Genomic biomarkers of ipatasertib response in patients with hormone receptor-positive metastatic breast cancer

AKT inhibitor biomarkers remain undefined in metastatic breast cancer (MBC). The phase Ib TAKTIC trial evaluated ipatasertib with endocrine therapy, or with fulvestrant plus palbociclib, in endocrine-resistant HR + /HER2- MBC. Exploratory baseline ± post-progression circulating-tumor DNA (ctDNA) was analyzed for genomic alterations associated with outcomes. Progression-free survival (PFS) was assessed using Kaplan-Meier and Cox modeling. McNemar’s test compared acquired alterations in paired samples. Combinatorial effects were explored in patient-derived cell lines treated with ipatasertib and palbociclib. Forty-seven patients received doublet ( n = 21) or triplet ( n = 26) therapy, and 87% had prior CDK4/6 inhibitor exposure. Median PFS was 5.72 months. PI3K pathway alterations ( PIK3CA/AKT1/PTEN ) correlated with longer PFS on triplet therapy (15.66 vs 5.57 months, HR 0.38, 95% CI 0.15–0.93) but not in the doublet group or overall cohort. FGFR1 amplifications (13%) trended toward poorer PFS (3.64 vs 6.96 months, HR 2.36, 95% CI 0.91–5.24), and EGFR amplifications (9%) correlated with shorter PFS (2.97 vs 6.96 months, HR 4.26, 95% CI 1.31–11.21). ESR1 mutations (30%) were associated with worse PFS (3.36 vs 7.29 months, HR 2.33, 95% CI 1.18–4.41). Paired ctDNA from 31 patients demonstrated emergent FGFR1, EGFR , and ESR1 alterations at progression, each occurring in 10–13% of cases. Ipatasertib with palbociclib had greater efficacy in PIK3CA- mutant than wild-type cell lines. Overall, ctDNA biomarkers correlated with PFS on ipatasertib-based therapy, and predictive versus prognostic significance requires validation.