A New Genetic Risk Score to Predict the Outcome of Locally Advanced or Metastatic Breast Cancer Patients Treated With First-Line Exemestane: Results From a Prospective Study

Sara Gagno, Mario Rosario D'Andrea, Mauro Mansutti, Chiara Zanusso, Fabio Puglisi, Eva Dreussi, Marcella Montico, Paola Biason, Erika Cecchin, Donatella Iacono, Stefania Russo, Marika Cinausero, Silvana Saracchini, Giampietro Gasparini, Donata Sartori, Mario Bari, Elena Collovà, Rosa Meo, Ghassan Merkabaoui, Ilaria SpagnolettiArianna Pellegrino, Lorenzo Gianni, Paolo Sandri, Elisabetta Cretella, Emanuela Vattemi, Andrea Rocca, Patrizia Serra, Maria Agnese Fabbri, Giovanni Benedetti, Laura Foghini, Michele Medici, Umberto Basso, Vito Amoroso, Ferdinando Riccardi, Anna Maria Baldelli, Mario Clerico, Salvatore Bonura, Chiara Saggia, Federico Innocenti, Giuseppe Toffoli

Research output: Contribution to journalArticle

Abstract

INTRODUCTION: Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival.

PATIENTS AND METHODS: Three hundred two locally advanced or MBC patients treated with first-line exemestane were genotyped for 74 germ line polymorphisms in 39 candidate genes involved in drug activity, hormone balance, DNA replication and repair, and cell signaling pathways. Associations with progression-free survival (PFS) and overall survival (OS) were tested with multivariate Cox regression. Bootstrap resampling was used as an internal assessment of results reproducibility.

RESULTS: Cytochrome P450 19A1-rs10046TC/CC, solute carrier organic anion transporter 1B1-rs4149056TT, adenosine triphosphate binding cassette subfamily G member 2-rs2046134GG, fibroblast growth factor receptor-4-rs351855TT, and X-ray repair cross complementing 3-rs861539TT were significantly associated with PFS and then combined into a risk score (0-1, 2, 3, or 4-6 risk points). Patients with the highest risk score (4-6 risk points) compared with ones with the lowest score (0-1 risk points) had a median PFS of 10 months versus 26.3 months (adjusted hazard ratio [AdjHR], 3.12 [95% confidence interval (CI), 2.18-4.48]; P < .001) and a median OS of 38.9 months versus 63.0 months (AdjHR, 2.41 [95% CI, 1.22-4.79], P = .012), respectively.

CONCLUSION: In this study we defined a score including 5 polymorphisms to stratify patients for PFS and OS. This score, if validated, might be translated to personalize locally advanced or MBC patient treatment and management.

Original languageEnglish
JournalClinical Breast Cancer
DOIs
Publication statusE-pub ahead of print - Nov 24 2018

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exemestane
Prospective Studies
Breast Neoplasms
Disease-Free Survival
Survival
Germ Cells
Receptor, Fibroblast Growth Factor, Type 4
Biomarkers
Confidence Intervals
DNA Replication
Reproducibility of Results
DNA Repair
Cytochrome P-450 Enzyme System

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A New Genetic Risk Score to Predict the Outcome of Locally Advanced or Metastatic Breast Cancer Patients Treated With First-Line Exemestane : Results From a Prospective Study. / Gagno, Sara; D'Andrea, Mario Rosario; Mansutti, Mauro; Zanusso, Chiara; Puglisi, Fabio; Dreussi, Eva; Montico, Marcella; Biason, Paola; Cecchin, Erika; Iacono, Donatella; Russo, Stefania; Cinausero, Marika; Saracchini, Silvana; Gasparini, Giampietro; Sartori, Donata; Bari, Mario; Collovà, Elena; Meo, Rosa; Merkabaoui, Ghassan; Spagnoletti, Ilaria; Pellegrino, Arianna; Gianni, Lorenzo; Sandri, Paolo; Cretella, Elisabetta; Vattemi, Emanuela; Rocca, Andrea; Serra, Patrizia; Fabbri, Maria Agnese; Benedetti, Giovanni; Foghini, Laura; Medici, Michele; Basso, Umberto; Amoroso, Vito; Riccardi, Ferdinando; Baldelli, Anna Maria; Clerico, Mario; Bonura, Salvatore; Saggia, Chiara; Innocenti, Federico; Toffoli, Giuseppe.

In: Clinical Breast Cancer, 24.11.2018.

Research output: Contribution to journalArticle

Gagno, S, D'Andrea, MR, Mansutti, M, Zanusso, C, Puglisi, F, Dreussi, E, Montico, M, Biason, P, Cecchin, E, Iacono, D, Russo, S, Cinausero, M, Saracchini, S, Gasparini, G, Sartori, D, Bari, M, Collovà, E, Meo, R, Merkabaoui, G, Spagnoletti, I, Pellegrino, A, Gianni, L, Sandri, P, Cretella, E, Vattemi, E, Rocca, A, Serra, P, Fabbri, MA, Benedetti, G, Foghini, L, Medici, M, Basso, U, Amoroso, V, Riccardi, F, Baldelli, AM, Clerico, M, Bonura, S, Saggia, C, Innocenti, F & Toffoli, G 2018, 'A New Genetic Risk Score to Predict the Outcome of Locally Advanced or Metastatic Breast Cancer Patients Treated With First-Line Exemestane: Results From a Prospective Study', Clinical Breast Cancer. https://doi.org/10.1016/j.clbc.2018.11.009
Gagno, Sara ; D'Andrea, Mario Rosario ; Mansutti, Mauro ; Zanusso, Chiara ; Puglisi, Fabio ; Dreussi, Eva ; Montico, Marcella ; Biason, Paola ; Cecchin, Erika ; Iacono, Donatella ; Russo, Stefania ; Cinausero, Marika ; Saracchini, Silvana ; Gasparini, Giampietro ; Sartori, Donata ; Bari, Mario ; Collovà, Elena ; Meo, Rosa ; Merkabaoui, Ghassan ; Spagnoletti, Ilaria ; Pellegrino, Arianna ; Gianni, Lorenzo ; Sandri, Paolo ; Cretella, Elisabetta ; Vattemi, Emanuela ; Rocca, Andrea ; Serra, Patrizia ; Fabbri, Maria Agnese ; Benedetti, Giovanni ; Foghini, Laura ; Medici, Michele ; Basso, Umberto ; Amoroso, Vito ; Riccardi, Ferdinando ; Baldelli, Anna Maria ; Clerico, Mario ; Bonura, Salvatore ; Saggia, Chiara ; Innocenti, Federico ; Toffoli, Giuseppe. / A New Genetic Risk Score to Predict the Outcome of Locally Advanced or Metastatic Breast Cancer Patients Treated With First-Line Exemestane : Results From a Prospective Study. In: Clinical Breast Cancer. 2018.
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title = "A New Genetic Risk Score to Predict the Outcome of Locally Advanced or Metastatic Breast Cancer Patients Treated With First-Line Exemestane: Results From a Prospective Study",
abstract = "INTRODUCTION: Approximately 50{\%} of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival.PATIENTS AND METHODS: Three hundred two locally advanced or MBC patients treated with first-line exemestane were genotyped for 74 germ line polymorphisms in 39 candidate genes involved in drug activity, hormone balance, DNA replication and repair, and cell signaling pathways. Associations with progression-free survival (PFS) and overall survival (OS) were tested with multivariate Cox regression. Bootstrap resampling was used as an internal assessment of results reproducibility.RESULTS: Cytochrome P450 19A1-rs10046TC/CC, solute carrier organic anion transporter 1B1-rs4149056TT, adenosine triphosphate binding cassette subfamily G member 2-rs2046134GG, fibroblast growth factor receptor-4-rs351855TT, and X-ray repair cross complementing 3-rs861539TT were significantly associated with PFS and then combined into a risk score (0-1, 2, 3, or 4-6 risk points). Patients with the highest risk score (4-6 risk points) compared with ones with the lowest score (0-1 risk points) had a median PFS of 10 months versus 26.3 months (adjusted hazard ratio [AdjHR], 3.12 [95{\%} confidence interval (CI), 2.18-4.48]; P < .001) and a median OS of 38.9 months versus 63.0 months (AdjHR, 2.41 [95{\%} CI, 1.22-4.79], P = .012), respectively.CONCLUSION: In this study we defined a score including 5 polymorphisms to stratify patients for PFS and OS. This score, if validated, might be translated to personalize locally advanced or MBC patient treatment and management.",
author = "Sara Gagno and D'Andrea, {Mario Rosario} and Mauro Mansutti and Chiara Zanusso and Fabio Puglisi and Eva Dreussi and Marcella Montico and Paola Biason and Erika Cecchin and Donatella Iacono and Stefania Russo and Marika Cinausero and Silvana Saracchini and Giampietro Gasparini and Donata Sartori and Mario Bari and Elena Collov{\`a} and Rosa Meo and Ghassan Merkabaoui and Ilaria Spagnoletti and Arianna Pellegrino and Lorenzo Gianni and Paolo Sandri and Elisabetta Cretella and Emanuela Vattemi and Andrea Rocca and Patrizia Serra and Fabbri, {Maria Agnese} and Giovanni Benedetti and Laura Foghini and Michele Medici and Umberto Basso and Vito Amoroso and Ferdinando Riccardi and Baldelli, {Anna Maria} and Mario Clerico and Salvatore Bonura and Chiara Saggia and Federico Innocenti and Giuseppe Toffoli",
note = "Copyright {\circledC} 2018 The Authors. Published by Elsevier Inc. All rights reserved.",
year = "2018",
month = "11",
day = "24",
doi = "10.1016/j.clbc.2018.11.009",
language = "English",
journal = "Clinical Breast Cancer",
issn = "1526-8209",
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TY - JOUR

T1 - A New Genetic Risk Score to Predict the Outcome of Locally Advanced or Metastatic Breast Cancer Patients Treated With First-Line Exemestane

T2 - Results From a Prospective Study

AU - Gagno, Sara

AU - D'Andrea, Mario Rosario

AU - Mansutti, Mauro

AU - Zanusso, Chiara

AU - Puglisi, Fabio

AU - Dreussi, Eva

AU - Montico, Marcella

AU - Biason, Paola

AU - Cecchin, Erika

AU - Iacono, Donatella

AU - Russo, Stefania

AU - Cinausero, Marika

AU - Saracchini, Silvana

AU - Gasparini, Giampietro

AU - Sartori, Donata

AU - Bari, Mario

AU - Collovà, Elena

AU - Meo, Rosa

AU - Merkabaoui, Ghassan

AU - Spagnoletti, Ilaria

AU - Pellegrino, Arianna

AU - Gianni, Lorenzo

AU - Sandri, Paolo

AU - Cretella, Elisabetta

AU - Vattemi, Emanuela

AU - Rocca, Andrea

AU - Serra, Patrizia

AU - Fabbri, Maria Agnese

AU - Benedetti, Giovanni

AU - Foghini, Laura

AU - Medici, Michele

AU - Basso, Umberto

AU - Amoroso, Vito

AU - Riccardi, Ferdinando

AU - Baldelli, Anna Maria

AU - Clerico, Mario

AU - Bonura, Salvatore

AU - Saggia, Chiara

AU - Innocenti, Federico

AU - Toffoli, Giuseppe

N1 - Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2018/11/24

Y1 - 2018/11/24

N2 - INTRODUCTION: Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival.PATIENTS AND METHODS: Three hundred two locally advanced or MBC patients treated with first-line exemestane were genotyped for 74 germ line polymorphisms in 39 candidate genes involved in drug activity, hormone balance, DNA replication and repair, and cell signaling pathways. Associations with progression-free survival (PFS) and overall survival (OS) were tested with multivariate Cox regression. Bootstrap resampling was used as an internal assessment of results reproducibility.RESULTS: Cytochrome P450 19A1-rs10046TC/CC, solute carrier organic anion transporter 1B1-rs4149056TT, adenosine triphosphate binding cassette subfamily G member 2-rs2046134GG, fibroblast growth factor receptor-4-rs351855TT, and X-ray repair cross complementing 3-rs861539TT were significantly associated with PFS and then combined into a risk score (0-1, 2, 3, or 4-6 risk points). Patients with the highest risk score (4-6 risk points) compared with ones with the lowest score (0-1 risk points) had a median PFS of 10 months versus 26.3 months (adjusted hazard ratio [AdjHR], 3.12 [95% confidence interval (CI), 2.18-4.48]; P < .001) and a median OS of 38.9 months versus 63.0 months (AdjHR, 2.41 [95% CI, 1.22-4.79], P = .012), respectively.CONCLUSION: In this study we defined a score including 5 polymorphisms to stratify patients for PFS and OS. This score, if validated, might be translated to personalize locally advanced or MBC patient treatment and management.

AB - INTRODUCTION: Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival.PATIENTS AND METHODS: Three hundred two locally advanced or MBC patients treated with first-line exemestane were genotyped for 74 germ line polymorphisms in 39 candidate genes involved in drug activity, hormone balance, DNA replication and repair, and cell signaling pathways. Associations with progression-free survival (PFS) and overall survival (OS) were tested with multivariate Cox regression. Bootstrap resampling was used as an internal assessment of results reproducibility.RESULTS: Cytochrome P450 19A1-rs10046TC/CC, solute carrier organic anion transporter 1B1-rs4149056TT, adenosine triphosphate binding cassette subfamily G member 2-rs2046134GG, fibroblast growth factor receptor-4-rs351855TT, and X-ray repair cross complementing 3-rs861539TT were significantly associated with PFS and then combined into a risk score (0-1, 2, 3, or 4-6 risk points). Patients with the highest risk score (4-6 risk points) compared with ones with the lowest score (0-1 risk points) had a median PFS of 10 months versus 26.3 months (adjusted hazard ratio [AdjHR], 3.12 [95% confidence interval (CI), 2.18-4.48]; P < .001) and a median OS of 38.9 months versus 63.0 months (AdjHR, 2.41 [95% CI, 1.22-4.79], P = .012), respectively.CONCLUSION: In this study we defined a score including 5 polymorphisms to stratify patients for PFS and OS. This score, if validated, might be translated to personalize locally advanced or MBC patient treatment and management.

U2 - 10.1016/j.clbc.2018.11.009

DO - 10.1016/j.clbc.2018.11.009

M3 - Article

C2 - 30584056

JO - Clinical Breast Cancer

JF - Clinical Breast Cancer

SN - 1526-8209

ER -