L. Biganzoli (Prato, Italy)
Nuovo Ospedale di Prato Santo Stefano - Azienda Usl Toscana CentroAuthor Of 1 Presentation
Mentor (ID 377)
Presenter Of 1 Presentation
Mentor (ID 377)
Author Of 1 Presentation
- L. Malorni (Prato, Italy)
- M. Benelli (Prato, Italy)
- F. Galardi (Prato, Italy)
- C. Biagioni (Prato, Italy)
- G. Curigliano (Milan, Italy)
- A. Minisini (Udine, Italy)
- E. Moretti (Prato, Italy)
- E. Risi (Prato, Italy)
- F. De Luca (Prato, Italy)
- A. McCartney (Melbourne, VI, Australia)
- A. Di Leo (Prato, Italy)
- L. Biganzoli (Prato, Italy)
- I. Migliaccio (Prato, Italy)
8P - Mutational analysis of circulating tumor DNA (ctDNA) in patients with ER+/HER2- advanced breast cancer (ABC) receiving palbociclib (P): results from the TREnd trial.
Abstract
Background
Cyclin-dependent kinase 4 and 6 inhibitors like palbociclib (P) are a mainstay of treatment for ER+/HER2- ABC; however intrinsic or acquired resistance is a major clinical issue. We performed a mutational analysis on ctDNA samples from patients (pts) included in the c-TREnd study, the translational cohort of the TREnd trial (NCT02549430) which randomized pts to receive P alone or in combination with the endocrine treatment (ET) to which they had progressed in the previous line of ET.
Methods
Forty-six pts were enrolled in c-TREnd. Plasma was collected before treatment (T0), after the first cycle of therapy (T1) and at the time of progression (T2). Hybridization and capture were performed using the TruSight Tumor 170 Kit (Illumina). Single nucleotide variants (SNVs) were detected and annotated using LoFreq and Oncotator, and further refined by ABEMUS. Tumor Mutational burden (TMB) was the sum of silent and non-silent mutations. Tumor fraction (TF) was based on the dispersion of Copy Number Alteration (CNA) genomic profiles. Progression free survival (PFS) was estimated using the Kaplan–Meier method and compared with the log-rank test.
Results
Thirty-two pts (87 samples), 14 from the P arm and 18 from the P+ET arm, were included in the final analysis. The most frequently mutated genes at T0 were ESR1 (23%), PIK3CA (17%), AR, FGFR2 and TP53 (10%). At T0, mutations in ESR1, but not in PIK3CA, were significantly prognostic (median PFS – mPFS 3.7 mo vs 11 mo in ESR1 mut vs WT, p=0.015). A significantly worse mPFS was observed when a broader analysis of PI3K pathway (adding AKT1, PTEN, TSC1/2 and BRAF) was performed (mPFS 5.2 m in mut vs 10.8 m in WT, p=0.04). Mutations in AR tended to confer a better, although not statistically significant, mPFS (14.2 mo vs 5.5 in WT, p=0.29). At T2 we observed the emergence of 9 new mutations in 7 genes (ESR1, AKT1, ARID1A, BRIP1, CCNE1, MTOR and TP53). TMB and TF at T0 or TF change between T1 and T0 were not associated with PFS.
Conclusions
Mutations in ESR1 and in PI3K pathway genes were associated with worse prognosis in pts treated with P, while TMB and TF were not. Larger studies are needed to validate these observations.
Legal entity responsible for the study
Fondazione Sandro Pitigliani per la Lotta Contro i Tumori ONLUS.
Funding
Pfizer.
Disclosure
L. Malorni: Advisory/Consultancy: Eli Lilly; Advisory/Consultancy, Research grant/Funding (self): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Novartis. M. Benelli: Honoraria (self): Novartis. G. Curigliano: Advisory/Consultancy: Novartis; Advisory/Consultancy: Roche; Advisory/Consultancy: Lilly; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Veracyte; Advisory/Consultancy: Genomic Health; Honoraria (self): Ellipsis. A.M. Minisini: Advisory/Consultancy: Novartis; Advisory/Consultancy: MSD; Advisory/Consultancy: Pierre Fabre; Speaker Bureau/Expert testimony: SunPharma. E. Risi: Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Amgen; Honoraria (self): Lilly. A. Di Leo: Honoraria (institution), Advisory/Consultancy: Lilly; Honoraria (institution), Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer; Honoraria (institution), Advisory/Consultancy: AstraZeneca. L. Biganzoli: Advisory/Consultancy: Lilly; Honoraria (institution), Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer. All other authors have declared no conflicts of interest.