title: A Randomized Phase II Neoadjuvant Study of Cisplatin, Paclitaxel With or Without Everolimus in Patients with Stage II/III Triple-Negative Breast Cancer (TNBC): Responses and Long-term Outcome Correlated with Increased Frequency of DNA Damage Response Gene Mutations, TNBC Subtype, AR Status, and Ki67.
abstract: Purpose:Because of inherent disease heterogeneity, targeted therapies have eluded triple-negative breast cancer (TNBC), and biomarkers predictive of treatment response have not yet been identified. This study was designed to determine whether the mTOR inhibitor everolimus with cisplatin and paclitaxel would provide synergistic antitumor effects in TNBC.Methods:Patients with stage II/III TNBC were enrolled in a randomized phase II trial of preoperative weekly cisplatin, paclitaxel and daily everolimus or placebo for 12 weeks, until definitive surgery. Tumor specimens were obtained at baseline, cycle 1, and surgery. Primary endpoint was pathologic complete response (pCR); secondary endpoints included clinical responses, breast conservation rate, safety, and discovery of molecular features associated with outcome.Results:Between 2009 and 2013, 145 patients were accrued; 36% of patients in the everolimus arm and 49% of patients in the placebo arm achieved pCR; in each arm, 50% of patients achieved complete responses by imaging. Higher rates of neutropenia, mucositis, and transaminase elevation were seen with everolimus. Clinical response to therapy and long-term outcome correlated with increased frequency of DNA damage response (DDR) gene mutations, Basal-like1 and Mesenchymal TNBC-subtypes, AR-negative status, and high Ki67, but not with tumor-infiltrating lymphocytes.Conclusions:The paclitaxel/cisplatin combination was well tolerated and active, but addition of everolimus was associated with more adverse events without improvement in pCR or clinical response. However, discoveries made from correlative studies could lead to predictive TNBC biomarkers that may impact clinical decision-making and provide new avenues for mechanistic exploration that could lead to clinical utility.Clin Cancer Res; 23(15); 4035-45. ©2017 AACR.
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Bojana
authors.initials: B
authors.lastname: Jovanović
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. ingrid.mayer@vanderbilt.edu jennifer.pietenpol@vanderbilt.edu.
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Mayer
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Mayer
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Vandana G
authors.initials: VG
authors.lastname: Abramson
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Aditya
authors.initials: A
authors.lastname: Bardia
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Sanders
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: M Gabriela
authors.initials: MG
authors.lastname: Kuba
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Monica V
authors.initials: MV
authors.lastname: Estrada
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Beeler
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Shaver
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Johnson
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Violeta
authors.initials: V
authors.lastname: Sanchez
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Rosenbluth
authors.affiliation: University of Virginia Health Sciences Center, Charlottesville, Virginia.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Dillon
authors.affiliation: University of Alabama, Birmingham, Alabama.
authors.forename: Andres
authors.initials: A
authors.lastname: Forero-Torres
authors.affiliation: Methodist Hospital Research Institute, Houston, Texas.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Meszoely
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Grau
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lehmann
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Quanhu
authors.initials: Q
authors.lastname: Sheng
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Sheau-Chiann
authors.initials: SC
authors.lastname: Chen
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. ingrid.mayer@vanderbilt.edu jennifer.pietenpol@vanderbilt.edu.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Pietenpol
mesh_terms: D000328:Adult; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects; D004249:DNA Damage / Q000187:drug effects; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics / Q000473:pathology; D000068338:Everolimus / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects; D011944:Receptors, Androgen / Q000235:genetics; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D019394:Ki-67 Antigen; D011944:Receptors, Androgen; D000068338:Everolimus; D017239:Paclitaxel; D002945:Cisplatin