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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.
Jovanovic, Bojana; Mayer, Ingrid A; Mayer, Erica L; Abramson, Vandana G; Bardia, Aditya; Sanders, Melinda E; Kuba, M Gabriela; Estrada, Monica V; Beeler, J Scott; Shaver, Timothy M; Johnson, Kimberly C; Sanchez, Violeta; Rosenbluth, Jennifer M; Dillon, Patrick M; Forero-Torres, Andres; Chang, Jenny C; Meszoely, Ingrid M; Grau, Ana M; Lehmann, Brian D; Shyr, Yu; Sheng, Quanhu; Chen, Sheau-Chiann; Arteaga, Carlos L; Pietenpol, Jennifer A.
Afiliação
  • Jovanovic B; Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Mayer IA; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. ingrid.mayer@vanderbilt.edu jennifer.pietenpol@vanderbilt.edu.
  • Mayer EL; Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Abramson VG; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Bardia A; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
  • Sanders ME; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Kuba MG; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Estrada MV; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Beeler JS; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Shaver TM; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Johnson KC; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Sanchez V; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Rosenbluth JM; Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Dillon PM; University of Virginia Health Sciences Center, Charlottesville, Virginia.
  • Forero-Torres A; University of Alabama, Birmingham, Alabama.
  • Chang JC; Methodist Hospital Research Institute, Houston, Texas.
  • Meszoely IM; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Grau AM; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Lehmann BD; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Shyr Y; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Sheng Q; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Chen SC; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Arteaga CL; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
  • Pietenpol JA; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. ingrid.mayer@vanderbilt.edu jennifer.pietenpol@vanderbilt.edu.
Clin Cancer Res ; 23(15): 4035-4045, 2017 Aug 01.
Article em En | MEDLINE | ID: mdl-28270498
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cisplatino / Paclitaxel / Neoplasias de Mama Triplo Negativas / Everolimo Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Adult / Female / Humans / Middle aged Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cisplatino / Paclitaxel / Neoplasias de Mama Triplo Negativas / Everolimo Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Adult / Female / Humans / Middle aged Idioma: En Ano de publicação: 2017 Tipo de documento: Article