Research Papers:

Increased risk of brain metastases in women with breast cancer and p16 expression in metastatic lymph-nodes

Elise Furet, Morad El Bouchtaoui, Jean-Paul Feugeas, Catherine Miquel, Christophe Leboeuf, Clémentine Beytout, Philippe Bertheau, Emilie Le Rhun, Jacques Bonneterre, Anne Janin and Guilhem Bousquet _

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Oncotarget. 2017; 8:37332-37341. https://doi.org/10.18632/oncotarget.16953

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Elise Furet1,2,*, Morad El Bouchtaoui2,*, Jean-Paul Feugeas3,4, Catherine Miquel1,2,5, Christophe Leboeuf1,2, Clémentine Beytout2, Philippe Bertheau1,2,5, Emilie Le Rhun6,7,8, Jacques Bonneterre6,9, Anne Janin1,2,5,#, Guilhem Bousquet1,2,10,11,#

1Université Paris Diderot, Inserm, Paris, France

2INSERM, U1165-Paris, France

3INSERM, U1137-Paris, France

4Université de Franche-Comté, Département de Biologie, Besançon, France

5Hôpital Saint-Louis, APHP, Service de Pathologie, Paris, France

6Centre Oscar Lambret, Département de Sénologie, Lille, France

7CHRU de Lille, Neuro-oncologie, Département de neurochirurgie, Lille, France

8INSERM, Villeneuve d’Ascq, France

9Université Lille 2, Département de Sénologie, Lille, France

10Université Paris 13, Service d’Oncologie, Villetaneuse, France

11Hôpital Avicenne, APHP, Service d’Oncologie Médicale, Bobigny, France

*These authors have contributed equally to this work

#Co-senior authors

Correspondence to:

Guilhem Bousquet, email: [email protected]

Anne Janin, email: [email protected]

Keywords: brain metastases, breast cancer, p16

Received: November 01, 2016     Accepted: March 08, 2017     Published: April 08, 2017


Purpose: Metastatic breast cancer is a leading cause of mortality in women, partly on account of brain metastases. However, the mechanisms by which cancer cells cross the blood-brain barrier remain undeciphered. Most molecular studies predicting metastatic risk have been performed on primary breast cancer samples. Here we studied metastatic lymph-nodes from patients with breast cancers to identify markers associated with the occurrence of brain metastases.

Results: Transcriptomic analyses identified CDKN2A/p16 as a gene potentially associated with brain metastases.

Materials and Methods: Fifty-two patients with HER2-overexpressing or triple-negative breast carcinoma with lymph nodes and distant metastases were included in this study. Transcriptomic analyses were performed on laser-microdissected tumor cells from 28 metastatic lymph-nodes. Supervised analyses compared the transcriptomic profiles of women who developed brain metastases and those who did not. As a validation series, we studied metastatic lymph-nodes from 24 other patients.

Immunohistochemistry investigations showed that p16 mean scores were significantly higher in patients with brain metastases than in patients without (7.4 vs. 1.7 respectively, p < 0.01). This result was confirmed on the validation series. Multivariate analyses showed that the p16 score was the only variable positively associated with the risk of brain metastases (p = 0.01).

With the same threshold of 5 for p16 scores using a Cox model, overall survival was shorter in women with a p16 score over 5 in both series.

Conclusions: The risk of brain metastases in women with HER2-overexpressing or triple-negative breast cancer could be better assessed by studying p16 protein expression on surgically removed axillary lymph-nodes.

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