Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer.
In spite of adjuvant chemotherapy, a significant fraction of patients with localized breast cancer (BC) relapse after optimal treatment. We determined the occurrence of cytoplasmic MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3B)-positive puncta, as well as the presence of nuclear HMGB1 (high mobility group box 1) in cancer cells within surgical BC specimens by immunohistochemistry, first in a test cohort (152 patients) and then in a validation cohort of localized BC patients who all received adjuvant anthracycline-based chemotherapy (1646 patients). Cytoplasmic LC3B(+) puncta inversely correlated with the intensity of SQSTM1 staining, suggesting that a high percentage cells of LC3B(+) puncta reflects increased autophagic flux. After setting optimal thresholds in the test cohort, cytoplasmic LC3B(+) puncta and nuclear HMGB1 were scored as positive in 27.2% and 28.6% of the tumors, respectively, in the validation cohort, while 8.7% were considered as double positive. LC3B(+) puncta or HMGB1 expression alone did not constitute independent prognostic factors for metastasis-free survival (MFS) in multivariate analyses. However, the combined positivity for LC3B(+) puncta and nuclear HMGB1 constituted an independent prognostic factor significantly associated with prolonged MFS (hazard ratio: 0.49 95% confidence interval [0.26-0.89]; P = 0.02), and improved breast cancer specific survival (hazard ratio: 0.21 95% confidence interval [0.05-0.85]; P = 0.029). Subgroup analyses revealed that within patients with poor-prognosis BC, HMGB1(+) LC3B(+) double-positive tumors had a better prognosis than BC that lacked one or both of these markers. Altogether, these results suggest that the combined positivity for LC3B(+) puncta and nuclear HMGB1 is a positive predictor for longer BC survival.
a Department of Medical Oncology, Georges François Leclerc Center ; Dijon , France.|b Institut National de la Santé et de la Recherche Médicale; U1015, Equipe labellisée Ligue Nationale Contre le Cancer; Institut Gustave Roussy , Villejuif , France.
Sylvain
S
Ladoire
c Centre Jean Perrin, EA 4677 Clermont-Ferrand ; Clermont-Ferrand , France.|d ERTICa; EA 4677 University of Auvergne ; Clermont-Ferrand , France.
Frédérique
F
Penault-Llorca
e Equipe 11 labellisée pas la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers ; Paris , France.|f Metabolomics and Cell Biology Platforms; Gustave Roussy Cancer Campus ; Villejuif , France.
Laura
L
Senovilla
g Biostatistics and Epidemiology Unit; EA 4184; Centre Georges Francois Leclerc Dijon , France.
Cécile
C
Dalban
f Metabolomics and Cell Biology Platforms; Gustave Roussy Cancer Campus ; Villejuif , France.
David
D
Enot
b Institut National de la Santé et de la Recherche Médicale; U1015, Equipe labellisée Ligue Nationale Contre le Cancer; Institut Gustave Roussy , Villejuif , France.
Clara
C
Locher
b Institut National de la Santé et de la Recherche Médicale; U1015, Equipe labellisée Ligue Nationale Contre le Cancer; Institut Gustave Roussy , Villejuif , France.
Nicole
N
Prada
b Institut National de la Santé et de la Recherche Médicale; U1015, Equipe labellisée Ligue Nationale Contre le Cancer; Institut Gustave Roussy , Villejuif , France.
Vichnou
V
Poirier-Colame
e Equipe 11 labellisée pas la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers ; Paris , France.|h Université Paris Descartes; Sorbonne Paris Cité ; Paris , France.
Kariman
K
Chaba
i Department of Pathology and Tumor Biology; Georges François Leclerc Center ; Dijon , France.
Laurent
L
Arnould
a Department of Medical Oncology, Georges François Leclerc Center ; Dijon , France.|j Institut National de la Santé et de la Recherche Médicale; Avenir Team INSERM; CRI-866 University of Burgundy , Dijon , France.
François
F
Ghiringhelli
a Department of Medical Oncology, Georges François Leclerc Center ; Dijon , France.
Pierre
P
Fumoleau
k Department of Medical Oncology and Breast Cancer Group; Institut Gustave Roussy , Villejuif , France.
Marc
M
Spielmann
k Department of Medical Oncology and Breast Cancer Group; Institut Gustave Roussy , Villejuif , France.
Suzette
S
Delaloge
g Biostatistics and Epidemiology Unit; EA 4184; Centre Georges Francois Leclerc Dijon , France.
Marie Laure
ML
Poillot
g Biostatistics and Epidemiology Unit; EA 4184; Centre Georges Francois Leclerc Dijon , France.
Patrick
P
Arveux
l INSERM U981 "Identification of molecular predictors and new targets for cancer treatment"; Institut Gustave Roussy ; Villejuif , France.
Aicha
A
Goubar
k Department of Medical Oncology and Breast Cancer Group; Institut Gustave Roussy , Villejuif , France.|l INSERM U981 "Identification of molecular predictors and new targets for cancer treatment"; Institut Gustave Roussy ; Villejuif , France.
Fabrice
F
Andre
b Institut National de la Santé et de la Recherche Médicale; U1015, Equipe labellisée Ligue Nationale Contre le Cancer; Institut Gustave Roussy , Villejuif , France.|m University of Paris Sud XI , Villejuif , France.|n Center of Clinical Investigations in Biotherapies of Cancer (CICBT) , Villejuif , France.
Laurence
L
Zitvogel
f Metabolomics and Cell Biology Platforms; Gustave Roussy Cancer Campus ; Villejuif , France.|o Pôle de Biologie; Hôpital Européen Georges Pompidou; Assistance Publique-Hôpitaux de Paris ; Paris , France.|p INSERM; U1138 , Paris , France.
Guido
G
Kroemer
D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy*; D017024:Chemotherapy, Adjuvant / Q000379:methods; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D012008:Recurrence; D012307:Risk Factors
D014408:Biomarkers, Tumor; D024243:HMGB1 Protein; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins
HMGB1; LC3; breast cancer; histology; pathology; prognostic; tumor microarray