Thesis etd-10262023-130753 |
Link copiato negli appunti
Thesis type
Tesi di specializzazione (5 anni)
Author
LORENZINI, GIULIA
URN
etd-10262023-130753
Thesis title
Analysis of ESR1 and PIK3CA mutations in circulating tumor DNA from a real world population of patients with HR+/HER2-Metastatic Breast Cancer treated with CDK 4/6 inhibitors
Department
RICERCA TRASLAZIONALE E DELLE NUOVE TECNOLOGIE IN MEDICINA E CHIRURGIA
Course of study
ONCOLOGIA MEDICA
Supervisors
relatore Prof.ssa Cremolini, Chiara
relatore Dott. Fontana, Andrea
relatore Dott. Fontana, Andrea
Keywords
- breast cancer
- CDK4/6 inhibitors
- ESR1
- PIK3CA
Graduation session start date
14/11/2023
Availability
Withheld
Release date
14/11/2093
Summary
Background: Current treatment guidelines recommend the addition of a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in combination with endocrine therapy for the treatment of patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) MBC.
These inhibitors elicit potent anti-proliferative benefits; however, resistance invariably occurs and a small proportion of patients doesn’t benefit from these treatments as endocrine resistant. Mechanisms of endocrine resistance are complex and include both ER dependent and ER independent.
The ESR1 and PIK3CA/AKT/mTOR pathways are two separate cellular signaling pathways that interact in various ways within cells.
Data suggest that these two mutations have a prognostic implication.
Study objectives: In the present study we investigated the presence of ESR1 and PIK3CA mutations and we describe the clinical outcome in a real world cohort of patients treated with CDK4/6 inhibitors and endocrine therapy at our institute on the basis of the presence of ESR1 mutations and PIK3CA mutations.
Materials and methods: The present retrospective pharmacogenetic study looked at mBC patients treated with palbociclib/ribociclib/abemaciclib as first- or second-line therapy in association with hormonal therapy (AI or fulvestrant) as per approved label.
Twelve ml of blood was collected at baseline (prior to CDK4/6i) and ESR1 and PIK3CA mutations were evaluated by cfDNA analysis
Results: Among the study population 42 patients samples were successfully analyzed for ESR1 mutations and 13 (30,9 %) were found to have a mutation, 49 patients samples were tested for PIK3CA mutations and 31 (63 %) were found to have a mutation. 37 patients samples were analyzed for both ESR1 and PIK3CA mutations and 9 patients (24,3 %) were found to have both ESR1 and PIK3CA mutations.
No statistically significant differences in terms of PFS were found comparing ESR1 mutant and non mutant patients (13 vs 29 pts: p=0,4257). Also no statistically significant differences in terms of PFS were found comparing PIK3CA mutant and non mutant patients (31 vs 23 pts; p=0.5451). Lastly no statistically significant differences in terms of PFS were found comparing patients who received CDK4/6 inhibitors as first line of treatment that harbor one mutation vs both vs who were wt (21 vs 9 vs 7 pts).
Among patients tested for ESR1 who received adjuvant treatment nine (32%) presented with an ESR1 mutation: in particular two patients were carriers of p.D538G, four harbored p.Y537C, two showed p.E380Q and one had L536R mutation.
Three patients (30 %) received tamoxifen and six patients (50 %) were treated with AI. No statistical difference between the presence of ESR1 mutation and the type of adjuvant hormonal therapy were found (p=0.39). Patients harboring an ESR1 mutation in blood at disease recurrence (first line therapy baseline) had a significantly shorter DFS compared to patients without ESR1 mutations (30 vs 110 months; 9 vs 19 patients p=0.006)
Conclusions: Treatment with CDK4/6 inhibitors is effective regardless of PIK3CA or ESR1 mutational status. Nevertheless, knowing beforehand and monitoring, through a noninvasive method such as liquid biopsy, which patients harbor a PIK3CA and/or a ESR1 mutation, may play a role in guiding therapeutic decisions.
These inhibitors elicit potent anti-proliferative benefits; however, resistance invariably occurs and a small proportion of patients doesn’t benefit from these treatments as endocrine resistant. Mechanisms of endocrine resistance are complex and include both ER dependent and ER independent.
The ESR1 and PIK3CA/AKT/mTOR pathways are two separate cellular signaling pathways that interact in various ways within cells.
Data suggest that these two mutations have a prognostic implication.
Study objectives: In the present study we investigated the presence of ESR1 and PIK3CA mutations and we describe the clinical outcome in a real world cohort of patients treated with CDK4/6 inhibitors and endocrine therapy at our institute on the basis of the presence of ESR1 mutations and PIK3CA mutations.
Materials and methods: The present retrospective pharmacogenetic study looked at mBC patients treated with palbociclib/ribociclib/abemaciclib as first- or second-line therapy in association with hormonal therapy (AI or fulvestrant) as per approved label.
Twelve ml of blood was collected at baseline (prior to CDK4/6i) and ESR1 and PIK3CA mutations were evaluated by cfDNA analysis
Results: Among the study population 42 patients samples were successfully analyzed for ESR1 mutations and 13 (30,9 %) were found to have a mutation, 49 patients samples were tested for PIK3CA mutations and 31 (63 %) were found to have a mutation. 37 patients samples were analyzed for both ESR1 and PIK3CA mutations and 9 patients (24,3 %) were found to have both ESR1 and PIK3CA mutations.
No statistically significant differences in terms of PFS were found comparing ESR1 mutant and non mutant patients (13 vs 29 pts: p=0,4257). Also no statistically significant differences in terms of PFS were found comparing PIK3CA mutant and non mutant patients (31 vs 23 pts; p=0.5451). Lastly no statistically significant differences in terms of PFS were found comparing patients who received CDK4/6 inhibitors as first line of treatment that harbor one mutation vs both vs who were wt (21 vs 9 vs 7 pts).
Among patients tested for ESR1 who received adjuvant treatment nine (32%) presented with an ESR1 mutation: in particular two patients were carriers of p.D538G, four harbored p.Y537C, two showed p.E380Q and one had L536R mutation.
Three patients (30 %) received tamoxifen and six patients (50 %) were treated with AI. No statistical difference between the presence of ESR1 mutation and the type of adjuvant hormonal therapy were found (p=0.39). Patients harboring an ESR1 mutation in blood at disease recurrence (first line therapy baseline) had a significantly shorter DFS compared to patients without ESR1 mutations (30 vs 110 months; 9 vs 19 patients p=0.006)
Conclusions: Treatment with CDK4/6 inhibitors is effective regardless of PIK3CA or ESR1 mutational status. Nevertheless, knowing beforehand and monitoring, through a noninvasive method such as liquid biopsy, which patients harbor a PIK3CA and/or a ESR1 mutation, may play a role in guiding therapeutic decisions.
File
Nome file | Dimensione |
---|---|
Thesis not available for consultation. |