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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\u003Cp id=\u0022p-1\u0022\u003EPatients with stage II or stage III breast cancer treatable by surgery received neoadjuvant therapy with paclitaxel and trastuzumab with or without lapatinib. A mutational analysis on pretreatment tumors showed frequent mutations in TP53; these were associated with a greater rate of pathologic complete remission.\u003C\/p\u003E\u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Eneoadjuvant\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ecombination treatment\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Emutational analysis\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Estage 2\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Estage 3\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group drug\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Etrastuzumab\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Elapatinib\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Epaclitaxel\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EPaclitaxel and Trastuzumab With or Without Lapatinib in Treating Patients With Stage II or Stage III Breast Cancer That Can Be Removed by Surgery\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECALGB 40601\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ENCT00770809\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\u003Cp id=\u0022p-2\u0022\u003EKatherine A. Hoadley, PhD, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA, presented the mutational analysis of the Paclitaxel and Trastuzumab With or Without Lapatinib in Treating Patients With Stage II or Stage III Breast Cancer That Can Be Removed by Surgery trial [CALGB 40601; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00770809\u0026amp;atom=%2Fspmdc%2F14%2F56%2F8.atom\u0022\u003ENCT00770809\u003C\/a\u003E].\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003ECALGB 40601 was a neoadjuvant trial in which patients with human epidermal growth factor receptor 2 (HER2)\u2013positive clinical stage II or III breast cancer (BC) had a pretreatment biopsy research tissue sample taken at random assignment to weekly paclitaxel (T) plus trastuzumab (H) plus lapatinib (L) for 16 weeks (n\u2009=\u2009118); or T plus H for 16 weeks (n\u2009=\u2009120); or T plus L for 16 weeks (n\u2009=\u200967) [Carey LA et al. ASCO 2013 (abstr 500)]. A second research tissue sample was obtained at surgery following the neoadjuvant treatment. There was no statistically significant difference between treatment groups in pathologic complete remission (pCR) rates. RNA from pretreatment samples were correlated with pCR by intrinsic subtype in all arms (n\u2009=\u2009265). The pCR rate for the HER2-enriched subtype (n\u2009=\u200982) has twice the pCR rate (70%) as luminal A (n\u2009=\u200980; 34%) or luminal B (n\u2009=\u200980; 36%) [Carey LA et al. \u003Cem\u003EJ Clin Oncol.\u003C\/em\u003E 2014].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EThe mutational analysis evaluated 181 HER-positive pretreatment tumors and correlated 9 genes (\u003Cem\u003ETP53, PIK3CA, GATA3, AKT1, ERBB2, MAP3K1, MAP2K4, TRPS1\u003C\/em\u003E, and \u003Cem\u003EMALAT1\u003C\/em\u003E) with pCR rates. To increase the power to detect somatic mutations, UNCeqR, a program that integrates RNA and DNA sequencing, was used [Wilkerson MD et al. \u003Cem\u003ENucleic Acids Res\u003C\/em\u003E. 2014].\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EA median of 62 total mutations (interquartile range 32-118) was found. The number of mutations varied significantly by intrinsic subtype (\u003Cem\u003EP\u003C\/em\u003E\u2009\u0026lt;\u2009.001) and by \u003Cem\u003ETP53\u003C\/em\u003E mutation status (\u003Cem\u003EP\u003C\/em\u003E\u2009\u0026lt;\u2009.001). The HER2-enriched and luminal B subtypes had higher numbers of mutations. \u003Cem\u003ETP53\u003C\/em\u003E mutations also correlated with higher numbers of mutations.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003E\n            \u003Cem\u003ETP53\u003C\/em\u003E had a mutation frequency of 56%, \u003Cem\u003EPIK3CA\u003C\/em\u003E had a mutation frequency of 20%, and the rest of the 9 genes had a mutation frequency of \u0026lt;\u200910%. \u003Cem\u003ETP53\u003C\/em\u003E mutations were significantly associated with pCR. In the overall population, the odds ratio was 3.67 (\u003Cem\u003EP\u003C\/em\u003E\u2009\u0026lt;\u2009.001) for pCR vs wild type for those with mutated \u003Cem\u003ETP53\u003C\/em\u003E; the odds ratio was 5.23 (\u003Cem\u003EP\u003C\/em\u003E\u2009=\u2009.007) for pCR with luminal A mutations vs wild type. No other genes examined were correlated with pCR.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EThere were 8 \u003Cem\u003EHER2\u003C\/em\u003E\/\u003Cem\u003EERBB2\u003C\/em\u003E mutations in 7 patients; 2 of the 8 \u003Cem\u003EHER2\u003C\/em\u003E mutations were previously shown to be activating mutations [Bose R et al. \u003Cem\u003ECancer Discov\u003C\/em\u003E. 2013]. A patient in the THL arm with HER2-enriched with V777L, preclinically predicted sensitive to L, had pCR. A patient in the TL arm with luminal A with L755S, preclinically predicted resistant to L, did not have pCR.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003E\n            \u003Cem\u003ETP53\u003C\/em\u003E was the most frequently mutated gene in this cohort and was associated with increased pCR and a higher somatic mutation rate. Activating \u003Cem\u003EHER2\u003C\/em\u003E mutations were uncommon but behaved as predicted from preclinical studies. Future studies to use genomic signatures, somatic mutations, and clinical variables for pCR predictions are underway.\u003C\/p\u003E\u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 SAGE Publications\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/56\/8.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzo7oe\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}