Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor–Positive Early Breast Cancer: PALLET Trial
| Autor: | David Dolling, Maria Koehler, Robert Stein, Mothaffar F. Rimawi, Stuart McIntosh, Vera Martins, Sophie Perry, Cynthia Huang Bartlett, Maggie Wilcox, Chris Holcombe, C. Kent Osborne, Claire Snowdon, Arjun Modi, Peter A. Barry, Duncan Wheatley, Andrew Dodson, Ibrahim A. Shalaby, Katherine L. Pogue-Geile, Mairead MacKenzie, Jean Francois Boileau, Mitch Dowsett, Shannon Puhalla, Kate Fisher, Alistair Ring, Louise Provencher, James P Morden, Maggie C.U. Cheang, Thomas B. Julian, Stephen R. D. Johnston, Chester Cornman, Judith M Bliss, M. Thirlwell, Leona M. Batten, Norman Wolmark, André Robidoux, Lisa K. Jeffs, Samuel A. Jacobs |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Oncology Cancer Research medicine.medical_specialty Pyridines Receptor ErbB-2 medicine.medical_treatment Estrogen receptor Phases of clinical research Breast Neoplasms Palbociclib Drug Administration Schedule Piperazines law.invention 03 medical and health sciences 0302 clinical medicine Randomized controlled trial SDG 3 - Good Health and Well-being law Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans Protein Kinase Inhibitors Neoadjuvant therapy Aged Chemotherapy business.industry Aromatase Inhibitors Letrozole Middle Aged medicine.disease Metastatic breast cancer Neoadjuvant Therapy Postmenopause 030104 developmental biology Receptors Estrogen Chemotherapy Adjuvant 030220 oncology & carcinogenesis Female business medicine.drug |
| Zdroj: | Johnston, S, Puhalla, S, Wheatley, D, Ring, A, Barry, P, Holcombe, C, Boileau, J F, Provencher, L, Robidoux, A, Rimawi, M, McIntosh, S A, Shalaby, I, Stein, R C, Thirlwell, M, Dolling, D, Morden, J, Snowdon, C, Perry, S, Cornman, C, Batten, L M, Jeffs, L K, Dodson, A, Martins, V, Modi, A, Kent Osborne, C, Pogue-Geile, K L, Cheang, M C U, Wolmark, N, Julian, T B, Fisher, K, MacKenzie, M, Wilcox, M, Bartlett, C H, Koehler, M, Dowsett, M, Bliss, J M & Jacobs, S A 2019, ' Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor–Positive Early Breast Cancer: PALLET Trial ', Journal of Clinical Oncology, vol. 37, no. 3, pp. 178-189 . https://doi.org/10.1200/JCO.18.01624 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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