{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T15:07:07Z","timestamp":1792681627435,"version":"4.5.0"},"reference-count":18,"publisher":"American Medical Association (AMA)","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"Importance<\/jats:title>PIK3CA<\/jats:italic> mutations may be associated with outcomes of patients with ERBB2\/HER2-positive early breast cancer (EBC).<\/jats:p><\/jats:sec>Objectives<\/jats:title>To assess if PIK3CA<\/jats:italic> mutations among patients with ERBB2\/HER2-positive EBC are associated with treatment response and outcome, and if these associations vary by hormone receptor (HR) status or intrinsic molecular subtype (IMS).<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>This cohort study derived data on 184 patients from the phase 3 neoadjuvant Cancer and Leukemia Group B (CALGB) 40601 trial that enrolled patients with ERBB2\/HER2-positive EBC in North America between January 1, 2008, and December 31, 2012. Participants received neoadjuvant paclitaxel with trastuzumab, lapatinib, or both. Statistical analysis was performed from March 23, 2022, to March 9, 2023.<\/jats:p><\/jats:sec>Exposures<\/jats:title>Gene expression profiling by RNA sequencing with Prediction Analysis of Microarray 50\u2013determined IMS and PIK3CA<\/jats:italic> mutations from whole-exome sequencing were obtained from pretreatment biopsies from 184 of 305 trial participants.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>The primary end point was pathologic complete response (pCR) and the secondary end point of event-free survival (EFS). The association of PIK3CA<\/jats:italic> mutations with pCR and EFS by HR status and IMS was estimated using logistic and Cox proportional hazards regression models.<\/jats:p><\/jats:sec>Results<\/jats:title>All 184 participants were women, with a median age of 49 years (range 24-75 years). A total of 121 participants (66%) had clinical stage II tumors; 32 (17%) had PIK3CA<\/jats:italic> mutations, most frequently H1047R (38% [12 of 32]) and E545K (22% [7 of 32]). PIK3CA<\/jats:italic> mutations were present in 20 of 102 cases of HR-positive EBC (20%) and 12 of 82 cases HR-negative EBC (15%) and varied by IMS (luminal B, 9 of 25 [36%]; luminal A, 2 of 21 [10%]; and ERBB2\/HER2-enriched tumors, 19 of 102 [19%]). Pathologic complete response rates were lower in PIK3CA<\/jats:italic> mutated than PIK3CA<\/jats:italic> wild type in the overall population (34% [11 of 32] vs 49% [74 of 152]; P<\/jats:italic>\u2009=\u2009.14) and were significantly different among those receiving trastuzumab (30% [7 of 23] vs 54% [63 of 117]; P<\/jats:italic>\u2009=\u2009.045). At a median follow-up of 9 years, PIK3CA<\/jats:italic> mutations were significantly associated with worse EFS in the overall cohort (hazard ratio, 2.58 [95% CI, 1.24-5.35]; P<\/jats:italic>\u2009=\u2009.01), which persisted in a multivariable model including pCR, HR status, stage, and IMS (hazard ratio, 2.52 [95% CI, 1.16-5.47]; P<\/jats:italic>\u2009=\u2009.02). The negative association of PIK3CA<\/jats:italic> mutation was significant in HR-positive (hazard ratio, 3.60 [95% CI, 1.45-8.96]; P<\/jats:italic>\u2009=\u2009.006) and luminal subtypes (hazard ratio, 4.84 [95% CI, 1.08-21.70]; P<\/jats:italic>\u2009=\u2009.04), but not in nonluminal and HR-negative tumors.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>In ERBB2\/HER2-positive EBC, PIK3CA<\/jats:italic> mutations were associated with lower pCR rates and independently associated with worse long-term EFS. These findings appear to be associated with PIK3CA<\/jats:italic> mutations in HR-positive and luminal EBC.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2023.48814","type":"journal-article","created":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T16:02:35Z","timestamp":1703088155000},"page":"e2348814","source":"Crossref","is-referenced-by-count":21,"title":["Association of PIK3CA<\/i> Mutation With Pathologic Complete Response and Outcome by Hormone Receptor Status and Intrinsic Subtype in Early-Stage ERBB2\/HER2-Positive Breast Cancer"],"prefix":"10.1001","volume":"6","author":[{"given":"Paola","family":"Zagami","sequence":"first","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill"},{"name":"Division of Medical Oncology, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aranzazu","family":"Fernandez-Martinez","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill"},{"name":"Department of Genetics, University of North Carolina, Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naim U.","family":"Rashid","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of North Carolina, Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A.","family":"Hoadley","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill"},{"name":"Department of Genetics, University of North Carolina, Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia A.","family":"Spears","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Curigliano","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, University of Milan, Milan, Italy"},{"name":"Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles M.","family":"Perou","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill"},{"name":"Department of Genetics, University of North Carolina, Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa A.","family":"Carey","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill"},{"name":"Division of Medical Oncology, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2023,12,20]]},"reference":[{"issue":"3","key":"zoi231419r1","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1007\/s10549-017-4533-9","article-title":"Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer.","volume":"167","author":"Rimawi","year":"2018","journal-title":"Breast Cancer Res Treat"},{"issue":"1","key":"zoi231419r2","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s13058-020-01284-9","article-title":"Frequency and spectrum of PIK3CA somatic mutations in breast cancer.","volume":"22","author":"Mart\u00ednez-S\u00e1ez","year":"2020","journal-title":"Breast Cancer Res"},{"issue":"8","key":"zoi231419r3","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1093\/annonc\/mdw197","article-title":"PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab.","volume":"27","author":"Loibl","year":"2016","journal-title":"Ann Oncol"},{"issue":"16","key":"zoi231419r4","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1200\/JCO.2022.40.16_suppl.509","article-title":"Prognostic and predictive implications of the intrinsic subtypes and gene expression signatures in early-stage HER2+ breast cancer: a pooled analysis of CALGB 40601, NeoALTTO, and NSABP B-41 trials.","volume":"40","author":"Fernandez-Martinez","year":"2022","journal-title":"J Clin Oncol"},{"issue":"4","key":"zoi231419r5","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1001\/jamaoncol.2015.0830","article-title":"Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO trial.","volume":"1","author":"Salgado","year":"2015","journal-title":"JAMA Oncol"},{"issue":"9","key":"zoi231419r6","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1634\/theoncologist.2015-0138","article-title":"Prospective biomarker analysis of the randomized CHER-LOB study evaluating the dual anti-HER2 treatment with trastuzumab and lapatinib plus chemotherapy as neoadjuvant therapy for HER2-positive breast cancer.","volume":"20","author":"Guarneri","year":"2015","journal-title":"Oncologist"},{"issue":"13","key":"zoi231419r7","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1093\/jnci\/djt121","article-title":"Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer.","volume":"105","author":"Loi","year":"2013","journal-title":"J Natl Cancer Inst"},{"issue":"22","key":"zoi231419r8","doi-asserted-by":"publisher","first-page":"5843","DOI":"10.1158\/1078-0432.CCR-20-1731","article-title":"PIK3CA mutation in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer: association with prognosis and integration with PAM50 subtype.","volume":"26","author":"Guarneri","year":"2020","journal-title":"Clin Cancer Res"},{"issue":"8","key":"zoi231419r9","doi-asserted-by":"publisher","first-page":"2034","DOI":"10.1093\/annonc\/mdr546","article-title":"PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab.","volume":"23","author":"Jensen","year":"2012","journal-title":"Ann Oncol"},{"issue":"35","key":"zoi231419r10","doi-asserted-by":"publisher","first-page":"4184","DOI":"10.1200\/JCO.20.01276","article-title":"Survival, pathologic response, and genomics in CALGB 40601 (Alliance), a neoadjuvant phase III trial of paclitaxel-trastuzumab with or without lapatinib in HER2-positive breast cancer.","volume":"38","author":"Fernandez-Martinez","year":"2020","journal-title":"J Clin Oncol"},{"issue":"6","key":"zoi231419r11","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1200\/JCO.2015.62.1268","article-title":"Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib.","volume":"34","author":"Carey","year":"2016","journal-title":"J Clin Oncol"},{"issue":"21","key":"zoi231419r12","doi-asserted-by":"publisher","first-page":"5292","DOI":"10.1158\/1078-0432.CCR-17-3431","article-title":"Integrated analysis of RNA and DNA from the phase III trial CALGB 40601 identifies predictors of response to trastuzumab-based neoadjuvant chemotherapy in HER2-positive breast cancer.","volume":"24","author":"Tanioka","year":"2018","journal-title":"Clin Cancer Res"},{"issue":"4","key":"zoi231419r13","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1200\/JOP.777003","article-title":"American Society Of Clinical Oncology\/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer.","volume":"6","author":"Hammond","year":"2010","journal-title":"J Oncol Pract"},{"issue":"16","key":"zoi231419r14","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1093\/jnci\/dji237","article-title":"Reporting recommendations for tumor marker prognostic studies (REMARK).","volume":"97","author":"McShane","year":"2005","journal-title":"J Natl Cancer Inst"},{"key":"zoi231419r15","doi-asserted-by":"publisher","journal-title":"Lancet Oncol","DOI":"10.1016\/S1470-2045(14)70320-1"},{"key":"zoi231419r16","doi-asserted-by":"publisher","journal-title":"Breast Cancer Res Treat","DOI":"10.1007\/s10549-012-2189-z"},{"issue":"12","key":"zoi231419r17","doi-asserted-by":"publisher","first-page":"1334","DOI":"10.1200\/JCO.2014.55.2158","article-title":"PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2\u2013targeted therapies in breast cancer.","volume":"33","author":"Majewski","year":"2015","journal-title":"J Clin Oncol"},{"issue":"4","key":"zoi231419r18","doi-asserted-by":"publisher","DOI":"10.1136\/esmoopen-2020-000890","article-title":"PIK3CA mutation inhibition in hormone receptor-positive breast cancer: time has come.","volume":"5","author":"De Mattos-Arruda","year":"2020","journal-title":"ESMO Open"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2813160\/zagami_2023_oi_231419_1702412413.43704.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T16:02:37Z","timestamp":1703088157000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2813160"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,20]]},"references-count":18,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2023,12,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2023.48814","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,20]]}}}