• Stephen Johnston, Shannon Puhalla, Duncan Wheatley, Alistair Ring, Peter Barry, Chris Holcombe, Jean Francois Boileau, Louise Provencher, André Robidoux, Mothaffar Rimawi, Stuart A McIntosh, Ibrahim Shalaby, Robert C Stein, Michael Thirlwell, David Dolling, James Morden, Claire Snowdon, Sophie Perry, Chester Cornman, Leona M Batten, Lisa K Jeffs, Andrew Dodson, Vera Martins, Arjun Modi, C Kent Osborne, Katherine L Pogue-Geile, Cheang Maggie Chon U MCU 14 The Institute of Cancer Research, London, United Kingdom., Norman Wolmark, Thomas B Julian, Kate Fisher, Mairead MacKenzie, Maggie Wilcox, Cynthia Huang Bartlett, Maria Koehler, Mitch Dowsett, Judith M Bliss, and Samuel A Jacobs.
• 1 The Royal Marsden National Health Service Foundation Trust, London, United Kingdom.
• J. Clin. Oncol. 2019 Jan 20; 37 (3): 178-189.

PurposeCDK4/6 inhibitors are used to treat estrogen receptor (ER)-positive metastatic breast cancer (BC) in combination with endocrine therapy. PALLET is a phase II randomized trial that evaluated the effects of combination palbociclib plus letrozole as neoadjuvant therapy.Patients And MethodsPostmenopausal women with ER-positive primary BC and tumors greater than or equal to 2.0 cm were randomly assigned 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. Palbociclib 125 mg/d was administered orally on a 21-days-on, 7-days-off schedule. Core-cut biopsies were taken at baseline and 2 and 14 weeks. Coprimary end points for letrozole versus palbociclib plus letrozole groups (A v B + C + D) were 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. Complete cell-cycle arrest was defined as Ki-67 less than or equal to 2.7%. Apoptosis was characterized by cleaved poly (ADP-ribose) polymerase.ResultsThree hundred seven patients were recruited. Clinical response was not significantly different between palbociclib plus letrozole and letrozole groups ( P = .20; complete response + partial response, 54.3% v 49.5%), and progressive disease was 3.2% versus 5.4%, respectively. Median log-fold change in Ki-67 was greater with palbociclib plus letrozole compared with letrozole (-4.1 v -2.2; P < .001) in the 190 evaluable patients (61.9%), corresponding to a geometric mean change of -97.4% versus -88.5%. More patients on palbociclib plus letrozole achieved complete cell-cycle arrest (90% v 59%; P < .001). Median log-fold change (suppression) of cleaved poly (ADP-ribose) polymerase was greater with palbociclib plus letrozole versus letrozole (-0.80 v -0.42; P < .001). More patients had grade 3 or greater toxicity on palbociclib plus letrozole (49.8% v 17.0%; P < .001) mainly because of asymptomatic neutropenia.ConclusionAdding palbociclib to letrozole significantly enhanced the suppression of malignant cell proliferation (Ki-67) in primary ER-positive BC, but did not increase the clinical response rate over 14 weeks, which was possibly related to a concurrent reduction in apoptosis.

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