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| Profile Name | PTEN L325R |
| Gene Variant Detail | |
| Relevant Treatment Approaches | Akt Inhibitor (Pan) Akt1 Inhibitor Akt2 Inhibitor PI3K Inhibitor (Pan) PIK3CB inhibitor |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| PTEN mutant | breast cancer | sensitive | Sapanisertib | Preclinical | Actionable | In a preclinical study, Sapanisertib (MLN0128) induced apoptosis and inhibited MTORC1 signaling in breast cancer cells harboring a PTEN mutation (PMID: 25261369). | 25261369 |
| PTEN mutant | endometrial cancer | sensitive | Dactolisib | Preclinical | Actionable | In a preclinical study, BEZ235 decreased growth of endometrial cancer cells harboring a PTEN nonsense mutation in culture and in xenograft models (PMID: 22662154). | 22662154 |
| PTEN mutant | endometrial cancer | sensitive | Everolimus | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Afinitor (everolimus) inhibited growth of endometrial cancer cells harboring a PTEN nonsense mutation in culture and in xenograft models (PMID: 22662154). | 22662154 |
| PTEN mutant | head and neck squamous cell carcinoma | resistant | Taselisib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, head and neck squamous cell carcinoma cell lines and cell line xenograft models with PTEN alterations were resistant to the apoptotic effects of Taselisib (GDC-0032) (PMID: 26589432). | 26589432 |
| PTEN mutant | uterine cancer | sensitive | GSK2256098 | Preclinical | Actionable | In a preclinical study, uterine cancer cells harboring a PTEN mutation demonstrated sensitivity to GSK2256098, resulting in inhibition of Ptk2 (Fak) phosphorylation, decreased tumor growth, and apoptosis both in culture and in mouse models (PMID: 25833835). | 25833835 |
| PTEN mutant | endometrial cancer | no benefit | Temsirolimus | Phase II | Actionable | In a retrospective study of a Phase II trial, mutation status of PTEN was not associated with progression-free survival or response rate in advanced endometrial cancer patients treated with Torisel (temsirolimus) (PMID: 27016228). | 27016228 |
| PTEN mutant | endometrial cancer | resistant | GSK2636771 | Preclinical | Actionable | In a preclinical study, endometrioid endometrial cancer cell lines harboring PTEN mutations demonstrated resistance to GSK2636771 induced growth inhibition in culture (PMID: 23674493). | 23674493 |
| PTEN mutant | endometrial cancer | resistant | AZD6482 | Preclinical | Actionable | In a preclinical study, endometrioid endometrial cancer cell lines harboring PTEN mutations demonstrated resistance to AZD6482 induced growth inhibition in culture (PMID: 23674493). | 23674493 |
| PTEN mutant | endometrial cancer | resistant | TGX-221 | Preclinical | Actionable | In a preclinical study, endometrioid endometrial cancer cell lines harboring PTEN mutations demonstrated resistance to TGX-221 induced growth inhibition in culture (PMID: 23674493). | 23674493 |
| PTEN mutant | endometrial cancer | resistant | A66 | Preclinical | Actionable | In a preclinical study, endometrioid endometrial cancer cell lines harboring PTEN mutations demonstrated resistance to A66 induced growth inhibition in culture (PMID: 23674493). | 23674493 |
| PTEN mutant | endometrial cancer | sensitive | A66 + AZD6482 | Preclinical | Actionable | In a preclinical study, A66 and AZD6482 combination treatment inhibited viability of endometrioid endometrial cancer cell lines harboring PTEN mutations in culture (PMID: 23674493). | 23674493 |
| PTEN mutant | endometrial cancer | sensitive | A66 + GSK2636771 | Preclinical | Actionable | In a preclinical study, A66 and GSK2636771 combination treatment inhibited viability of endometrioid endometrial cancer cell lines harboring PTEN mutations in culture (PMID: 23674493). | 23674493 |
| PTEN mutant | endometrial cancer | sensitive | Apitolisib | Phase II | Actionable | In a Phase II trial, Apitolisib (GDC-0980) was poorly tolerated, but demonstrated efficacy in endometrial cancer patients harboring mutations in PIK3CA, PTEN, or AKT1 (J Clin Oncol 32:5s, 2014 (suppl; abstr 5513)). | detail... |
| PTEN mutant | uterine cancer | sensitive | GSK2256098 + Paclitaxel | Preclinical | Actionable | In a preclinical study, uterine cancer cells harboring a PTEN mutation were more sensitive to the combination of GSK2256098 and Taxol (paclitaxel) than uterine cancer cells wild-type for PTEN, resulting in decreased tumor growth in culture and in mouse models (PMID: 25833835). | 25833835 |
| PTEN mutant | uterine cancer | sensitive | GSK2256098 + Topotecan | Preclinical | Actionable | In a preclinical study, uterine cancer cells harboring a PTEN mutation were more sensitive to the combination of GSK2256098 and Hycamtin (topotecan) than uterine cancer cells wild-type for PTEN, resulting in decreased tumor growth in culture and in mouse models (PMID: 25833835). | 25833835 |
| PTEN inact mut | prostate adenocarcinoma | sensitive | XL147 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, XL147 inhibited PI3K signaling, growth, and migration of a human prostate adenocarcinoma cell line harboring a PTEN inactivating mutation in culture, and inhibited tumor growth and vascularization in xenograft models (PMID: 25637314). | 25637314 |
| PTEN inact mut | prostate adenocarcinoma | sensitive | Paclitaxel + XL147 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the combination of XL147 and Taxol (paclitaxel) inhibited tumor growth and angiogenesis in xenograft models of a human prostate adenocarcinoma cell line harboring an inactivating mutation in PTEN, with increased efficacy compared to either agent alone (PMID: 25637314). | 25637314 |
| PTEN inact mut | estrogen-receptor positive breast cancer | sensitive | Pictilisib | Preclinical - Cell culture | Actionable | In a preclinical study, a PTEN deficient estrogen-receptor (ER) positive breast cancer cell line demonstrated increased sensitivity to treatment in culture when Pictilisib (GDC-0941) was given at a higher dose for a shorter duration, resulting in inhibition of cell growth (PMID: 26733612). | 26733612 |
| PTEN inact mut | estrogen-receptor positive breast cancer | sensitive | Fulvestrant + Pictilisib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Faslodex (fulvestrant) and PIctilisib (GDC-0941) resulted in decreased cell viability and increased apoptotic activity in PTEN deficient estrogen-receptor (ER) positive breast cancer cells in culture (PMID: 26733612). | 26733612 |
| PTEN mutant | breast cancer | predicted - sensitive | MS417 + Pictilisib | Preclinical - Cell culture | Actionable | In a preclinical study, Pictilisib (GDC-0941) and MS417 in combination resulted in improved growth inhibition and increased cell death compared to either agent alone in a PTEN-mutant breast cancer cell line in culture (PMID: 26058079). | 26058079 |
| PTEN inact mut | kidney cancer | sensitive | LY3023414 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, LY3023414 inhibited proliferation of renal cancer cells harboring PTEN inactivating mutation in culture, resulted in tumor growth inhibition in cell line xenograft models (PMID: 27439478). | 27439478 |
| PTEN inact mut | Advanced Solid Tumor | sensitive | Capivasertib | Preclinical - Cell culture | Actionable | In a preclinical study, Truqap (capivasertib) inhibited growth of various solid tumor cell culture models with inactivating Pten mutations (PMID: 22294718). | 22294718 |
| PTEN mutant | breast cancer | sensitive | CUDC-907 | Preclinical - Cell culture | Actionable | In a preclinical study, CUDC-907 inhibited growth of breast cancer cells lines harboring Pten mutations and/or deletions (PMID: 22693356). | 22693356 |
| PTEN mutant | melanoma | sensitive | BI-69A11 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, BI-69A11 resulted in antitumor activity in a melanoma cell line harboring a PTEN mutation, including induction of cell death in culture, and in xenograft models, tumor growth inhibition and tumor regression (PMID: 19175524). | 19175524 |
| PTEN inact mut | glioblastoma | sensitive | Voxtalisib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, a glioblastoma cell line harboring a PTEN inactivating mutation was sensitive to XL765 (SAR245409), demonstrating inhibition of cell proliferation in culture, and inhibition of tumor growth in cell line xenograft models (PMID: 24634413). | 24634413 |
| PTEN inact mut | glioblastoma | sensitive | SF1126 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, a glioblastoma cell line harboring a PTEN inactivating mutation (PMID: 24634413) was sensitive to SF1126, demonstrating inhibition of tumor growth in cell line xenograft models (PMID: 18172313). | 18172313 24634413 |
| PTEN mutant | hepatocellular carcinoma | decreased response | Sorafenib | Clinical Study - Cohort | Actionable | In a clinical case study, Nexavar (sorafenib) treatment of patients with hepatocellular carcinoma harboring Mtor pathway mutations in PIK3CA, PTEN, TSC2, or TSC1 (n=12), resulted in a lower disease control rate (8.3% vs. 40.2%), shorter progression-free survival (1.9 months vs. 5.3 months) and shorter overall survival (10.4 months vs. 17.9 months) compared to patients without mutations in this pathway (n=67) (PMID: 30373752; NCT01775072). | 30373752 |
| PTEN inact mut | triple-receptor negative breast cancer | predicted - sensitive | Capivasertib + Paclitaxel | Phase II | Actionable | In a Phase II trial (PAKT), addition of Truqap (capivasertib) to Taxol (paclitaxel) as first-line therapy significantly improved median progression-free survival (9.3 vs 3.7 months, HR=0.30, p=0.01) and reduced risk (66%, HR=0.34, p=0.04) compared to Taxol (paclitaxel) alone in patients with metastatic triple-negative breast cancer harboring activating mutations in AKT1 (n=1) or PIK3CA (n=17), or inactivating mutations or gene loss in PTEN (n=13) (PMID: 31841354; NCT02423603). | 31841354 |
| PTEN inact mut | lung non-small cell carcinoma | predicted - resistant | Osimertinib | Case Reports/Case Series | Actionable | In a retrospective analysis, inactivating PTEN mutations were identified in 3 of 100 patients with non-small cell lung cancer at treatment discontinuation of Tagrisso (osimertinib) (PMID: 31839416). | 31839416 |
| PTEN mutant | glioblastoma | no benefit | Buparlisib + Capmatinib | Phase Ib/II | Actionable | In a Phase Ib/II trial, combination of Buparlisib (BKM120) and Tabrecta (capmatinib) did not reach target exposure due to potential drug-drug interaction, and demonstrated minimal activity in patients with glioblastoma harboring PTEN alterations including deletion, mutation, or negative protein expression, therefore, Phase II of the trial was not initiated (PMID: 31776899; NCT01870726). | 31776899 |
| PTEN mutant | lung adenocarcinoma | no benefit | Capivasertib | Case Reports/Case Series | Actionable | In a Phase II trial (NLMT), Truqap (capivasertib) treatment did not result in a confirmed response (0/8) or durable clinical benefit (0/8) in patients with lung adenocarcinoma harboring mutations in PIK3CA, PTEN, or AKT, thus the cohort was closed due to futility (PMID: 32669708, NCT02664935). | 32669708 |
| PTEN mutant | skin melanoma | not applicable | N/A | Guideline | Risk Factor | Germline PTEN mutations or polymorphisms are associated with increased risk of developing single or multiple primary cutaneous melanomas (NCCN.org). | detail... |
| PTEN inact mut | triple-receptor negative breast cancer | no benefit | Ipatasertib + Paclitaxel | Phase II | Actionable | In a Phase II trial (LOTUS), Ipatasertib (GDC-0068) in combination with Abraxane (paclitaxel) resulted a median progression free survival of 6.2 vs 4.9 months with placebo in triple-receptor negative breast cancer patients harboring activating mutations in PIK3CA or AKT1, or inactivating mutations in PTEN (PMID: 28800861; NCT02162719). | 28800861 |
| PTEN inact mut | triple-receptor negative breast cancer | no benefit | Ipatasertib + Paclitaxel | Phase III | Actionable | In a Phase III trial (IPATunity 130), the addition of Ipatasertib (GDC-0068) to treatment with Abraxane (paclitaxel) did not result in improved progression-free survival in patients with triple-negative breast cancer harboring PIK3CA and/or AKT activating mutations or PTEN alterations, with a median PFS of 7.4 months with Ipatasertib (GDC-0068) plus Abraxane (paclitaxel) vs. 6.1 months with placebo plus Abraxane (paclitaxel) (SABCS 2020, Abstract GS3-04; NCT03337724). | detail... |
| PTEN inact mut | endometrial cancer | no benefit | LY3023414 | Phase II | Actionable | In a Phase II trial, patients with advanced endometrial cancer harboring a PI3K pathway mutation, including PTEN inactivating mutations, demonstrated only a modest clinical benefit with an overall response rate of 16% (4/25), a clinical benefit rate of 28% (7/25) at 12 weeks, a progression-free survival of 2.5 months, and overall survival of 9.2 months when treated with LY3023414 (PMID: 31880826; NCT01775072). | 31880826 |
| PTEN inact mut | castration-resistant prostate carcinoma | predicted - sensitive | CC-115 + Enzalutamide | Phase I | Actionable | In a Phase Ib trial, Xtandi (enzalutamide) plus CC-115 was safe and led to a PSA reduction >= 50% (PSA50) in 80% (32/40) and >=90% (PSA90) in 58% (23/40) of patients with metastatic castration-resistant prostate cancer at 12 weeks, and patients harboring PTEN mutation or deletion (n=11) achieved PSA50 of 91%, PSA90 of 55%, and median radiographic progression-free survival was not reached, compared to 75%, 55%, and 19.6 mo, respectively, in PTEN wild-type patients (n=20) (PMID: 37980367; NCT02833883). | 37980367 |
| PTEN inact mut | glioblastoma | predicted - sensitive | Atezolizumab + Ipatasertib | Phase I | Actionable | In a Phase I trial (Ice-CAP), combination treatment with Ipatasertib (GDC-0068) and Tecentriq (atezolizumab) demonstrated safety and tolerability in glioblastoma patients harboring PTEN loss or PTEN mutations, and led to a clinical benefit rate of 29% (2/7), with 1 pathological complete response, and stable disease in 1 patient of 7 patients (Cancer Res 2021;81(13_Suppl):Abstract nr CT120; NCT03673787). | detail... |
| PTEN mutant | gastrointestinal system cancer | decreased response | Pembrolizumab | Clinical Study - Cohort | Actionable | In a retrospective analysis, patients with MSI high, dMMR gastrointestinal tumors including gastric (n=18), colorectal (n=17), cholangiocarcinoma (n=5), small intestine (n=2), pancreatic (n=2), and duodenal cancer (n=1) harboring PTEN mutations demonstrated a decreased objective response rate (21.4 vs 54.8%), overall survival (15.2 vs 25.7 mo), and progression-free survival (4.3 vs 15.6 mo) compared to PTEN-wild-type patients when treated with Keytruda (pembrolizumab) or Opdivo (nivolumab) (PMID: 33926917). | 33926917 |
| PTEN mutant | gastrointestinal system cancer | decreased response | Nivolumab | Clinical Study - Cohort | Actionable | In a retrospective analysis, patients with MSI high, dMMR gastrointestinal tumors including gastric (n=18), colorectal (n=17), cholangiocarcinoma (n=5), small intestine (n=2), pancreatic (n=2), and duodenal cancer (n=1) harboring PTEN mutations demonstrated a decreased objective response rate (21.4 vs 54.8%), overall survival (15.2 vs 25.7 mo), and progression-free survival (4.3 vs 15.6 mo) compared to PTEN-wild-type patients when treated with Keytruda (pembrolizumab) or Opdivo (nivolumab) (PMID: 33926917). | 33926917 |
| PTEN inact mut | head and neck cancer | predicted - sensitive | RMC-5552 | Case Reports/Case Series | Actionable | In a Phase I/Ib trial, RMC-5552 treatment resulted in an objective response rate of 20% (1/5) and 3 stable disease in patients with advanced solid tumors, with 1 partial response observed in a patient with head and neck cancer harboring a pathogenic PTEN mutation (J of Clin Oncol40, no. 16_suppl (June 01, 2022) 3098; NCT04774952). | detail... |
| PTEN inact mut | breast cancer | predicted - sensitive | TAS-117 | Case Reports/Case Series | Actionable | In a Phase II trial, TAS-117 treatment demonstrated tolerability in patients with advanced solid tumors harboring germline inactivating PTEN mutations, and resulted in an unconfirmed partial response in one patient with breast cancer and target tumor lesion shrinkage of approximately 15% and stable disease lasting more than 8 months in another breast cancer patient (Ann Oncol (2022) 33 (suppl_7): S754-S755; NCT04770246). | detail... |
| PTEN inact mut | Advanced Solid Tumor | predicted - sensitive | Temsirolimus | Phase II | Actionable | In a Phase II trial (TAPUR), Torisel (temsirolimus) treatment resulted in a disease control rate of 26% (7/27, 2 partial responses and 5 with stable disease >=16 weeks) and an objective response rate of 7% (2/27) in patients with advanced solid tumors harboring inactivating PTEN mutations, with a median progression-free survival of 10 weeks and a median overall survival of 32 weeks (Cancer Res (2023) 83 (8_Supplement): CT231; NCT02693535). | detail... |
| PTEN inact mut | breast cancer | predicted - sensitive | AZD5991 + AZD8186 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the combination of AZD5991 and AZD8186 synergistically inhibited proliferation and induced apoptosis in a triple-negative breast cancer cell line and hormone receptor-positive breast cancer cell line each harboring a PTEN inactivating mutation in culture and inhibited tumor growth in cell line xenograft models (PMID: 36241868). | 36241868 |
| PTEN inact mut | breast cancer | predicted - sensitive | AZD5991 + Capivasertib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the combination of AZD5991 and Truqap (capivasertib) synergistically inhibited proliferation and induced apoptosis in a triple-negative breast cancer cell line and hormone-receptor positive breast cancer cell line each harboring a PTEN inactivating mutation in culture and inhibited tumor growth in cell line xenograft models (PMID: 36241868). | 36241868 |
| PTEN inact mut | Advanced Solid Tumor | no benefit | Atezolizumab + Ipatasertib | Phase II | Actionable | In a Phase II trial (CRAFT), treatment with Ipatasertib (GDC-0068) plus Tecentriq (atezolizumab) demonstrated safety but limited clinical benefit in advanced solid tumor patients harboring PI3K-AKT pathway mutations (n=13), including PTEN deletion/inactivating mutations or activating mutations in PIK3CA or AKT1, with a partial response in a breast cancer patient with AKT1 E17K and stable disease in a prostate cancer patient with PTEN loss (Ann Oncol (2023) 34 (suppl_2): S256-S257;NCT04551521). | detail... |
| PTEN inact mut | Advanced Solid Tumor | predicted - sensitive | Copanlisib + Nivolumab | Phase II | Actionable | In a Phase II trial (BaCoN), treatment with the combination of Aliqopa (copanlisib) and Opdivo (nivolumab) was well tolerated in patients with advanced solid tumors harboring an inactivating mutation in PTEN, and resulted in a complete response/partial response (CR/PR) in 20% (3/15, 3 cPR) and a clinical benefit rate (CR or PR or stable disease > 4 months) of 33% (Ann Oncol 34 (2023): S487-S488; NCT04317105). | detail... |
| PTEN mutant | breast cancer | not applicable | N/A | Guideline | Risk Factor | Germline PTEN mutations result in Cowden syndrome, which is associated with increased risk of developing breast cancer (NCCN.org). | detail... |
| PTEN inact mut | Advanced Solid Tumor | no benefit | Talazoparib | Phase II | Actionable | In a Phase II trial, Talzenna (talazoparib) treatment resulted in limited clinical benefit in patients with advanced solid tumors harboring PTEN deleterious mutations or loss (by IHC), with a clinical benefit rate of 9.4% (1/14, 1 with stable disease >/=24 weeks) and a median overall survival of 8.5 months and a median progression-free survival of 7.7 weeks (PMID: 39085400; NCT02286687). | 39085400 |
| PTEN inact mut | Advanced Solid Tumor | no benefit | LY3023414 | Case Reports/Case Series | Actionable | In a Phase II trial (NCI-COG Pediatric MATCH), Samotolisib (LY3023414) treatment resulted in no objective responses in pediatric patients with advanced solid tumors harboring PI3K/mTOR pathway mutations, including PTEN (n=6), PIK3CA (n=5), TSC1 (n=2), TSC2 (n=3), and PIK3R1 (n=1), and resulted in a 3-month progression-free survival of 12%, a 6-month overall survival of 44%, and a 12-month overall survival of 15% (PMID: 39298693; NCT03155620). | 39298693 |