Circulating tumor DNA as a dynamic biomarker of response to palbociclib and fulvestrant in metastatic breast cancer patients

Abstract

Background 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). 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. Methods ER+ 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. Results Twenty-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. Conclusion 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.

Circulating Biomarkers of CDK4/6 Inhibitors Response in Hormone Receptor Positive and HER2 Negative Breast Cancer

“…Clearance of ctDNA observed at day 30 was associated with longer PFS, while an increase of ctDNA levels at day 30 compared to baseline was predictive of shorter PFS. Of note, in this study, dynamics at day 15 had no prognostic impact [ 56 ]. To overcome the need of prioritizing mutations based on tumor tissue genomics, Martínez-Sáez and colleagues sequenced plasma samples from 45 patients with CDK4/6i-treated HR+/HER2− MBC using the standardized Guardant360 assay [ 57 ].…”

“…However, only 22% and 25.6% of patients analyzed in this study had PIK3CA and ESR1 ctDNA mutations, respectively [ 26 ]. To bypass this problem, in the ALCINA study (NCT02866149), 25 HR+/HER2− MBC patients receiving palbociclib and fulvestrant were assessed for ctDNA by droplet-digital PCR (ddPCR) based on somatic mutations found on their primary or metastatic tissue that could be tracked in circulating DNA, the majority being found in PIK3CA ( n = 21), but also in TP53 ( n = 2) and AKT1 ( n = 2) genes [ 56 ]. At baseline, 84% of patients had detectable ctDNA levels, but these were not prognostic.…”

The Emerging Role of Circulating Tumor DNA in the Management of Breast Cancer

“…Existing literature has highlighted the use of ctDNA as a biomarker for response to various chemotherapeutic drugs, such as palbociclib, fulvestrant, and bevacizumab, among others [30,31]. For instance, a study by Chen et al characterized the correlation between ctDNA levels and treatment efficacy in breast cancer patients.…”

Integrating Molecular Biomarker Inputs Into Development and Use of Clinical Cancer Therapeutics

“…ctDNA is tumor-released single- or double-stranded DNA that enters the bloodstream and can be detected for diagnosis, guidance of treatment, and monitoring of disease progression. Recently, ctDNA has been used to guide clinical decision-making in several tumor types including CRC ( Chen et al, 2021 ), NSCLC ( Song et al, 2020 ), and metastatic breast cancer (MBC) ( Darrigues et al, 2021 ). In CRC, postoperative serial ctDNA detection identified recurrence before radiological imaging and was predictive of high relapse risk ( Chen et al, 2021 ).…”

“…The FDA has approved the use of liquid biopsy for analysis of sensitizing and resistance mutations in NSCLC due to multiple studies where the application of biomarkers derived from liquid biopsy successfully guided treatment decisions ( Saarenheimo et al, 2019 ). In MBC, ctDNA was a prognostic factor of PFS and efficacy of treatment was effectively monitored by serial ctDNA analyses before radiological evaluation ( Darrigues et al, 2021 ). Analysis of ctDNA has been employed to differentiate between the clinical scenarios of pseudoprogression and hyperprogression following treatment of patients with immune checkpoint blockade therapy ( Jia et al, 2019 ; Ma et al, 2019 ).…”