{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T03:15:21Z","timestamp":1792638921501,"version":"4.5.0"},"reference-count":47,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"4","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO Precis Oncol"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>PURPOSE<\/jats:title>\n                    <jats:p>\n                      To comprehensively characterize the clinical and genomic landscapes of\n                      <jats:italic toggle=\"yes\">PIK3CA<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">AKT1<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">PTEN<\/jats:italic>\n                      alterations and examine their functional and therapeutic implications in AKT-driven breast cancer.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Comprehensive genomic profiling of 51,767 breast tumors was performed using FoundationOne CDx or FoundationOne. We examined the genomic landscape of\n                      <jats:italic toggle=\"yes\">PIK3CA<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">AKT1<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">PTEN<\/jats:italic>\n                      alterations and their distribution across clinical variables of interest. Prior deep mutational scanning (DMS) data were used to functionally characterize clinical\n                      <jats:italic toggle=\"yes\">PTEN<\/jats:italic>\n                      variants. Real-world clinical outcomes were assessed in patients treated with capivasertib plus fulvestrant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      A total of 29,157 variants were identified across the three genes, including pathogenic variants and variants of uncertain significance. The most frequently altered gene was\n                      <jats:italic toggle=\"yes\">PIK3CA<\/jats:italic>\n                      (37.4% of cases), followed by\n                      <jats:italic toggle=\"yes\">PTEN<\/jats:italic>\n                      (13.5%) and\n                      <jats:italic toggle=\"yes\">AKT1<\/jats:italic>\n                      (5.4%). The most common alterations in each gene were\n                      <jats:italic toggle=\"yes\">PIK3CA<\/jats:italic>\n                      H1047R (35.6% of\n                      <jats:italic toggle=\"yes\">PIK3CA<\/jats:italic>\n                      -altered cases), E545K (19.7%), and E542K (11.7%);\n                      <jats:italic toggle=\"yes\">AKT1<\/jats:italic>\n                      E17K (69.7%); and\n                      <jats:italic toggle=\"yes\">PTEN<\/jats:italic>\n                      homozygous copy number deletion (37.3%).\n                      <jats:italic toggle=\"yes\">PIK3CA<\/jats:italic>\n                      alterations were less prevalent in patients of African genetic ancestry (27.1% vs 38.6% in European genetic ancestry), whereas\n                      <jats:italic toggle=\"yes\">AKT1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">PTEN<\/jats:italic>\n                      alterations were balanced across ancestries. DMS data on missense\n                      <jats:italic toggle=\"yes\">PTEN<\/jats:italic>\n                      mutations revealed that 32.5% showed discordant effects on protein stability and phosphatase activity. A subset of patients with rare AKT pathway variants derived meaningful progression-free survival and overall survival benefit from capivasertib.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>\n                      Here, we present the landscape of\n                      <jats:italic toggle=\"yes\">PIK3CA<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">AKT1<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">PTEN<\/jats:italic>\n                      alterations in, to our knowledge, the largest clinical cohort examined to date. The functional complexity of rare\n                      <jats:italic toggle=\"yes\">PTEN<\/jats:italic>\n                      variants underscores the need for functional validation by tools such as DMS. Rare AKT pathway variants may predict clinical benefit from AKT inhibitors and warrant further clinical investigation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1200\/po-25-00609","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T19:59:10Z","timestamp":1775764750000},"update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":3,"title":["Clinicogenomic Landscape and Function of\n                    <i>PIK3CA<\/i>\n                    ,\n                    <i>AKT1<\/i>\n                    , and\n                    <i>PTEN<\/i>\n                    Mutations in Breast Cancer"],"prefix":"10.1200","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1806-1269","authenticated-orcid":true,"given":"Jacqueline J.","family":"Tao","sequence":"first","affiliation":[{"name":"Columbia University Irving Medical Center, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7276-8084","authenticated-orcid":true,"given":"Saumya D.","family":"Sisoudiya","sequence":"additional","affiliation":[{"name":"Foundation Medicine Inc, Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0777-7555","authenticated-orcid":true,"given":"Hanna","family":"Tukachinsky","sequence":"additional","affiliation":[{"name":"Foundation Medicine Inc, Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0106-9096","authenticated-orcid":true,"given":"Alexa B.","family":"Schrock","sequence":"additional","affiliation":[{"name":"Foundation Medicine Inc, Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ericka M.","family":"Ebot","sequence":"additional","affiliation":[{"name":"Foundation Medicine Inc, Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7790-5615","authenticated-orcid":true,"given":"Smruthy","family":"Sivakumar","sequence":"additional","affiliation":[{"name":"Foundation Medicine Inc, Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2988-0537","authenticated-orcid":true,"given":"Ethan S.","family":"Sokol","sequence":"additional","affiliation":[{"name":"Foundation Medicine Inc, Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1779-484X","authenticated-orcid":true,"given":"Neil","family":"Vasan","sequence":"additional","affiliation":[{"name":"Department of Medicine, New York University Grossman School of Medicine, New York, NY"},{"name":"Perlmutter Cancer Center, NYU Langone Health, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","reference":[{"key":"e_1_3_8_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00633-1"},{"key":"e_1_3_8_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00209-1"},{"key":"e_1_3_8_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-021-00218-4"},{"key":"e_1_3_8_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1813904"},{"key":"e_1_3_8_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2404625"},{"key":"e_1_3_8_7_2","volume-title":"FDA Approves Capivasertib with Fulvestrant for Breast Cancer","author":"U.S. Food and Drug Administration","year":"2023","unstructured":"U.S. Food and Drug Administration: FDA Approves Capivasertib with Fulvestrant for Breast Cancer. 2023. https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-approves-capivasertib-fulvestrant-breast-cancer"},{"key":"e_1_3_8_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2214131"},{"key":"e_1_3_8_9_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2016.0891"},{"key":"e_1_3_8_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.08.008"},{"key":"e_1_3_8_11_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-6854"},{"key":"e_1_3_8_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12282-024-01639-6"},{"key":"e_1_3_8_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-024-07376-w"},{"key":"e_1_3_8_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2696"},{"key":"e_1_3_8_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0264138"},{"key":"e_1_3_8_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.10.003"},{"key":"e_1_3_8_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0122-z"},{"key":"e_1_3_8_18_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-021-00984-x"},{"key":"e_1_3_8_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.03.018"},{"key":"e_1_3_8_20_2","volume-title":"Database Characterization Guide","author":"Flatiron Health","year":"2025","unstructured":"Flatiron Health: Database Characterization Guide. 2025. https:\/\/flatiron.com\/database-characterization"},{"key":"e_1_3_8_21_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.3241"},{"key":"e_1_3_8_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1096502"},{"key":"e_1_3_8_23_2","doi-asserted-by":"publisher","DOI":"10.7150\/jca.52993"},{"key":"e_1_3_8_24_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25052695"},{"key":"e_1_3_8_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.09.056"},{"key":"e_1_3_8_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.09.033"},{"key":"e_1_3_8_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41523-019-0126-6"},{"key":"e_1_3_8_28_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.25118"},{"key":"e_1_3_8_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2019.11.006"},{"key":"e_1_3_8_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy497"},{"key":"e_1_3_8_31_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.285.5436.2122"},{"key":"e_1_3_8_32_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201404402"},{"key":"e_1_3_8_33_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.010710"},{"key":"e_1_3_8_34_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-016-2626-1"},{"key":"e_1_3_8_35_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-020-01284-9"},{"key":"e_1_3_8_36_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-22-2115"},{"key":"e_1_3_8_37_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0701005104"},{"key":"e_1_3_8_38_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-1654"},{"key":"e_1_3_8_39_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw9032"},{"key":"e_1_3_8_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29638-1"},{"key":"e_1_3_8_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz133"},{"key":"e_1_3_8_42_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdw562"},{"key":"e_1_3_8_43_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-24-0465"},{"key":"e_1_3_8_44_2","unstructured":"AstraZeneca: Update on the CAPItello-290 phase III trial for truqap plus chemotherapy in advanced or metastatic triple-negative breast cancer. 2024. https:\/\/www.astrazeneca.com\/media-centre\/press-releases\/2024\/update-on-capitello-290-phase-iii-trial.html"},{"key":"e_1_3_8_45_2","article-title":"Comparison of PIK3CA mutation prevalence in breast cancer across predicted ancestry populations","author":"Chen JW","unstructured":"Chen JW, Murugesan K, Newberg JY, et al: Comparison of PIK3CA mutation prevalence in breast cancer across predicted ancestry populations. JCO Precis Oncol 10.1200\/PO.22.00341","journal-title":"JCO Precis Oncol"},{"key":"e_1_3_8_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06616-0"},{"key":"e_1_3_8_47_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-018-4811-x"},{"key":"e_1_3_8_48_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-020-05693-4"}],"updated-by":[{"DOI":"10.1200\/po-26-01021","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000}}],"container-title":["JCO Precision Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascopubs.org\/doi\/pdfdirect\/10.1200\/PO-25-00609","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:59:08Z","timestamp":1791921548000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascopubs.org\/doi\/10.1200\/PO-25-00609"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4]]},"references-count":47,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1200\/PO-25-00609"],"URL":"https:\/\/doi.org\/10.1200\/po-25-00609","relation":{},"ISSN":["2473-4284"],"issn-type":[{"value":"2473-4284","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4]]},"assertion":[{"value":"2025-07-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-19","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2500609"}}