Biomarkers of Response and Resistance to Palbociclib Plus Letrozole in Patients With ER+/HER2- Breast Cancer

被引：12

作者：

Dowsett, Mitch ^{[1
,2
]}

Kilburn, Lucy ^{[3
]}

Rimawi, Mothaffar F. ^{[4
]}

Osborne, C. Kent ^{[4
]}

Pogue-Geile, Katherine ^{[5
]}

Liu, Yuan ^{[6
]}

Jacobs, Samuel A. ^{[5
]}

Finnigan, Melanie ^{[5
]}

Puhalla, Shannon ^{[5
,7
]}

Dodson, Andrew ^{[1
]}

Martins, Vera ^{[1
]}

Cheang, Maggie ^{[3
]}

Perry, Sophie ^{[3
]}

Holcombe, Chris ^{[8
]}

Turner, Nick ^{[1
,2
]}

Swift, Claire ^{[1
,2
]}

Bliss, Judith M. ^{[3
]}

Johnston, Stephen ^{[1
]}

机构：

[1] Royal Marsden Hosp, London SW3 6JJ, England

[2] Inst Canc Res, Breast Canc Now Toby Robins Ctr Breast Canc Res, London, England

[3] Inst Canc Res, Clin Trials & Stat Unit, Sutton, Surrey, England

[4] Baylor Coll Med, Houston, TX 77030 USA

[5] NSABP Fdn, Pittsburgh, PA USA

[6] Pfizer, New York, NY USA

[7] Univ Pittsburgh, Med Ctr, Canc Ctr, Pittsburgh, PA USA

[8] Royal Liverpool & Broadgreen Univ Hosp Natl Hlth, Liverpool, Merseyside, England

来源：

CLINICAL CANCER RESEARCH | 2022年 / 28卷 / 01期

关键词：

KINASE; 4/6; INHIBITOR; ENDOCRINE THERAPY; PROGNOSTIC VALUE; OPEN-LABEL; TAMOXIFEN; PROLIFERATION; ANASTROZOLE; COMBINATION; MULTICENTER; EXPRESSION;

D O I：

10.1158/1078-0432.CCR-21-1628

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. lmmunohistochemical 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.

引用

页码：163 / 174

页数：12

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