{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:28:00Z","timestamp":1785414480118,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,18]]},"group-title":"Genomics","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"National Cancer Institute","award":["R01 CA279221"],"award-info":[{"award-number":["R01 CA279221"]}]},{"name":"National Cancer Institute","award":["R01CA272657"],"award-info":[{"award-number":["R01CA272657"]}]},{"name":"National Cancer Institute","award":["P30 CA006516"],"award-info":[{"award-number":["P30 CA006516"]}]},{"name":"National Cancer Institute","award":["K08 CA282969"],"award-info":[{"award-number":["K08 CA282969"]}]},{"award":["Career Development Award"],"award-info":[{"award-number":["Career Development Award"]}],"id":[{"id":"https:\/\/ror.org\/04p3pep55","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Karin Grunebaum Cancer Research Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background and Objectives<\/jats:title>\n                  <jats:p>Intravesical gemcitabine\/docetaxel (Gem\/Doce) is an effective therapy for Bacillus Calmette\u2013 Gu\u00e9rin (BCG)-unresponsive non\u2013muscle-invasive bladder cancer (NMIBC), achieving 50% complete responses at 2 years. However, the genomic determinants underlying response and resistance to Gem\/Doce remain poorly defined. Our objective was to define the mutational landscape of BCG-unresponsive NMIBC and nominate genomic features associated with response or resistance Gem\/Doce.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Patients with BCG-unresponsive NMIBC treated with Gem\/Doce were classified as responders (recurrence-free survival [RFS] &gt;12 months) or non-responders (RFS &lt;12 months). Whole-exome sequencing was performed on tumors prior to Gem\/Doce treatment (n=23). Single nucleotide variants were identified and annotated using a Cancer Genome Analysis pipeline. Copy number alterations were inferred with ABSOLUTE, and clonal architecture was reconstructed using PhylogicNDT.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Key Findings and Limitations<\/jats:title>\n                  <jats:p>\n                    Responders demonstrated significantly prolonged time to high-grade recurrence (3.5 vs 42 months, p&lt;0.001) and cystectomy compared with non-responders (9.5 months vs not reached; p&lt;0.001). Non-responders exhibited higher tumor mutational burden (13.66 vs 8.71; p=0.02) and more frequent whole-genome doubling (2\/2 non-responders vs 0\/1 responders; p=0.33). Phylogenetic analyses revealed clonal\n                    <jats:italic>BAP1<\/jats:italic>\n                    and subclonal\n                    <jats:italic>BRCA2<\/jats:italic>\n                    mutations in responders, whereas non-responders harbored clonal\n                    <jats:italic>FGFR3<\/jats:italic>\n                    mutations. Limitations include small sample size and retrospective design.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions and Clinical Implications<\/jats:title>\n                  <jats:p>\n                    Distinct genomic features underlie differential response to Gem\/Doce in BCG-unresponsive NMIBC. In responders, alterations in DNA repair pathways (e.g.,\n                    <jats:italic>BRCA2<\/jats:italic>\n                    ) may sensitize tumors to chemotherapy, while non-responders with FGFR3 mutations may benefit from alternative targeted strategies. These findings warrant validation in larger cohorts and support the development of biomarker-driven clinical trials.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Patient summary<\/jats:title>\n                  <jats:p>In this report we analyzed bladder tumors and found that some tumors respond well to treatment because they have defects in repairing DNA, making them more vulnerable to chemotherapy. In contrast, tumors that do not respond to chemotherapy harbor different genetic changes that help them survive and grow. These findings may help physicians choose more effective and personalized treatments in the future.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.10.724123","type":"posted-content","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T08:35:19Z","timestamp":1779093319000},"source":"Crossref","is-referenced-by-count":0,"title":["Genomic analysis of BCG unresponsive non-muscle-invasive bladder cancer identifies drivers of sensitivity to intravesical Gemcitabine\/Docetaxel"],"prefix":"10.64898","author":[{"given":"Kendrick","family":"Yim","sequence":"first","affiliation":[{"name":"Department of Urology, Brigham and Women\u2019s Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matias","family":"Vergara","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana Farber Cancer Institute, Boston, 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Urology, Brigham and Women\u2019s Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Mossanen","sequence":"additional","affiliation":[{"name":"Department of Urology, Brigham and Women\u2019s Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme S","family":"Steele","sequence":"additional","affiliation":[{"name":"Department of Urology, Brigham and Women\u2019s Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Bolduc","sequence":"additional","affiliation":[{"name":"Department of Urology, Brigham and Women\u2019s Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Hirsch","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women\u2019s Hospital, Boston, 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