title: TBCRC 008: early change in 18F-FDG uptake on PET predicts response to preoperative systemic therapy in human epidermal growth factor receptor 2-negative primary operable breast cancer.
abstract: Epigenetic modifiers, including the histone deacetylase inhibitor vorinostat, may sensitize tumors to chemotherapy and enhance outcomes. We conducted a multicenter randomized phase II neoadjuvant trial of carboplatin and nanoparticle albumin-bound paclitaxel (CP) with vorinostat or placebo in women with stage II/III, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, in which we also examined whether change in maximum standardized uptake values corrected for lean body mass (SUL(max)) on (18)F-FDG PET predicted pathologic complete response (pCR) in breast and axillary lymph nodes.
  
  
  METHODS
  Participants were randomly assigned to 12 wk of preoperative carboplatin (area under the curve of 2, weekly) and nab-paclitaxel (100 mg/m(2) weekly) with vorinostat (400 mg orally daily, days 1-3 of every 7-d period) or placebo. All patients underwent (18)F-FDG PET and research biopsy at baseline and on cycle 1 day 15. The primary endpoint was the pCR rate. Secondary objectives included correlation of change in tumor SUL(max) on (18)F-FDG PET by cycle 1 day 15 with pCR and correlation of baseline and change in Ki-67 with pCR.
  
  
  RESULTS
  In an intent-to-treat analysis (n = 62), overall pCR was 27.4% (vorinostat, 25.8%; placebo, 29.0%). In a pooled analysis (n = 59), we observed a significant difference in median change in SUL(max) 15 d after initiating preoperative therapy between those achieving pCR versus not (percentage reduction, 63.0% vs. 32.9%; P = 0.003). Patients with 50% or greater reduction in SUL(max) were more likely to achieve pCR, which remained statistically significant in multivariable analysis including estrogen receptor status (odds ratio, 5.1; 95% confidence interval, 1.3-22.7; P = 0.023). Differences in baseline and change in Ki-67 were not significantly different between those achieving pCR versus not.
  
  
  CONCLUSIONS
  Preoperative CP with vorinostat or placebo is associated with similar pCR rates. Early change in SUL(max) on (18)F-FDG PET 15 d after the initiation of preoperative therapy has potential in predicting pCR in patients with HER2-negative breast cancer. Future studies will further test (18)F-FDG PET as a potential treatment-selection biomarker.
authors.affiliation: From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Roisin M
authors.initials: RM
authors.lastname: Connolly
authors.affiliation: Division of Nuclear Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Leal
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Goetz
authors.affiliation: From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Xian C
authors.initials: XC
authors.lastname: Zhou
authors.affiliation: From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Jacobs
authors.affiliation: Division of Nuclear Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Joyce
authors.initials: J
authors.lastname: Mhlanga
authors.affiliation: Division of Nuclear Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Joo H
authors.initials: JH
authors.lastname: O
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: John
authors.initials: J
authors.lastname: Carpenter
authors.affiliation: Indiana University, Indianapolis, Indiana.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Storniolo
authors.affiliation: Anne Arundel Medical Center, Annapolis, Maryland.
authors.forename: Stanley
authors.initials: S
authors.lastname: Watkins
authors.affiliation: From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: John H
authors.initials: JH
authors.lastname: Fetting
authors.affiliation: From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Miller
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Kostandinos
authors.initials: K
authors.lastname: Sideras
authors.affiliation: From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Stacie C
authors.initials: SC
authors.lastname: Jeter
authors.affiliation: From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Bridget
authors.initials: B
authors.lastname: Walsh
authors.affiliation: From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Penny
authors.initials: P
authors.lastname: Powers
authors.affiliation: From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Jane
authors.initials: J
authors.lastname: Zorzi
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Judy C
authors.initials: JC
authors.lastname: Boughey
authors.affiliation: University of Pittsburgh Cancer Institute and UPMC Cancer Center, Pittsburgh, Pennsylvania; and.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
authors.affiliation: University of North Carolina-Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
authors.affiliation: From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Wolff
authors.affiliation: From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Nagi
authors.initials: N
authors.lastname: Khouri
authors.affiliation: From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Edward
authors.initials: E
authors.lastname: Gabrielson
authors.affiliation: From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland Division of Nuclear Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Wahl
authors.affiliation: From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland vstearn1@jhmi.edu.
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001692:Biological Transport; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D016190:Carboplatin / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D017239:Paclitaxel / Q000009:adverse effects / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D057234:Preoperative Period; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012449:Safety; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016190:Carboplatin; D019788:Fluorodeoxyglucose F18; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: 18F-FDG PET; biomarker; breast cancer; neoadjuvant; vorinostat