Abstract
Circulating tumor DNA (ctDNA) levels may predict response to anticancer drugs, including CDK4/6 inhibitors and endocrine therapy combinations (CDK4/6i+ET); however, critical questions remain unanswered such as which assay or statistical method to use. Here, we obtained paired plasma samples at baseline and week 4 in 45 consecutive patients with advanced breast cancer treated with CDK4/6i+ET. ctDNA was detected in 96% of cases using the 74-gene Guardant360 assay. A variant allele fraction ratio (VAFR) was calculated for each of the 79 detected mutations between both timepoints. Mean of all VAFRs (mVAFR) was computed for each patient. In our dataset, mVAFR was significantly associated with progression-free survival (PFS). Baseline VAF, on-treatment VAF or absolute changes in VAF were not associated with PFS, nor were CA-15.3 levels at baseline, week 4 or the CA-15.3 ratio. These findings demonstrate that ctDNA dynamics using a standardized multi-gene panel and a unique methodological approach predicts treatment outcome. Clinical trials in patients with an unfavorable ctDNA response are needed.
Highlights
In hormone receptor positive (HR+)/HER2-negative advanced breast cancer (BC), CDK4/6i plus ET have remarkably improved survival outcomes and are considered a standard treatment for most patients[1]
We undertook a prospective study from May/2016 to June/2019 of 50 consecutive pre and postmenopausal patients with metastatic HR+/HER2negative BC treated as per standard practice with CDK4/6i and ET (Fig. 1a)
Mutations in 42 genes were identified at baseline and the 4 most frequent altered genes were PIK3CA, ESR1, TP53, and ATM (Fig. 1d); ≥1 mutation with ≥VAF 0.4% in any of these 4 genes was found in 24 patients (53.3%)
Summary
In hormone receptor positive (HR+)/HER2-negative advanced breast cancer (BC), CDK4/6i plus ET have remarkably improved survival outcomes and are considered a standard treatment for most patients[1]. PIK3CA mutation levels from baseline to day 15 of therapy were associated with PFS Only 22% of patients with HR+/HER2-negative advanced BC had detectable PIK3CA mutations in plasma.
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