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

Autor: Marc Michel, Romain Geiss, Francesco Ricci, François-Clément Bidard, Luc Cabel, Paul Cottu, Charlotte Proudhon, Jean-Yves Pierga, Lauren Darrigues, Ivan Bièche, Anne Vincent-Salomon, Coraline Dubot, Amanda Bartolini Silveira, Alice Bernard-Tessier, Delphine Loirat
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Oncology
medicine.medical_specialty
Pyridines
Estrogen receptor
Breast Neoplasms
Palbociclib
lcsh:RC254-282
Piperazines
03 medical and health sciences
0302 clinical medicine
Breast cancer
Surgical oncology
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
Biomarkers
Tumor
medicine
Humans
Treatment follow-up
Neoplasm Metastasis
Fulvestrant
Aged
Neoplasm Staging
030304 developmental biology
Aged
80 and over
0303 health sciences
Circulating tumor DNA
business.industry
Precision medicine
Palbociclib-fulvestrant
Middle Aged
Prognosis
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Survival Analysis
Metastatic breast cancer
Treatment Outcome
Tumor progression
030220 oncology & carcinogenesis
Mutation
Biomarker (medicine)
Female
business
Research Article
medicine.drug
Zdroj: Breast Cancer Research, Vol 23, Iss 1, Pp 1-10 (2021)
Breast Cancer Research : BCR
Popis: 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.
Databáze: OpenAIRE
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