Abstract The Signature program comprises a series of 8 tissue-agnostic, mutation-specific protocols without predetermined study sites. Eligible patients have advanced solid and hematologic cancers without remaining standard therapeutic options. Clinical benefit (stable disease [SD], partial response [PR], or complete response [CR]) at 16 weeks as assessed by the investigator (Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1 or appropriate hematologic criteria) is the primary endpoint of each study. Through local enrollment via physician-directed genetic profiling, patients can be rapidly matched with a relevant targeted-treatment protocol, effectively bringing the protocol to the patient. One protocol involves buparlisib (BKM120), a highly specific and potent oral pan-class I inhibitor of phosphatidylinositol 3-kinase (PI3K) currently in clinical development. A total of 146 patients were accrued in the buparlisib protocol in the Signature program from March 2013 to January 2015. Here, we describe a gynecologic cancer subset of this population, including patients with cervical (n = 11), ovarian (n = 12), uterine (n = 3), and vaginal cancer (n = 4). The median age was 61 years, and patients had a median of 4 lines of prior therapy; 83% of patients were Caucasian, and 47% and 53% had an Eastern Cooperative Oncology Group performance status of 0 and 1, respectively. All patients met mutational inclusion criteria, including 47% with PIK3CA mutations, 20% with PTEN loss (immunohistochemistry), 17% with PTEN mutation or loss (DNA), and 17% with PIK3CA amplification. Best responses of SD, PR, and CR at any time were observed in 13, 1, and 1 patients, respectively; of these, 7 patients had clinical benefit (SD, n = 6; PR, n = 1) at 16 weeks. Tolerability was consistent with that in other studies of buparlisib monotherapy: the most common adverse events (≥ 25%) were diarrhea (33%), nausea (33%), fatigue (33%), and hyperglycemia (30%). A large multigene next-generation sequencing assay was performed on pretreatment tissue biopsies from all patients. Preliminary findings indicate that among buparlisib-treated patients with gynecologic cancers in this analysis, those with cervical cancer had more gene amplifications and fewer gene losses and those with ovarian cancer had more p53 deregulations and fewer PIK3CA mutations. Although no clear correlation between clinical benefit and specific mutational profile has been observed, further analysis is ongoing. Citation Format: Sarina A. Piha-Paul, Daniel L. Spitz, J. Thaddeus Beck, Fadi S. Braiteh, Joseph Buscema, Richard Frank, Sudha Parasuraman, Barinder P. Kang, Renata M. Matys, Eric D. Slosberg. Outcomes and genomic mutation profiling results in a subset of patients with gynecologic cancers treated with buparlisib in the Signature Program. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A53.