Abstract
BackgroundFollowing the PALOMA-3 study results, the combination of palbociclib, a CDK4/6 inhibitor, with fulvestrant, a selective estrogen receptor degrader, has become a standard therapy in women with estrogen receptor-positive (ER+) HER2-negative (HER2−) metastatic breast cancer (MBC). Palbociclib has been shown to increase the progression-free survival (PFS) overall but no predictive biomarker of palbociclib efficacy has been validated so far. We thus evaluated whether early changes of circulating tumor DNA (ctDNA) levels are associated with palbociclib plus fulvestrant efficiency.MethodsER+ HER2− MBC patients were included in a prospective observational cohort before treatment initiation. Tumor response was assessed by radiological evaluation (RECIST v1.1) every 3 months. Plasma samples were collected before treatment (baseline), at day 15 (D15), at day 30 (D30), and at disease progression. We searched for somatic mutations from archived tumor tissues by targeted deep sequencing. For patients with somatic mutations identified, circulating tumor DNA (ctDNA) was tracked using digital droplet PCR. Ratios of ctDNA levels ([D15/baseline] and [D30/baseline]) were then correlated with prospectively registered patient characteristics and outcomes.ResultsTwenty-five of the 61 patients enrolled had a somatic mutation testable in plasma (NPIK3CA = 21, NTP53 = 2, NAKT1 = 2). At baseline, 84% of patients had detectable ctDNA levels but ctDNA levels had no prognostic impact on PFS (p = 0.10). Among those patients, ctDNA was still detected in 82% at D15 and 68% at D30. ctDNA clearance observed at day 30 was associated with longer PFS (HR = 7.2, 95% CI = 1.5–32.6, p = 0.004). On the contrary, a [D30/baseline] ctDNA ratio > 1 was associated with a shorter PFS (HR = 5.1, 95% CI = 1.4–18.3, p = 0.02) and all 5 patients with increased ctDNA levels at D30 showed disease progression after 3 months under palbociclib-fulvestrant. Finally, at the time of radiological tumor progression, ctDNA was detected in all patients tested.ConclusionOur study demonstrates that the efficiency of palbociclib and fulvestrant can be monitored by serial analyses of ctDNA before radiological evaluation and that early ctDNA variation is a prognostic factor of PFS.
Highlights
CDK4/6 inhibitors target the proliferative function of cyclin D-associated kinases to induce cell-cycle exit
CtDNA was still detected in 82% at day 15 (D15) and 68% at D30. circulating tumor DNA (ctDNA) clearance observed at day 30 was associated with longer progression-free survival (PFS) (HR = 7.2, 95% CI = 1.5–32.6, p = 0.004)
Our study demonstrates that the efficiency of palbociclib and fulvestrant can be monitored by serial analyses of ctDNA before radiological evaluation and that early ctDNA variation is a prognostic factor of PFS
Summary
CDK4/6 inhibitors target the proliferative function of cyclin D-associated kinases to induce cell-cycle exit. In pre-treated estrogen receptor-positive (ER+), HER2-negative (HER2−) metastatic breast cancer (MBC), pivotal phase 3 trials demonstrated that adding CDK4/6 inhibitors to the hormonetherapy agent fulvestrant led to significant improvement of progression-free survival (PFS) [2,3,4]. In the PALOMA-3 study, patients treated by combination of palbociclib, the first-in-class CDK4/6 inhibitor, and fulvestrant had a median PFS of 9.5 months, while those treated by placebo and fulvestrant had a median PFS of 4.5 months [2]. In the PALOMA-3 study, about 21% of patients treated with palbociclib and fulvestrant experienced a PFS shorter than 3 months. Following the PALOMA-3 study results, the combination of palbociclib, a CDK4/6 inhibitor, with fulvestrant, a selective estrogen receptor degrader, has become a standard therapy in women with estrogen receptor-positive (ER+) HER2-negative (HER2−) metastatic breast cancer (MBC). We evaluated whether early changes of circulating tumor DNA (ctDNA) levels are associated with palbociclib plus fulvestrant efficiency
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