title: Topical Imiquimod Plus Nab-paclitaxel for Breast Cancer Cutaneous Metastases: A Phase 2 Clinical Trial.
abstract: OBJECTIVE
  Salvage chemotherapy for recurrent chest wall lesions in breast cancer results in response rates of 20% to 30%. Preclinical studies showed significant disease regression could be induced in murine chest wall mammary cancers with a topical toll-like receptor (TLR)-7 agonist, imiquimod.
  
  
  OBJECTIVE
  To evaluate the safety and objective response rate (ORR) of imiquimod in combination with systemic albumin bound paclitaxel in treatment-refractory breast cancer of the chest wall.
  A single arm phase 2 clinical trial of 15 patients with breast cancer previously treated in an academic medical center setting between 2009 and 2012 for chest wall disease that had recurred.
  
  
  METHODS
  Imiquimod cream, 5%, was applied topically to a designated target lesion once per day for 4 consecutive days on days 1 through 4, 8 through 11, 15 through 18, and 22 through 25 of a 28-day cycle, for 12 weeks. Albumin bound paclitaxel, 100 mg/m2, was given intravenously on days 1, 8, and 15, and repeated every 28 days over the 12-week period.
  
  
  METHODS
  The primary endpoint was safety and ORR. Secondary endpoints included the generation of tumor-infiltrating lymphocytes and modulation of immune cell populations.
  
  
  RESULTS
  The median age at baseline of the 15 study participants was 54 years (range, 46-92 years). Fourteen patients were evaluable. Combination therapy was associated with low-grade toxic effects. Of 358 adverse events 330 (92%) were grades 1 and 2. Five (36%) patients achieved a compete response and another 5 (36%) were partial responders for an overall response rate of 72% (10 of 14). The response duration was limited. Pretreatment levels of programmed death-1 (PD-1)+ peripheral blood T cells (PD-1+ cluster of differentiation [CD]4+; 95% CI, 2.68-6.63; P < .001 and PD-1+CD8+; 95% CI, 1.13-8.35; P = .01) and monocytic myeloid derived suppressor cells (mMDSC) (95% CI, 3.62-12.74; P = .001) greater than controls predicted suboptimal clinical response.
  
  
  CONCLUSIONS
  Chemoimmunomodulation with a TLR-7 agonist and albumin bound paclitaxel is effective in inducing disease regression in treatment-refractory breast cancer chest wall metastases but responses are short-lived. Preexisting levels of cells indicating either T-cell exhaustion or systemic immunosuppression may be markers of selection for responsive patients.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00821964.
authors.affiliation: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle.
authors.forename: Lupe G
authors.initials: LG
authors.lastname: Salazar
authors.affiliation: Immune Design, Seattle, Washington.
authors.forename: Hailing
authors.initials: H
authors.lastname: Lu
authors.affiliation: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Reichow
authors.affiliation: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Childs
authors.affiliation: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Coveler
authors.affiliation: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle.
authors.forename: Doreen M
authors.initials: DM
authors.lastname: Higgins
authors.affiliation: Medical Oncology, City of Hope, Durante, California.
authors.forename: James
authors.initials: J
authors.lastname: Waisman
authors.affiliation: Department of Pathology, Stanford University, Stanford, California.
authors.forename: Kimberly H
authors.initials: KH
authors.lastname: Allison
authors.affiliation: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle.
authors.forename: Yushe
authors.initials: Y
authors.lastname: Dang
authors.affiliation: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Disis
mesh_terms: D000279:Administration, Cutaneous; D061605:Administration, Intravenous; D000368:Aged; D000369:Aged, 80 and over; D000418:Albumins / Q000008:administration & dosage; D000634:Aminoquinolines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D000077271:Imiquimod; D016246:Lymphocytes, Tumor-Infiltrating; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D016879:Salvage Therapy; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D016896:Treatment Outcome
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000634:Aminoquinolines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077271:Imiquimod; D017239:Paclitaxel