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 and in a minority of patients (6/127, 4.7%, P = 0.041). New driver mutations emerged in PIK3CA (P = 0.00069) and ESR1
after treatment in both arms, in particular ESR1 Y537S (P = 0.0037). Evolution of driver gene mutations was uncommon in patients progressing early on
palbociclib plus
fulvestrant but common in patients progressing later on treatment. These findings inform future treatment strategies to address resistance to
palbociclib plus
fulvestrant.Significance: Acquired mutations from
fulvestrant are a major driver of resistance to
fulvestrant and
palbociclib combination
therapy. ESR1 Y537S mutation promotes resistance to
fulvestrant. Clonal evolution results in frequent acquisition of driver mutations in patients progressing late on
therapy, which suggests that early and late progression have distinct mechanisms of resistance.
Cancer Discov; 8(11); 1390-403. ©2018 AACR. See related commentary by Schiff and Jeselsohn, p. 1352 This article is highlighted in the In This Issue feature, p. 1333.