Biomarkers of response and resistance to palbociclib plus letrozole in patients with ER+/HER2- breast cancer.

Purpose: To determine (i) the relationship between candidate biomarkers of the antiproliferative (Ki67) response to letrozole and palbociclib alone and combined in ER+/HER2- breast cancer; (ii) the pharmacodynamic effect of the agents on the biomarkers. Experimental design: 307 postmenopausal women with ER+/HER2- primary breast cancer were randomly assigned to neoadjuvant treatment with letrozole for 14 weeks; letrozole for 2 weeks, then letrozole+palbociclib to 14 weeks; palbociclib for 2 weeks, then letrozole+palbociclib to 14 weeks; or letrozole+palbociclib for 14 weeks. Biopsies were taken at baseline, 2 and 14 weeks and surgery at varying times after stopping palbociclib. Immunohistochemical analyses were conducted for Ki67, c-PARP, ER, PgR, RB1, CCNE1 and CCND1. Results: Higher baseline ER and PgR were significantly associated with a greater chance of Complete Cell Cycle Arrest (CCCA: Ki67 <2.7%) at 14 weeks and higher baseline Ki67, c-PARP and CCNE1 with a lower chance. The interaction with treatment was significant only for c-PARP. CCND1 levels were decreased c.20% by letrozole at 2 and 14 weeks but showed a tendency to increase with palbociclib. CCNE1 levels fell 82% (median) in tumours showing CCCA but were unchanged in those with no CCCA. Only 2/9 tumours showed CCCA 3-9 days after stopping palbociclib. ESR1 mutations were found in 2/4 tumours for which surgery took place {greater than or equal to}6 months after starting treatment. Conclusion: High CCNE1 levels were confirmed as a biomarker of resistance to letrozole+palbociclib. Ki67 recovery within 3-9 days of discontinuing palbociclib indicates incomplete suppression of proliferation during the "off" week of its schedule.