Addition of Neoadjuvant Palbociclib to Letrozole in Estrogen Receptor–Positive Early Breast Cancer


Key Points

  • No difference in clinical response rates were observed between palbociclib plus letrozole vs letrozole.
  • Palbociclib plus letrozole was associated with increased complete cell-cycle arrest but reduced apoptosis vs letrozole.

In the phase II PALLET trial reported in the Journal of Clinical Oncology, Johnston et al found that the addition of neoadjuvant palbociclib (Ibrance) to letrozole increased rates of complete cell-cycle arrest, reduced apoptosis, and did not significantly improve clinical response rate in patients with estrogen receptor–positive early breast cancer.

Study Details

In the trial, 307 women from sites in the United Kingdom and North America were randomly allocated 3:2:2:2 between February 2015 and March 2018 to receive one of the following 4 treatment courses:

  • Letrozole at 2.5 mg/d for 14 weeks (n = 103)
  • Letrozole for 2 weeks, then palbociclib plus letrozole to 14 weeks (n = 68)
  • Palbociclib for 2 weeks, then palbociclib plus letrozole to 14 weeks (n = 69)
  • Palbociclib plus letrozole for 14 weeks (n = 67).

Palbociclib was given at 125 mg/d on a 21-days-on, 7-days-off schedule. Core-cut biopsies were obtained at baseline and at 2 and 14 weeks. The primary outcome measures were change in Ki-67 protein as a measure of malignant cell proliferation at 14 weeks (complete cell-cycle arrest defined as ≤ 2.7%) and clinical response at 14 weeks for patients receiving letrozole alone vs those receiving the combination (total = 204). Apoptosis was measured as change in cleaved poly (ADP-ribose) polymerase (cPARP).

Treatment Outcomes

Overall response rates were 54.3% in the combined palbociclib/letrozole groups vs 49.5% in the letrozole group (P = .20), with progressive disease observed in 3.2% vs 5.4%. Among 190 evaluable patients, median log-fold change in Ki-67 at 14 weeks was −4.1 for palbociclib-letrozole vs −2.2 for letrozole, with complete cell-cycle arrest occurring in 90% vs 59% of patients (P < .001). Median log-fold reduction in cPARP, representing a decrease in apoptosis, was −0.80 vs −0.42 (P < .001). Grade ≥ 3 adverse events occurred in 50% of the palbociclib-plus-letrozole groups, consisting mainly of neutropenia (41%), vs 17% of the letrozole-alone group (P < .001).

The investigators concluded, “Adding palbociclib to letrozole significantly enhanced the suppression of malignant cell proliferation (Ki-67) in primary [estrogen receptor]–positive [breast cancer], but did not increase the clinical response rate over 14 weeks, which was possibly related to a concurrent reduction in apoptosis.”

Stephen Johnston, MD, PhD, of The Royal Marsden NHS Foundation Trust, London, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by Pfizer. The study authors’ full disclosures can be found at

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