Johnston S, et al. - The combination palbociclib plus letrozole was tested as neoadjuvant therapy for primary estrogen receptor (ER)–positive breast cancer (BC) in PALLET, which was a phase II randomized trial. Findings revealed a remarkably enhanced suppression of malignant cell proliferation (Ki-67) in primary ER-positive BC treated with the combination palbociclib plus letrozole, however, this treatment strategy ceased to increase the clinical response rate over 14 weeks, which was possibly associated with a concurrent reduction in apoptosis.

Methods

• Participants were postmenopausal women with ER-positive primary BC and tumors greater than or equal to 2.0 cm.
• Random assignment of these participants 3:2:2:2 to letrozole (2.5 mg/d) for 14 weeks (A); letrozole for 2 weeks, then palbociclib plus letrozole to 14 weeks (B); palbociclib for 2 weeks, then palbociclib plus letrozole to 14 weeks (C); or palbociclib plus letrozole for 14 weeks, was done.
• On a 21-days-on, 7-days-off schedule, oral administration of palbociclib 125 mg/d was done.
• At baseline and 2 and 14 weeks, core-cut biopsies were taken.
• Change in Ki-67 (protein encoded by the MKI67 gene; immunohistochemistry) between baseline and 14 weeks and clinical response (ordinal and ultrasound) after 14 weeks were assessed as coprimary end points for letrozole vs palbociclib plus letrozole groups (A v B + C + D).
• The definition of complete cell-cycle arrest used in this study was Ki-67 less than or equal to 2.7%.
• Apoptosis was characterized by cleaved poly (ADP-ribose) polymerase.

Results

• Researchers recruited 307 patients.
• No remarkably different clinical response was seen between palbociclib plus letrozole and letrozole groups (P=.20; complete response + partial response, 54.3% vs 49.5%), and progressive disease was 3.2% vs 5.4%, respectively.
• With palbociclib plus letrozole vs letrozole, a greater median log-fold change in Ki-67 was observed (−4.1 v −2.2; P < .001) in the 190 evaluable patients (61.9%), corresponding to a geometric mean change of −97.4% vs −88.5%.
• Complete cell-cycle arrest was achieved by more patients on palbociclib plus letrozole (90% v 59%; P < .001).
• With palbociclib plus letrozole vs letrozole, a greater median log-fold change (suppression) of cleaved poly (ADP-ribose) polymerase was observed (−0.80 v −0.42; P < .001).
• Mainly owing to asymptomatic neutropenia, grade 3 or greater toxicity was experienced with palbociclib plus letrozole (49.8% v 17.0%; P < .001) by more patients.