1932MO - Ki67 expression and CDK4/6i activity: An emerging role for PIK3CA mutations in metastatic breast cancer patients

Background

Preclinical studies indicate that alterations of PIK3/AKT/mTOR pathway may be correlated with resistance to CDK4/6 inhibitors (CDK4/6i) in breast cancer (BC) cells and that PI3K inhibitors could prevent resistance to CDK4/6i [Abreu H MT, et al. Cancer Res 2016;76:2301]. For these compelling evidences the present study evaluated the impact of PI3K mutations on treatment outcome in metastatic BC (mBC) patients (pts) receiving CDK4/6i in association with hormonal therapy as per approved indication.

Methods

Thirty pts treated with palbociclib (n=26) or ribociclib (n=4) plus hormonal therapy were enrolled. Plasma samples were obtained prior to CDK4/6i treatment and circulating free DNA (cfDNA) extraction was performed using the QIAamp Circulating Nucleic Acid Kit (Qiagen). PI3K mutations (C420R, E542K, E545A, E545D, E545G, E545K, Q546E, Q546R, H1047L, H1047R, H1047Y) were analysed on cfDNA using a QX100 ddPCR (Bio-Rad).

Results

In pts with (n=12) vs. without (n=18) PI3K mutations, PFS was significantly shorter (5.9 vs 11.6 months, p=0.01, respectively). The univariate and multivariate analysis comparing PFS and clinically relevant data (i.e., age, metastasis, previous lines of hormonal or chemotherapy), confirmed PI3K as the only biomarker significantly associated to PFS (p=0.01). A significant correlation was observed between Ki67 expression in primary lesions and PI3K status. Higher Ki67 levels were associated with PI3K mutations vs. none (Ki67%, 25.36±11.02 vs. 13.17±10.14; p=0.006). The significance was maintained when PI3K mutant pts were stratified as low (<14%), intermediate (14–20%) and high (>20%) Ki67 levels (p=0.009). Despite the strong correlation, Ki67 did not appear significantly associated with median PFS to CDK4/6i, and the presence of PI3K mutations remained an independent predictor of clinical outcome to CDK4/6i.

Conclusions

In conclusion, PI3K status should be considered a potential predictive biomarker of CDK4/6i and, based on these data, the sequence of treatments (CDK4/6 vs. PI3Ki) may be reconsidered.

Clinical trial identification

Circus study - ID 5694.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.