Characteristics and Outcome of AKT1 E17K-Mutant Breast Cancer Defined through AACR Project GENIE, a Clinicogenomic Registry

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.

Figure 1.

Overall survival by AKT1 mutation status. (A) Time from metastatic diagnosis to death or last follow-up, as well as tumor sequencing*; (B) Overall survival using left truncation; (C) Overall survival without left truncation. *5 patients underwent tumor sequencing before their metastatic diagnosis

Figure 1.

Overall survival by AKT1 mutation status. (A) Time from metastatic diagnosis to death or last follow-up, as well as tumor sequencing*; (B) Overall survival using left truncation; (C) Overall survival without left truncation. *5 patients underwent tumor sequencing before their metastatic diagnosis

Figure 1.

Overall survival by AKT1 mutation status. (A) Time from metastatic diagnosis to death or last follow-up, as well as tumor sequencing*; (B) Overall survival using left truncation; (C) Overall survival without left truncation. *5 patients underwent tumor sequencing before their metastatic diagnosis

Figure 2.

Genomic landscape of breast cancer according to AKT1 mutations. Comparison of (A) mutation number; (B) fraction of genome altered (FGA); (C) copy number alteration (CNA) frequencies in AKT1-mutant (MT, green) vs AKT1-wildtype (WT, orange). False discovery rate (FDR) derived from the Fisher exact test. The red lines indicate significance FDR < 0.05; (D) Comparison of the alteration frequency for 72 genomic alterations in AKT1-MT vs. AKT1-WT tumors. *FDR < 0.1; (E) Radar plots showing the percentage of patients with alterations in the corresponding canonical oncogenic signaling pathways according to AKT1 mutation. Statistically significant pathways associated with AKT1 mutation are indicated with an asterisk (*; FDR < .05).