 | Positive | HR+/HER2- advanced breast cancer after aromatase inhibitor (± CDK4/6): capivasertib + fulvestrant vs placebo + fulvestrant | PFS HR 0.60 overall; HR 0.50 in AKT-pathway-altered. | |
CLEAR (KEYNOTE-581) NCT02811861 | 3 | Positive | Untreated advanced clear-cell RCC: lenvatinib + pembrolizumab vs sunitinib (and lenvatinib + everolimus arm) | PFS 23.9 vs 9.2 months (HR 0.39); OS HR 0.79. | |
SOLAR-1 NCT02437318 | 3 | Positive | HR+/HER2- advanced breast cancer after aromatase inhibitor: alpelisib + fulvestrant vs placebo + fulvestrant, by PIK3CA status | PFS 11.0 vs 5.7 months, HR 0.65 (PIK3CA-mutant). | |
CheckMate 025 NCT01668784 | 3 | Positive | Advanced clear cell renal cell carcinoma after one or two anti-angiogenic therapies: nivolumab against everolimus | Nivolumab improved overall survival and response rate over everolimus in previously treated clear cell renal cell carcinoma; approved in November 2015. | |
BOLERO-2 NCT00863655 | 3 | Positive | Postmenopausal hormone receptor-positive, HER2-negative advanced breast cancer after a non-steroidal aromatase inhibitor: exemestane with everolimus or placebo | Everolimus plus exemestane more than doubled progression-free survival compared with exemestane alone; approved in July 2012. | |
RADIANT-3 and RADIANT-4 NCT00510068 | 3 | Positive | Progressive pancreatic NETs (RADIANT-3, n=410) and lung/GI NETs (RADIANT-4, n=302): everolimus vs placebo | PFS HR 0.35 (pNET) and 0.48 (lung/GI). | |
| 3 | Active | A Phase IIIB Study to Evaluate the Use of Capivasertib in Combination With Fulvestrant in Patients With HR+ / HER2- Advanced Breast Cancer Who Have Relapsed/Progressed on ET and CDK4/6 Inhibitor Reflecting Real World Clinical Practice in Spain | - | ||
| 3 | Recruiting | A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Inavolisib Plus a CDK4/6 Inhibitor and Letrozole Versus Placebo Plus a CDK4/6 Inhibitor and Letrozole in Patients With Endocrine-Sensitive PIK3CA-Mutated, Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer | - | ||
| 3 | Recruiting | A Phase III, Multicenter, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Inavolisib Plus Fulvestrant Versus Alpelisib Plus Fulvestrant in Patients With Hormone Receptor-Positive, HER2-Negative, PIK3CA Mutated, Locally Advanced or Metastatic Breast Cancer Who Progressed During or After CDK4/6 Inhibitor and Endocrine Combination Therapy | - | ||
| 3 | Recruiting | A Multicentre, Open-label, Phase 3, Randomised Controlled Trial of Duvelisib Versus Investigator's Choice of Gemcitabine or Bendamustine in Patients With Relapsed/Refractory Nodal T Cell Lymphoma With T Follicular Helper (TFH) Phenotype | - | ||
| 3 | Recruiting | A Phase 3, Open-Label, Randomized Study of BGB-16673 Compared to Investigator's Choice (Idelalisib Plus Rituximab or Bendamustine Plus Rituximab or Venetoclax Plus Rituximab Retreatment) in Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Previously Exposed to Both BTK and BCL2 Inhibitors | - | ||
| 3 | Recruiting | A Phase 2, Randomized, Open-Label Dose Optimization and Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of LY4064809 Combined With a CDK4/6 Inhibitor and Endocrine Therapy in Adults With HR+, HER2-Advanced Breast Cancer With a PIK3CA Mutation Who Received No Prior Treatment for Advanced Breast Cancer (PIKALO-2) | - | ||
| 3 | Recruiting | A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Inavolisib in Combination With Phesgo Versus Placebo in Combination With Phesgo As Maintenance Therapy After First Line Induction Therapy in Participants With PIK3CA-Mutated HER2-Positive Locally Advanced or Metastatic Breast Cancer | - | ||
| 3 | Active | A Phase Ib/III, Open-label, Randomised Study of Capivasertib Plus CDK4/6 Inhibitors and Fulvestrant Versus CDK4/6 Inhibitors and Fulvestrant in Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced, Unresectable or Metastatic Breast Cancer (CAPItello-292) | - | ||
| 3 | Active | A Phase IIIb Single Arm, 2 Cohorts Study Assessing the Efficacy and Safety of Capivasertib+ Fulvestrant as Treatment for Locally Advanced(Inoperable) or Metastatic Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) Breast Cancer Following Recurrence or Progression On or After Treatment With Endocrine Therapy in Chinese Patients | - | ||
| 3 | Recruiting | Efficacy, Safety and Patient-reported Outcomes of Peptide Receptor Radionuclide Therapy With 177Lu-edotreotide Compared to Everolimus in Somatostatin Receptor Positive Neuroendocrine Tumors of the Lung and Thymus. | - | ||
| 3 | Active | Phase 3, Open-Label, Randomized, Study Comparing Gedatolisib Combined With Fulvestrant & With or Without Palbociclib to Standard-of-Care Therapies in Patients With HR-Positive, HER2-Negative Advanced Breast Cancer Previously Treated With a CDK4/6 Inhibitor in Combination w/Non-Steroidal Aromatase Inhibitor Therapy | - | ||
| 3 | Active | A Prospective, Randomised, Controlled, Open-label, Multicentre Study to Evaluate Efficacy, Safety and Patient-Reported Outcomes of Peptide Receptor Radionuclide Therapy (PRRT) With 177Lu-Edotreotide Compared to Best Standard of Care in Patients With Well-differentiated Aggressive Grade 2 and Grade 3, Somatostatin Receptor-Positive (SSTR+), Neuroendocrine Tumours of GastroEnteric or Pancreatic Origin | - | ||
| 3 | Recruiting | VIKTORIA-2: A Randomized, Open-Label, Phase 3 Study Evaluating Efficacy and Safety of Gedatolisib With Endocrine Therapy and Palbociclib vs Endocrine Therapy and Ribociclib as First-Line Treatment in Patients With HR-Positive and HER2-Negative Advanced Breast Cancer | - | ||
| 3 | Recruiting | A Phase 3 Open-Label Randomized Study Assessing the Efficacy and Safety of RLY-2608 + Fulvestrant Versus Capivasertib + Fulvestrant as Treatment for PIK3CA-mutant Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) Locally Advanced or Metastatic Breast Cancer Following Recurrence or Progression On or After Treatment With a CDK4/6 Inhibitor | - | ||
| 3 | Active | EPIK-B2: A Two Part, Phase III, Multicenter, Randomized (1:1), Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of Alpelisib (BYL719) in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy in Patients With HER2-positive Advanced Breast Cancer With a PIK3CA Mutation | - | ||
| 3 | Active | A Phase III Double-Blind, Randomised, Placebo-Controlled Study Assessing the Efficacy and Safety of Capivasertib + Docetaxel Versus Placebo + Docetaxel as Treatment for Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC) | - |
PIK3CA mutation, PTEN loss, or AKT1 E17K sustain growth independent of ER.
More receptor, or mutations (F877L, T878A) that turn antagonists into agonists.
Truncated receptor lacking the ligand-binding domain is constitutively active and invisible to enzalutamide.
RB1/TP53 loss enables transdifferentiation; AR-indifferent, DLL3-positive, PSMA-negative.
Reciprocal feedback between AR and PI3K pathways.
GR drives an AR-like transcriptional programme under enzalutamide.
Chronic myeloid leukaemia is caused by one broken gene: two chromosomes swap pieces and glue a kinase (ABL1) to a protein that forces it permanently on. Imatinib, the first drug to target it, turned a fatal disease into a manageable one, and later drugs cover the mutations that escape it.
Which nodes have drugs →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.
Which nodes have drugs →This KEGG map shows how chemicals in tobacco smoke, industrial pollutants, plastics and hormones cause cancer without directly damaging DNA: they switch on receptors that drive growth signalling. It matters because these routes explain part of the cancer burden from smoking, dioxins and hormone exposure, and several of the receptors are druggable.
Which nodes have drugs →Tumours come in three immune weathers: inflamed (T cells inside, checkpoint drugs work), excluded (T cells stuck at the edge), and desert (no T cells at all). Most common cancers are excluded or desert, and turning them 'hot' is the central problem of immunotherapy.
Which nodes have drugs →This KEGG map traces the step-by-step genetic route from normal bowel lining to colorectal cancer: APC loss unleashes Wnt, KRAS mutation drives growth, then TP53 and TGF-beta/SMAD4 loss remove the last brakes, or alternatively mismatch repair fails and mutations pile up. Knowing which route a tumour took decides which drugs work.
Which nodes have drugs →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.
Which nodes have drugs →Fibroblast growth factor receptors are growth antennas on the cell surface. Bladder cancer mutates FGFR3, bile duct cancer fuses FGFR2 to other genes, and stomach cancer overproduces FGFR2b; each has its own drug, and each brings a tell-tale side effect (high phosphate) because the same receptors control phosphate in the kidney.
Which nodes have drugs →This KEGG map splits stomach cancer into two routes: the intestinal type that accumulates TP53, APC and HER2 changes step by step, and the diffuse type driven by loss of the cell glue E-cadherin plus MET or FGFR2 amplification. It matters because HER2, FGFR2, claudin 18.2 and PD-1 status now decide first-line treatment.
Which nodes have drugs →This KEGG map shows the two genetic roads to glioblastoma: primary tumours amplify EGFR and lose PTEN and p16, secondary tumours from lower-grade astrocytomas over-express PDGF and CDK4 and lose TP53 and RB. It explains why growth-factor and cell-cycle drugs are the main targeted options in brain tumours, and why paediatric low-grade gliomas with BRAF changes respond to MAPK inhibitors.
Which nodes have drugs →This KEGG map shows the order of genetic hits that turn normal pancreatic duct cells into ductal adenocarcinoma: KRAS mutation first, then loss of the p16 brake, then loss of TP53, SMAD4 and BRCA2. It matters because nearly every pancreatic cancer is driven by KRAS, which until recently had no drug.
Which nodes have drugs →The cell's 'grow and survive' circuit. Growth signals from the surface switch on PI3K, which switches on AKT, which switches on mTOR, which builds proteins and blocks self-destruction.
Which nodes have drugs →This KEGG map shows how sugar-coated proteins on the cell surface and in the surrounding matrix (proteoglycans such as syndecans, glypicans, CD44 and decorin) catch growth factors and hand signals to receptors. It matters because these molecules set how loudly growth signals reach the tumour cell and how easily it invades.
Which nodes have drugs →Growth-factor receptors are antennas on the cell surface that pair up when a signal lands and switch on the growth relays inside. Cancers mutate, multiply, or fuse these antennas so they broadcast 'grow' with no signal at all. Most targeted drugs, antibodies and ADCs start here.
Which nodes have drugs →When a drug blocks a cancer's engine, the cancer has five ways back: change the part the drug binds, make more of it, take a side road, switch to a different engine altogether, or stop letting the drug in. Knowing which route a tumour took decides the next drug.
Which nodes have drugs →| 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 | |
| therascreen PIK3CA RGQ PCR Kit QIAGEN · FDA CDx 2019 | PCR | Mutation detected (alpelisib plus fulvestrant); plasma negative reflexes to tissue |
No model entry for this target yet; check the cancer entries on the models page.
No open questions recorded for this target yet. Suggest one.
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.
The dossier as machine-readable JSON, at /api/v1/dossiers/pik3ca.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/pik3ca.json. Licence CC BY-NC 4.0.