title: Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with pertuzumab.
abstract: Pertuzumab disrupts heterodimerization between human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), HER3, and HER4. Thus, pertuzumab could result in adverse events similar to those observed with EGFR antagonists, such as diarrhea. We report the incidence and severity of diarrhea observed with pertuzumab in the CLEOPATRA, NeoSphere, and TRYPHAENA studies.
  
  
  
  Patients (n = 1443) had metastatic [CLEOPATRA (n = 804)] or early-stage breast cancer [NeoSphere (n = 416) and TRYPHAENA (n = 223)]. The incidence and severity of diarrhea were analyzed by treatment received. The incidence of febrile neutropenia concurrent with diarrhea and the effect of pre-existing gastrointestinal comorbidities were also evaluated. Subgroup analyses were carried out using CLEOPATRA data.
  
  
  
  The incidence of all-grade diarrhea across studies was generally greater for pertuzumab-based treatment, ranging from 28% to 72% (grade 1, 21%-54%; grade 2, 8%-37%; grade 3, 0%-12%; grade 4, 0%). Incidence was highest during the first pertuzumab-containing cycle, decreasing with subsequent cycles. Dose delays or discontinuations due to diarrhea were infrequent, ranging from 0% to 8%. Among pertuzumab-treated patients with diarrhea, 47%-67% received pharmacological intervention, most commonly with loperamide. Overlap between diarrhea and febrile neutropenia was uncommon, ranging from 0% to 11%. No relationship was observed between pre-existing gastrointestinal comorbidities and diarrhea. In CLEOPATRA, patients ≥65 years treated with pertuzumab had a higher incidence of grade 3 diarrhea than patients <65 years (19% versus 8%). All-grade diarrhea occurred at greater frequency among pertuzumab-treated Asian versus white patients with metastatic breast cancer (74% versus 63%); the corresponding rates in the control arm were 53% and 45%, respectively.
  
  
  
  In both the metastatic and early-stage breast cancer settings, diarrhea was common but manageable for all pertuzumab-containing regimens. Diarrheal episodes were mainly low grade and occurred most often during the first treatment cycle. Diarrheal-related drug delays or discontinuations were uncommon.
  
  
  
  NCT00567190 (CLEOPATRA), NCT00545688 (NeoSphere), NCT00976989 (TRYPHAENA).
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Swain
authors.affiliation: National Center for Tumor Diseases, University Hospital Heidelberg, Germany.|Department of Gynecology and Obstetrics, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schneeweiss
authors.affiliation: Department of Medical Oncology, San Raffaele Hospital, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Gianni
authors.affiliation: Medical Oncology Service, National Cancer Institute, National Institutes of Health, Bethesda, MA, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Gao
authors.affiliation: BioOncology, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Stein
authors.affiliation: Clinical Development, Roche Products Ltd, Welwyn Garden City, UK.
authors.forename: M
authors.initials: M
authors.lastname: Waldron-Lynch
authors.affiliation: Clinical Development, Roche Products Ltd, Welwyn Garden City, UK.
authors.forename: S
authors.initials: S
authors.lastname: Heeson
authors.affiliation: BioOncology, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Beattie
authors.affiliation: Biostatistics, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Yoo
authors.affiliation: Ramon y Cajal University Hospital, Madrid, Spain.|Medical Oncology Department, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Cortes
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: J
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy*; D064146:Chemotherapy-Induced Febrile Neutropenia / Q000453:epidemiology; D003967:Diarrhea / Q000139:chemically induced* / Q000188:drug therapy / Q000453:epidemiology*; D005260:Female; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C485206:pertuzumab
keywords: EGFR; HER2; breast cancer; diarrhea; docetaxel; pertuzumab