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Ref Type Journal Article
PMID (30206110)
Authors O'Leary B, Cutts RJ, Liu Y, Hrebien S, Huang X, Fenwick K, André F, Loibl S, Loi S, Garcia-Murillas I, Cristofanilli M, Huang Bartlett C, Turner NC
Title The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial.
Abstract Text 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. 1352This article is highlighted in the In This Issue feature, p. 1333.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RB1 mutant estrogen-receptor positive breast cancer predicted - resistant Palbociclib Phase III Actionable In a Phase III trial (PALOMA-3), acquired RB1 mutations were identified in patents with ER-positive, ERBB2 (HER2)-negative breast cancer at the end of treatment in the Faslodex (fulvestrant) plus Ibrance (palbociclib) but not the Faslodex (fulvestrant) plus placebo arm, suggesting a role in conferring resistance to Ibrance (palbociclib) (PMID: 30206110; NCT01942135). 30206110