ABSTRACT
AKT inhibitors have promising activity in AKT1 E17K-mutant estrogen receptor (ER)-positive metastatic breast cancer, but the natural history of this rare genomic subtype remains unknown. Utilizing AACR Project GENIE, an international clinicogenomic data-sharing consortium, we conducted a comparative analysis of clinical outcomes of patients with matched AKT1 E17K-mutant (n = 153) and AKT1-wild-type (n = 302) metastatic breast cancer. AKT1-mutant cases had similar adjusted overall survival (OS) compared with AKT1-wild-type controls (median OS, 24.1 vs. 29.9, respectively; P = 0.98). AKT1-mutant cases enjoyed longer durations on mTOR inhibitor therapy, an observation previously unrecognized in pivotal clinical trials due to the rarity of this alteration. Other baseline clinicopathologic features, as well as durations on other classes of therapy, were broadly similar. In summary, we demonstrate the feasibility of using a novel and publicly accessible clincogenomic registry to define outcomes in a rare genomically defined cancer subtype, an approach with broad applicability to precision oncology. SIGNIFICANCE: We delineate the natural history of a rare genomically distinct cancer, AKT1 E17K-mutant ER-positive breast cancer, using a publicly accessible registry of real-world patient data, thereby illustrating the potential to inform drug registration through synthetic control data.See related commentary by Castellanos and Baxi, p. 490.
Subject(s)
Breast Neoplasms/genetics , Proto-Oncogene Proteins c-akt/metabolism , Adult , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Mutation , Registries , Treatment OutcomeABSTRACT
PURPOSE: Matching patients to investigational therapies requires new tools to support physician decision making. We designed and implemented Precision Insight Support Engine (PRECISE), an automated, just-in-time, clinical-grade informatics platform to identify and dynamically track patients on the basis of molecular and clinical criteria. Real-world use of this tool was analyzed to determine whether PRECISE facilitated enrollment to early-phase, genome-driven trials. MATERIALS AND METHODS: We analyzed patients who were enrolled in genome-driven, early-phase trials using PRECISE at Memorial Sloan Kettering Cancer Center between April 2014 and January 2018. Primary end point was the proportion of enrolled patients who were successfully identified using PRECISE before enrollment. Secondary end points included time from sequencing and PRECISE identification to enrollment. Reasons for a failure to identify genomically matched patients were also explored. RESULTS: Data were analyzed from 41 therapeutic trials led by 19 principal investigators. In total, 755 patients were accrued to these studies during the period that PRECISE was used. PRECISE successfully identified 327 patients (43%) before enrollment. Patients were diagnosed with 29 tumor types and harbored alterations in 43 oncogenes, most commonly ERBB2 (21.3%), PIK3CA (14.1%), and BRAF (8.7%). Median time from sequencing to enrollment was 163 days (interquartile range, 66 to 357 days), and from PRECISE identification to enrollment 87 days (interquartile range, 37 to 180 days). Common reasons for failing to identify patients before enrollment included accrual on the basis of molecular alterations that did not match pre-established PRECISE genomic eligibility (140 [33%] of 428) and external sequencing not available for parsing (127 [30%] of 428). CONCLUSION: PRECISE identified 43% of all patients accrued to a diverse cohort of early-phase, genome-matched studies. Purpose-built informatics platforms represent a novel and potentially effective method for matching patients to molecularly selected studies.
ABSTRACT
The Information Systems Department at Memorial Sloan Kettering Cancer Center developed the DARWIN Cohort Management System (DCMS). The DCMS identifies and tracks cohorts of patients based on genotypic and clinical data. It assists researchers and treating physicians in enrolling patients to genotype-matched IRB-approved clinical trials. The DCMS sends automated, actionable, and secure email notifications to users with information about eligible or enrolled patients before their upcoming appointments. The system also captures investigators input via annotations on patient eligibility and preferences on future status updates. As of August 2015, the DCMS is tracking 159,893 patients on both clinical operations and research cohorts. 134 research cohorts have been established and track 64,473 patients. 51,192 of these have had one or more genomic tests including MSK-IMPACT, comprising the pool eligible for genotype-matched studies. This paper describes the design and evolution of this Informatics solution.