{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:44:25Z","timestamp":1791996265316,"version":"4.4.0"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Patients with endocrine-resistant hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (MBC) have limited effective treatment options. Heat shock protein 90 (HSP90) regulates estrogen receptor stability and function; its inhibition has been proposed as a strategy to overcome endocrine resistance. Ganetespib is a second-generation HSP90 inhibitor with demonstrated anti-tumor activity in preclinical breast cancer models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this randomized phase II study, 50 patients with HR+ MBC previously treated with endocrine therapy were randomized 1:2 to fulvestrant alone (n\u2009=\u200915) or fulvestrant with ganetespib (n\u2009=\u200935), respectively. Median age was 53 years. Fulvestrant was administered at standard dosing; ganetespib (200\u2009mg\/m2) was given intravenously on days 1, 8, and 15 of each 28-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival and safety\/tolerability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Median PFS was similar between arms (3.7 vs. 3.6 months; log-rank p\u2009=\u20090.79). Toxicity was higher with ganetespib, with substantially increased diarrhea (97% vs. 7%) and nausea (63% vs. 40%). Exploratory genomic analysis of on-treatment biopsies (n\u2009=\u200913) showed ESR1 mutations were enriched among patients without clinical benefit, while all patients with clinical benefit exhibited a Luminal A transcriptional subtype. Tumors lacking clinical benefit showed enrichment of proliferative and cell cycle\u2013associated transcriptional programs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Adding ganetespib to fulvestrant did not improve clinical outcomes and increased toxicity in endocrine-resistant HR+ MBC. Our findings support the hypothesis that ESR1 alterations and proliferative transcriptional activity contribute to established endocrine resistance, limiting the therapeutic impact of HSP90 inhibition in this setting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>ClinicalTrials.gov Registration Number<\/jats:title>\n                    <jats:p>NCT01560416<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/oncolo\/oyag414","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:54:19Z","timestamp":1791978859000},"source":"Crossref","is-referenced-by-count":0,"title":["A randomized phase II study of fulvestrant with or without ganetespib in patients with endocrine resistant metastatic breast cancer"],"prefix":"10.1093","author":[{"given":"Albert","family":"Grinshpun","sequence":"first","affiliation":[{"name":"Dana-Farber Cancer Institute , Boston, MA,","place":["USA"]},{"name":"Hebrew University Shaare Zedek Medical Center and , Jerusalem,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrienne G","family":"Waks","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute , Boston, MA,","place":["USA"]},{"name":"Harvard Medical School , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxin","family":"Fu","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Kurnia","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Guo","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyu","family":"Li","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"McKenna","family":"Moore","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molly","family":"DiLullo","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashka","family":"Patel","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Whitesell","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research , Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Atanasov","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann H","family":"Partridge","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute , Boston, MA,","place":["USA"]},{"name":"Harvard Medical School , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica L","family":"Mayer","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute , Boston, MA,","place":["USA"]},{"name":"Harvard Medical School , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian E","family":"Krop","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandro","family":"Santagata","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myles","family":"Brown","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric P","family":"Winer","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Reeder-Hayes","sequence":"additional","affiliation":[{"name":"University of North Carolina Lineberger Cancer Center, , Chapel Hill, NC,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carey","family":"Anders","sequence":"additional","affiliation":[{"name":"Duke University Medical Center, Duke Cancer Institute , Durham, NC,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rinath","family":"Jeselsohn","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute , Boston, MA,","place":["USA"]},{"name":"Harvard Medical School , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2263-5413","authenticated-orcid":false,"given":"Nancy U","family":"Lin","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute , Boston, MA,","place":["USA"]},{"name":"Harvard Medical School , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,10,14]]},"container-title":["The 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