Cristofanilli, Massimo

Huang Bartlett, Cynthia

Turner, Nicholas C

Jefferson Digital Commons

Thomas Jefferson UniversityJefferson Digital CommonsDepartment of Medicine Faculty Papers Department of Medicine10-22-2015Palbociclib in Hormone-Receptor-PositiveAdvanced Breast Cancer.Nicholas C TurnerRoyal Marsden Hospital, London, United KingdomCynthia Huang BartlettPfizer, New York, NY, United StatesMassimo CristofanilliThomas Jefferson University, Philadelphia, PA, United States, Massimo.Cristofanilli@jefferson.eduLet us know how access to this document benefits youFollow this and additional works at: http://jdc.jefferson.edu/medfpPart of the Other Medical Specialties CommonsThis Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of ThomasJefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarlypublications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers andinterested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion inDepartment of Medicine Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact:JeffersonDigitalCommons@jefferson.edu.Recommended CitationTurner, Nicholas C; Huang Bartlett, Cynthia; and Cristofanilli, Massimo, "Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer." (2015). Department of Medicine Faculty Papers. Paper156.http://jdc.jefferson.edu/medfp/156n engl j med 373;17 nejm.org october 22, 20151672T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n ec o r r e s p o n d e n c ePalbociclib in Hormone-Receptor–Positive Advanced  Breast CancerTo the Editor: In the PALOMA3 study, Turner et al. (July 16 issue)1 report that the addition of pal-bociclib to fulvestrant improved progression-free survival as compared with fulvestrant alone in pa-tients with advanced breast cancer, with similar discontinuation rates because of adverse effects (2.6% and 1.7%, respectively). However, molecu-larly targeted therapies have moderate toxic effects that may become unacceptable over the long term and result in a deterioration in the quality of life, as shown in a previous report.2,3 The PALOMA1 study, a previous phase 2 trial of palbociclib with a median follow-up of approximately 30 months, showed that the combination of palbociclib and letrozole, as compared with letrozole alone, was associated with higher rates of discontinuation (11% vs. 2%) and dose interruption (33% vs. 4%) because of adverse effects.4 Furthermore, the rate of pulmonary embolism in the PALOMA1 study was higher than that in the PALOMA3 study (4% vs. 0.9%). Thus, because the authors report the results of a predetermined interim analysis with a median observation period of only 5.6 months, it is possible that further follow-up may reveal long-term toxic effects that disturb the regular administration of the combination therapy or hamper the use of subsequent therapies.Akihiko Ozaki, M.D.Minamisoma Municipal General Hospital Fukushima, Japan ozakiakihiko@gmail.comTetsuya Tanimoto, M.D.Jyoban Hospital Fukushima, JapanShigehira Saji, M.D., Ph.D.Fukushima Medical University Fukushima, JapanDr. Saji reports receiving lecture fees from Pfizer. No other potential conflict of interest relevant to this letter was reported.1. Turner NC, Ro J, André F, et al. Palbociclib in hormone-recep-tor–positive advanced breast cancer. N Engl J Med 2015;373:209-19.2. Soria JC. Phase 1 trials of molecular targeted therapies: are we evaluating toxicities properly? Eur J Cancer 2011;47:1443-5.3. Ratain MJ. Targeted therapies: redefining the primary objec-tive of phase I oncology trials. Nat Rev Clin Oncol 2014;11:503-4.4. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2015;16:25-35.DOI: 10.1056/NEJMc1510345The authors reply: In the PALOMA3 study, on the advice of the independent data and safety monitoring committee, we reported substantial efficacy for palbociclib in combination with ful-vestrant at the time of the interim analysis. The median of 5.6 months of follow-up at the interim analysis was too short a period to assess possible long-term adverse effects associated with palbo-ciclib. Ozaki and colleagues note that molecularly targeted therapies may have long-term low-grade toxic effects and suggest that such adverse events can lead to a reduced quality of life. In contrast, in PALOMA3, patients’ quality of life was main-tained among those receiving palbociclib–fulves-trant as compared with substantial deterioration among those receiving fulvestrant alone.Follow-up continues in the PALOMA3 study, this week’s letters1672 Palbociclib in Hormone-Receptor–Positive  Advanced Breast Cancer1673 Somatic Mutations and Clonal Hematopoiesis  in Aplastic Anemia1676 Ischemic Optic Neuropathiest1677 The 21st Century Cures Act1680 Intravenous Immune Globulin for Statin-Triggered Autoimmune MyopathyThe New England Journal of Medicine Downloaded from nejm.org at THOMAS JEFFERSON UNIVERSITY on May 8, 2016. For personal use only. No other uses without permission.  Copyright © 2015 Massachusetts Medical Society. All rights reserved. correspondencen engl j med 373;17 nejm.org october 22, 2015 1673and we will be updating efficacy and safety data. The first updated data, which were collect-ed in March 2015 with a median follow-up of 8.9 months, showed that the rate of pulmonary embolism remained low (0.9%) among patients treated with palbociclib. Moreover, the discon-tinuation rate because of adverse effects among patients receiving palbociclib remained at 4.0%, as compared with a rate of 1.7% for those receiv-ing fulvestrant alone. These findings support the long-term safety of palbociclib that was reported in the smaller PALOMA1 study.1Nicholas C. Turner, M.D., Ph.D.Royal Marsden Hospital London, United Kingdom nicholas.turner@icr.ac.ukCynthia Huang Bartlett, M.D.Pfizer New York, NYMassimo Cristofanilli, M.D.Thomas Jefferson University Philadelphia, PASince publication of their article, the authors report no fur-ther potential conflict of interest.1. Slamon D, Crown J, Lang I, et al. Long-term safety profile of palbociclib (P) in combination with letrozole (L) as first-line treat-ment for postmenopausal patients with ER+ and HER2- advanced breast cancer (ABC) (PALOMA-1/TRIO-18). J Clin Oncol 2015;33. abstract.DOI: 10.1056/NEJMc1510345Somatic Mutations and Clonal Hematopoiesis  in Aplastic AnemiaTo the Editor: In their study involving 439 pa-tients with aplastic anemia, Yoshizato and col-leagues (July 2 issue)1 bring us closer to under-standing clonal hematopoiesis in patients with this disease. However, a key conceptual aspect of the study is that the investigators prescreened patients for somatic mutations in genes that are mutated in myeloid cancers using targeted sequencing, followed by whole-exome sequencing, mainly in patients with mutations in the targeted genes. Fur-thermore, the study population included those with the post–aplastic anemia myelodysplastic syn-drome (MDS), which further biased the identified pattern of clonal hematopoiesis toward MDS-asso-ciated mutations. Using an unbiased approach of comparative whole-exome sequencing of bone marrow and skin DNA, we recently found so-matic mutations in 73% of 22 patients with aplastic anemia who were not prescreened with targeted sequencing.2 None of the patients who were included in our study had evidence of mye-lodysplasia. Somatic mutations were significantly enriched in pathways of immunity, whereas only 9% of the patients carried mutations associated with MDS. Further studies using unbiased ap-proaches with long-term follow-up will help to capture the full spectrum and biologic signifi-cance of clonal hematopoiesis in aplastic anemia.Daria V. Babushok, M.D., Ph.D.Hospital of the University of Pennsylvania Philadelphia, PATimothy S. Olson, M.D., Ph.D. Monica Bessler, M.D., Ph.D.Children’s Hospital of Philadelphia Philadelphia, PANo potential conflict of interest relevant to this letter was re-ported.1. Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic muta-tions and clonal hematopoiesis in aplastic anemia. N Engl J Med 2015;373:35-47.2. Babushok DV, Perdigones N, Perin JC, et al. Emergence of clonal hematopoiesis in the majority of patients with acquired aplastic anemia. Cancer Genet 2015;208:115-28.DOI: 101056/NEJMc1509703To the Editor: Yoshizato et al. report that so-matically mutated clones are detectable in 47% of patients with aplastic anemia. The single most frequently mutated gene was DNMT3A (in 8.4% of patients), which, along with ASXL1, was as-sociated with a poorer response to immunosup-pressive therapies than were mutations in PIGA or BCOR/BCORL1 and with worse overall survival. However, we notice that DNMT3A mutations were almost twice as frequent among Japanese patients as among U.S. patients. In the Japanese patients, whole blood was compared with buccal-smear DNA; in the U.S. patients, granulocytes were compared with CD3+ T cells. Since DNMT3A-mutated clones are frequently detectable in both myeloid and lymphoid cells of healthy older per-sons,1 the significance of their occurrence in pa-tients with aplastic anemia, as well as the discor-The New England Journal of Medicine Downloaded from nejm.org at THOMAS JEFFERSON UNIVERSITY on May 8, 2016. For personal use only. No other uses without permission.  Copyright © 2015 Massachusetts Medical Society. All rights reserved. 

Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer.

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Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer.

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