Abstract 10P
Background
A possible association between changes in tumor variant allele fraction (VAF) from baseline to cycle 2/ day 1 (C2D1) using the 74-gene Guardant360 assay and progression free survival (PFS) was observed in 45 patients (pts) with ABC treated with a CDK4/6i + ET. Here, we tested the same methodology in an independent dataset and explored the association between overall survival (OS), intrinsic subtype (IS) and ctDNA dynamics.
Methods
Baseline and C2D1 plasma samples were obtained from 113 pts with HR+/HER2-negative ABC treated with CDK4/6i + ET in an international, multicentric observational study. The first 45 pts were used to derive the mean VAF ratio (mVAFR: mean of the log VAFR for all mutations) methodology associated with PFS (NPJ Breast Cancer 2021). mVAFR was calculated for each alteration with a VAF ≥0.4% at any time point. Pts with VAFs <0.4% at all timepoints were considered to have ctDNA-low disease. Molecular response was defined by the mVAFR. The main objective was to assess the association of mVAFR with PFS in the 68-pt independent validation cohort. We also explored the association of mVAFR with OS (n=113) and with IS (n=54). PFS and OS uni- and multivariable cox models were performed adjusting for clinical variables.
Results
With a median follow up (mFUP) of 16.6 months (m), pts with medium or high mVAFR had shorter median PFS than pts with low mVAFR and ctDNA-low disease (11.2 vs 25.0m; adjusted hazard ratio [aHR]=2.85, 95% confidence interval [CI] 1.2-6.7, p=0.017). mVAFR as a continuous variable was also found associated with PFS (HR=2.0, 95% CI 1.0–4.1, p=0.047). In the 113-pt combined cohort, with a mFUP of 19.4m, pts with medium or high mVAFR had shorter OS than pts with either low mVAFR or ctDNA-low disease (31.3m vs not reached; aHR=10.9, 95% CI 3.7-31.6, p<0.001). mVAFR as a continuous variable was also found associated with OS (aHR=4.1, 95% CI 1.7-9.5, p<0.001). Finally, mVAFR was associated with IS (p=0.022).
Conclusions
Early ctDNA dynamics after CDK4/6i + ET can identify different pt populations. The absence of molecular response identifies pts with poor outcome, and future studies should focus on improving treatment options for this population.
Legal entity responsible for the study
The authors.
Funding
AstraZeneca.
Disclosure
O. Martinez Saez: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel expenses: Roche; Financial Interests, Personal, Other, Medical advisory: Reveal Genomics. F. Brasó-Maristany: Financial Interests, Personal, Invited Speaker: Reveal Genomics. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Lilly. M. Munoz: Financial Interests, Personal, Expert Testimony: Roche; Financial Interests, Personal, Expert Testimony: Novartis; Financial Interests, Personal, Other, International conference travel grants: Roche; Financial Interests, Personal, Other, International conference travel grants: Pfizer; Financial Interests, Personal, Other, International conference travel grants: Lilly; Financial Interests, Personal, Expert Testimony: Eisai; Financial Interests, Personal, Advisory Board: Pierre Fabre. I. Faull: Financial Interests, Member of the Board of Directors: Guardant Health. J. Odegaard: Financial Interests, Personal, Member of the Board of Directors: Guardant Health. G. Patel: Financial Interests, Personal, Member of the Board of Directors: AstraZeneca. R. McEwen: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. D. Carroll: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. E.M. Ciruelos: Financial Interests, Personal, Other, Speakers Bureau. Educational activities: Roche; Financial Interests, Personal, Invited Speaker, Symposia and Educational activities: Roche; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Roche; Financial Interests, Personal, Other, Speakers Bureau. Educational activities: Lilly; Financial Interests, Personal, Invited Speaker, Symposia and Education: Lilly; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Lilly; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Novartis; Financial Interests, Personal, Invited Speaker, Educational activities: Pfizer; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Pfizer; Financial Interests, Personal, Advisory Board, Non-permanent advisor: AstraZeneca; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Non-permanent advisor: MSD; Financial Interests, Institutional, Funding, PI for Patricia 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for Prometeo 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for TATEN trial (sponsor: SOLTI Group): MSD; Financial Interests, Institutional, Funding, PI for NEREA trial (sponsor: SOLTI Group): Puma; Financial Interests, Institutional, Funding, PI for ATREZZO trial (sponsor: SOLTI Group): Roche; Non-Financial Interests, Invited Speaker, Non-profit organization dedicated to breast cancer research: SOLTI Cooperative Group; Non-Financial Interests, Advisory Role, Scientific Evaluator at ISCIII (Spanish Government Academic Research Platform): Instituto de Salud Carlos III. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Contracted research:: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Amgen; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Amgen; Financial Interests, Personal, Invited Speaker, Lecture fees: BMS; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: BMS; Financial Interests, Personal, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: NanoString; Financial Interests, Institutional, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: Novartis; Financial Interests, Institutional, Other, Contracted research: Roche; Financial Interests, Institutional, Other, Contracted research: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Contracted research; Financial Interests, Personal, Invited Speaker, Lecture fees: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Puma; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Oncolytics; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: MSD; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Guardan Health; Financial Interests, Personal, Expert Testimony, Advisory role/consultancy: Peptomyc; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Lilly; Financial Interests, Institutional, Other, Clinical trials: Lilly; Financial Interests, Institutional, Other, Contracted research: Boehringer; Financial Interests, Institutional, Other, Contracted research: Sysmex Europa GmbH; Financial Interests, Institutional, Other, Contracted research: Medica Scientia inno. Research; Financial Interests, Institutional, Other, Contracted research: Celgene; Financial Interests, Institutional, Other, Contracted research: Astellas; Financial Interests, Institutional, Other, Clinical trials: Roche; Financial Interests, Institutional, Other, Clinical trials: Amgen; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Institutional, Other, Clinical trials: Boehringer; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: Actitud Frente al Cáncer Foundation. All other authors have declared no conflicts of interest.