TY - JOUR
T1 - Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer
AU - O'Leary, Ben
AU - Hrebien, Sarah
AU - Morden, James P.
AU - Beaney, Matthew
AU - Fribbens, Charlotte
AU - Huang, Xin
AU - Liu, Yuan
AU - Bartlett, Cynthia Huang
AU - Koehler, Maria
AU - Cristofanilli, Massimo
AU - Garcia-Murillas, Isaac
AU - Bliss, Judith M.
AU - Turner, Nicholas C.
N1 - Funding Information:
We thank the patients, families, and trial staff who took part in the PALOMA-3 trial. This research was funded by The Medical Research Council (MR/N002121/1), Breast Cancer Now with support from the Mary-Jean Mitchell Green Foundation, Le Cure, 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.
Publisher Copyright:
© The Author(s) 2018.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-03215-x
DO - 10.1038/s41467-018-03215-x
M3 - Article
C2 - 29497091
AN - SCOPUS:85042846495
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 896
ER -
