A decrease in circulating tumor DNA (ctDNA) soon after the initiation of treatment predicted longer progression-free survival (PFS) in patients with advanced or metastatic breast cancer. The study on the phase 1/2 trial of capivasertib plus paclitaxel provides more evidence of the potential usefulness of ctDNA as a surrogate for treatment outcomes. However, much work remains to be done to be able to determine whether this predictive biomarker could enter routine cancer care.  

The clinical trial, known as BEECH, began with an open-label safety study in 38 women with advanced breast cancer. All patients were treated with paclitaxel in 4-week cycles (3 weeks on and 1 week off) plus an increasing dose of AKT inhibitor capivasertib twice daily each week paclitaxel was received. Two different intermittent dosing schedules were investigated.

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With a safe dose of the experimental drug identified (400 mg capivasertib, 4 days on/3 days off), the researchers, led by Nicholas Turner, MBBS, oncologist at The Institute for Cancer Research, London, U.K., conducted the phase 2 portion, in which 110 women with estrogen receptor–positive, HER2-negative metastatic breast cancer were randomly assigned to receive treatment with paclitaxel plus either capivasertib or placebo. According to the results, published in the Annals of Oncology in March 2019, the addition of capivasertib did not prolong PFS in either the overall population or in the subset of patients with mutated PIK3CA, which is known to be sensitive to capivasertib.1   

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But Dr Turner and colleagues wanted to know more than whether the experimental drug helped their patients. They also wanted to see how early in the study they could make conclusions about efficacy. More specifically, they wondered whether an early look at ctDNA might tell them whether the drug was working. 

The researchers took plasma samples from patients at the start of each study phase and at several time points throughout, for a total of 872 on-treatment samples. The primary aim was to see if early suppression of ctDNA — a decrease in the amount within just a few days of starting treatment — predicted outcome among patients in the phase 2 portion of the trial.