Biomarkers of Response and Resistance to Palbociclib Plus Letrozole in Patients With ER+/HER2- Breast Cancer.
No Thumbnail Available
Embargo End Date
ICR Authors
Authors
Dowsett, M
Kilburn, L
Rimawi, MF
Osborne, CK
Pogue-Geile, K
Liu, Y
Jacobs, SA
Finnigan, M
Puhalla, S
Dodson, A
Martins, V
Cheang, M
Perry, S
Holcombe, C
Turner, N
Swift, C
Bliss, JM
Johnston, S
PALLET trialists,
Kilburn, L
Rimawi, MF
Osborne, CK
Pogue-Geile, K
Liu, Y
Jacobs, SA
Finnigan, M
Puhalla, S
Dodson, A
Martins, V
Cheang, M
Perry, S
Holcombe, C
Turner, N
Swift, C
Bliss, JM
Johnston, S
PALLET trialists,
Document Type
Journal Article
Date
2022-01-01
Date Accepted
2021-10-07
Abstract
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; and (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 baselines 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 tumors showing CCCA but were unchanged in those with no CCCA. Only 2/9 tumors showed CCCA 3-9 days after stopping palbociclib. ESR1 mutations were found in 2/4 tumors for which surgery took place ≥6 months after starting treatment. CONCLUSIONS: 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.
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2021
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Collections
Research Team
Clinical Trials & Statistics Unit