Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer

Ben O’Leary, Sarah Hrebien, James P. Morden, Matthew Beaney, Charlotte Fribbens, Xin Huang, Yuan Liu, Cynthia Huang Bartlett, Maria Koehler, Massimo Cristofanilli, Isaac Garcia-Murillas, Judith M. Bliss and Nicholas C. Turner ()
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Ben O’Leary: The Institute of Cancer Research
Sarah Hrebien: The Institute of Cancer Research
James P. Morden: The Institute of Cancer Research Clinical Trials and Statistics Unit
Matthew Beaney: The Institute of Cancer Research
Charlotte Fribbens: The Institute of Cancer Research
Xin Huang: Pfizer
Yuan Liu: Pfizer
Cynthia Huang Bartlett: Pfizer
Maria Koehler: Pfizer
Massimo Cristofanilli: Feinberg School of Medicine
Isaac Garcia-Murillas: The Institute of Cancer Research
Judith M. Bliss: The Institute of Cancer Research Clinical Trials and Statistics Unit
Nicholas C. Turner: The Institute of Cancer Research

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract CDK4/6 inhibition substantially improves progression-free survival (PFS) for women with advanced estrogen receptor-positive breast cancer, although there are no predictive biomarkers. Early changes in circulating tumor DNA (ctDNA) level may provide early response prediction, but the impact of tumor heterogeneity is unknown. Here we use plasma samples from patients in the randomized phase III PALOMA-3 study of CDK4/6 inhibitor palbociclib and fulvestrant for women with advanced breast cancer and show that relative change in PIK3CA ctDNA level after 15 days treatment strongly predicts PFS on palbociclib and fulvestrant (hazard ratio 3.94, log-rank p = 0.0013). ESR1 mutations selected by prior hormone therapy are shown to be frequently sub clonal, with ESR1 ctDNA dynamics offering limited prediction of clinical outcome. These results suggest that early ctDNA dynamics may provide a robust biomarker for CDK4/6 inhibitors, with early ctDNA dynamics demonstrating divergent response of tumor sub clones to treatment.

Date: 2018
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DOI: 10.1038/s41467-018-03215-x

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