Journal article
The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial
B O’leary, RJ Cutts, Y Liu, S Hrebien, X Huang, K Fenwick, F André, S Loibl, S Loi, I Garcia-Murillas, M Cristofanilli, CH Bartlett, NC Turner
Cancer Discovery | AMER ASSOC CANCER RESEARCH | Published : 2018
Abstract
CDK4/6 inhibition with endocrine therapy is now a standard of care for advanced estrogen receptor–positive breast cancer. Mechanisms of CDK4/6 inhibitor resistance have been described preclinically, with limited evidence from clinical samples. We conducted paired baseline and end-of-treatment circulating tumor DNA sequencing from 195 patients in the PALOMA-3 randomized phase III trial of palbociclib plus fulvestrant versus placebo plus fulvestrant. We show that clonal evolution occurs frequently during treatment, reflecting substantial subclonal complexity in breast cancer that has progressed after prior endocrine therapy. RB1 mutations emerged only in the palbociclib plus fulvestrant arm an..
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Awarded by Merck
Funding Acknowledgements
We thank the patients, families, and trial staff who took part in the PALOMA-3 trial. We thank Francesca Demichelis and Alessandro Romanel for their help in performing the CLONET validation analyses, Irene Chong for assistance with MYC amplification validation by digital PCR, and Erle Holgersen for advice regarding the circos plots. This research was funded by The Medical Research Council (MR/N002121/1) and Breast Cancer Now with support from the Mary-Jean Mitchell Green Foundation and Pfizer. ICR-CTSU receives program grant funding from Cancer Research UK (grant C1491/A15955). We acknowledge National Institute for Health Research funding to the Royal Marsden and Institute of Cancer Research Biomedical Research Centre.