Characteristics and Outcome of AKT1E17K_Mutant Breast Cancer Defined through AACR Project GENIE, a Clinicogenomic Registry

AKT inhibitors have promising activity in AKT1(EI7K)-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(E7K)-mutant (n=153) and AKT1-wild-type (n =302) metastatic breast cancer. AK T1-mutant cases had similar adjusted overall survival (05) compared with AKT1-wild-type controls (median 05, 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, AKT1E7Kmutant 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.