TPS636 Background: A potential mechanism of resistance to endocrine therapy in breast cancer involves changes in gene expression secondary to epigenetic modifications, which might be modulated with the use of histone deacetylase (HDAC) inhibitors such as entinostat. ENCORE 301, a phase II study evaluating the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in patients with hormone receptor (HR)-positive advanced breast cancer who had experienced disease progression after a non-steroidal AI (NSAI), showed a significant improvement in progression-free survival (PFS), and overall survival (OS). Entinostat has been designated a Breakthrough Therapy by the FDA. Methods: E2112 is a multicenter randomized double-blind placebo-controlled phase III study (NCT02115282) enrolling patients with advanced HR-positive, HER2-negative breast cancer with prior disease progression on a NSAI (n = 600). Patients receive exemestane 25mg po daily and entinostat/placebo 5mg po every week. Eligibility:...
The NCCN Guidelines for Survivorship are intended to help healthcare professionals working with cancer survivors to ensure that each survivor's complex and varied needs are addressed. The Guidelines provide screening, evaluation, and treatment recommendations for consequences of adult-onset cancer and its treatment; recommendations to help promote healthful lifestyle behaviors, weight management, and immunizations in survivors; and a framework for care coordination. This article summarizes the recommendations regarding employment and return to work for cancer survivors that were added in the 2021 version of the NCCN Guidelines.
168 Background: SCPs may address inadequate provider-to-provider communication but PCP views regarding EHR-generated SCPs have not been assessed. A multiple choice survey was used to evaluate an EHR-generated SCP for appropriate content, length, perceived accuracy, need for updates and preferred method of delivery (the Clinican survEy of Care Plan [ChECkuP]). Methods: PCPs were recruited from the Wisconsin Research and Education Network (WREN), a cohort of family practitioners working in urban and rural Wisconsin. WREN practitioners were e-mailed and invited to participate if they currently saw patients with a breast cancer history. PCPs were provided a sample 10-page EHR-generated SCP and completed the ChECkuP at one time point. Results: 36 PCPs participated in Summer 2014. Most PCPs reported the sample EHR-generated SCP as accurate (75%), easy to use (58%) and useful in coordinating care (75%). Few felt using SCPs would disrupt their clinic workflow (11%) or that SCP use would take too much time (14%). Most (75%) preferred receiving SCPs via EHR, vs paper (36%), having the patient provide (19%) or viewing the SCP on an external website (6%). Most deemed consistent provision (69%) and standard location (78%) important. With regards to timing, 42% reported desiring an SCP immediately after completion of primary treatment. However, PCPs requested some changes: 33% requested a shorter SCP (ideally 1-3 pages) and 53% advocated for SCPs specifically written for PCPs rather than producing one document for both PCP and survivor. Also, most (53%) felt that SCPs should be updated based on information changes rather than on a regular schedule, including changes to screening guidelines (100%), late or long term side effects (89%) and followup recommendations (95%). Conclusions: PCPs regarded EHR-generated SCPs as useful in coordinating care between oncologists and primary care. PCPs desired a standardized SCP accessible within the EHR. EHR-generated SCP content, length and layout will be revised based on the feedback provided. Clinical trial information: OS12122.
538 Background: Endocrine therapies are the treatment of choice for HR+ metastatic breast cancer; novel drugs are needed due to resistance. Reducing both androgens and estrogens may circumvent resistance by reducing androgen receptor stimulation. Orteronel is a selective, reversible, nonsteroidal inhibitor of the 17, 20-lyase enzyme (which generates androgens and estrogens). We conducted a phase 1b study of orteronel in HR+ metastatic breast cancer; the primary objective was the recommended phase 2 dose (RP2D) of orteronel in women. Methods: Key inclusion criteria were postmenopausal status and evaluable or measurable HR+ metastatic breast cancer. Doses escalated via standard 3+3 design. Initial dose was 300 mg BID and escalated to 400 mg BID (the RP2D in men). Cycle length was 28 days. Patients were evaluated every 8 weeks for progression. Correlative studies assessing hormone levels via liquid chromatography-mass spectrometry were performed. Results: Seven patients enrolled (median 56 yo, range 47-71). Patients were heavily pre-treated: 6 had prior endocrine therapy for metastatic cancer (median 4 lines, range 0-5) and 5 had prior chemotherapy regimens for metastatic cancer (median 2, range 0-5). Four received 300 mg BID at dose level 1 (1 was not evaluable per protocol); 3 received 400 mg BID at dose level 2. Orteronel was well tolerated: no dose limiting toxicities were observed. Common adverse events at least possibly related to therapy were: grade 1 hot flashes (28%), grade 1-2 nausea (28%), grade 1 hypokalemia (28%), and grade 1 elevated AST (28%). 6 patients received 14 cycles of treatment. 2 patients remain on therapy with evidence of clinical benefit: 1 with stable disease for > 6 months (best response) and 1 with stable disease for 3 months. Conclusions: Orteronel 400 mg BID is well tolerated in post-menopausal women, and significantly suppresses serum estrogens and testosterone. Clinical benefit was seen among heavily pretreated patients. Clinical trial information: NCT01808040.Mean levels ± standard deviation prior to and after orteronel. Cycle 1, day 1 (n=7) Cycle 2, day 1 (n=6) Cycle 3, day 1 (n=4) Estradiol (pg/ml) 6.2 ± 5.6 4.9 ± 4.4 0.5 ± 1 Estrone (pg/ml) 24.4 ± 12.8 2.7 ± 3.6 5.2 ± 6.4 Testosterone (pg/ml) 131.7 ± 102.9 7.3 ± 9 13.4 ± 25.5
ABSTRACT Objective Data extraction from the published literature is the most laborious step in conducting living systematic reviews (LSRs). We aim to build a generalizable, automated data extraction workflow leveraging large language models (LLMs) that mimics the real-world two-reviewer process. Materials and Methods A dataset of 10 clinical trials (22 publications) from a published LSR was used, focusing on 23 variables related to trial, population, and outcomes data. The dataset was split into prompt development (n=5) and held-out test sets (n=17). GPT-4-turbo and Claude-3-Opus were used for data extraction. Responses from the two LLMs were compared for concordance. In instances with discordance, original responses from each LLM were provided to the other LLM for cross-critique. Evaluation metrics, including accuracy, were used to assess performance against the manually curated gold standard. Results In the prompt development set, 110 (96%) responses were concordant, achieving an accuracy of 0.99 against the gold standard. In the test set, 342 (87%) responses were concordant. The accuracy of the concordant responses was 0.94. The accuracy of the discordant responses was 0.41 for GPT-4-turbo and 0.50 for Claude-3-Opus. Of the 49 discordant responses, 25 (51%) became concordant after cross-critique, with an increase in accuracy to 0.76. Discussion Concordant responses by the LLMs are likely to be accurate. In instances of discordant responses, cross-critique can further increase the accuracy. Conclusion Large language models, when simulated in a collaborative, two-reviewer workflow, can extract data with reasonable performance, enabling truly ‘living’ systematic reviews.
2607 Background: The AKT protein kinase is a key mediator of signaling in the human epidermal growth factor receptor-2 (HER2) pathway. HER2 inhibition can result in feedback regulation of signaling, leading to high AKT activity. Preclinical studies demonstrate activity of combined HER2 and AKT inhibition. Lapatinib is an oral tyrosine kinase inhibitor of HER2. MK-2206 is an oral selective inhibitor of AKT with a maximum tolerated dose (MTD) of 60mg qod. Both agents cause rash and diarrhea. This study was designed to determine the MTD, dose limiting toxicities (DLTs), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination. Methods: This phase I study evaluated the safety of MK-2206 (30-60 mg qod) and lapatinib (1000-1500 mg qd) continuously. Cycles were 28 days, except cycle 1 (35 days), due to a 1 week MK-2206 lead-in to evaluate for PK interactions. Because of the continuous nature of therapy, protocol-specified intolerable grade 2 AEs were considered DLTs during cycle 1. Results: 23 pts (median age 59 [range 22-72];15 female:8 male) were enrolled. The most common malignancies were colorectal (8 pts), lung (4 pts), and breast (3 pts). 4 pts were unevaluable per protocol; 19 evaluable pts were on study a median of 8 weeks (range 3-35). 3 pts experienced DLTs. At dose level one, 1 pt had grade (gr) 3 hyponatremia and fatigue. At dose level four, 1 pt had gr 4 hyponatremia, gr 3 rash and hypocalcemia and 1 pt had intolerable gr 2 mucositis with delivery of <75% of drug. The most common AEs at least possibly related to therapy included diarrhea (gr 3-4 in 3 pts; gr 1-2 in 16 pts), nausea (gr 3 in 2 pts; gr 1-2 in 14 pts) and rash (gr 3 in 2 pts; gr 1-2 in 12 pts). The MTD was 45mg po qod of MK-2206 with 1500 mg po qd of lapatinib, exceeding biologically active doses for each agent. One pt with adrenal cortical carcinoma was on study for 6 months with stable disease (SD) and 1 pt with colorectal cancer was on study for 5 months with significant tumor marker decline and SD. PK analyses are ongoing. Conclusions: MK-2206 in combination with lapatinib is well-tolerated at biologically active single agent doses. Anti-tumor activity will be evaluated further in a dose expansion cohort in pts with advanced HER2-positive breast cancer. Clinical trial information: NCT01245205.
