442O - Cell cycle biomarker analysis from the PALOMA-1/ TRIO 18 palbociclib plus letrozole phase II study in ER-positive/HER2-negative advanced breast can...

Date 27 September 2014
Event ESMO 2014
Session Developmental therapeutics
Topics Pathology/Molecular Biology
Translational Research
Breast Cancer
Basic Scientific Principles
Basic Principles in the Management and Treatment (of cancer)
Presenter Yuqiu Jiang
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors Y. Jiang1, S. Randolph1, P. English2, S. Kim2, X. Huang2, M.F. Press3, D. Slamon4, R. Finn5
  • 1Pfizer Oncology Business Unit, Pfizer Inc, 92121 - San Diego/US
  • 2Pfizer Oncology, Pfizer Inc, San Diego/US
  • 3Keck School Of Medicine Department Of Pathology, USC / Norris Comprehensive Cancer Center, Los Angeles/US
  • 4Division Of Hematology/oncology, UCLA School of Medicine, Los Angeles/US
  • 5Jonsson Cancer Center, UCLA, Los Angeles/US



Palbociclib (P) is a highly selective, reversible inhibitor of CDK 4/6. Preclinical data identified breast cancer cell lines representing ER+ luminal breast cancer as more sensitive to the anti-proliferative effects of P and with lower levels of CDKN2A and higher levels of Rb and CCND1 by RNA expression. Based on these data, a phase 2 randomized study of P plus letrozole (P + L) vs. L alone in the first-line treatment of postmenopausal women with ER + /HER2- ABC was conducted. Final results demonstrated a significant improvement in progression-free survival (PFS) with P + L (HR = 0.488; 95% CI 0.319-0.748, p = 0.0004) (Finn et al AACR 2014). We assessed potential biomarkers both retrospectively and prospectively, and their relationship with PFS.


165 patients were randomized. CCND1 and CDKN2A copy numbers were determined by four-color FISH assay. The expressions of pRb, CCND1, and Ki67 were measured by validated IHC assays at central laboratories.


The study consisted 2 parts. Part 1 (N = 66) enrolled patients (pts) with ER + /HER2- ABC. 46 of 66 pts had tissue available for retrospective CCND1 and CDKN2A FISH analysis. 21 pts were biomarker positive (BM+) (CCND1/CEP11 ratio ≥ 1.5 and/or CDKN2A/CEP9 ratio < 0.8) and 25 pts were BM negative (BM-). In the BM+ group, median PFS was 26.1 months (mos) for P + L and 7.5 mos for L alone (HR = 0.2, 95% CI: 0.07-0.71). For the BM- group, the median PFS was 35.3 mos for P + L and 5.7 mos for L alone (HR = 0.2, 95% CI: 0.07-0.71). Part 2 (N = 99) enrolled ER + /HER2- pts prospectively selected for being BM+. The median PFS was 18.1 mos and 11.1 mos for P + L and L, respectively (HR = 0.508, 95% CI: 0.303-0.853, p = 0.0046). Ki67 values were measured in 145 pts and no significant differences in PFS for Ki67 >20% vs. ≤20% were observed. 80 /165 pts had tissue for cyclin D1 and pRb protein IHC. 73/79 (92.4%) and 73/77 (94.8%) were positive for cyclin D1 and pRb, respectively.


P + L provides a consistent benefit in ER + /HER2- ABC compared to L alone. Both BM+ and BM- pts benefited from P + L. Ki67 staining did not identify a subgroup that benefited more from P + L. As expected, over 90% of the pts analyzed stained positive for pRb and cyclin D1.


Y. Jiang, S. Randolph, P. English, S. Kim and X. Huang: Employment: Pfizer; D. Slamon and R.S. Finn:: Research Support: Pfizer. All other authors have declared no conflicts of interest.