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

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

doi:10.18632/oncotarget.16953

Abstract

PurposeMetastatic 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.ResultsTranscriptomic analyses identified CDKN2A/p16 as a gene potentially associated with brain metastases.Materials and MethodsFifty-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.ConclusionsThe 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.

Highlights

Metastatic breast cancer is a leading cause of mortality in women, with a survival from 8.8 to 34.4 months [1], depending on metastasis distribution and histological sub-type
Transcriptomic analyses identified CDKN2A/p16 as a gene potentially associated with brain metastases
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

Summary

Introduction

Metastatic breast cancer is a leading cause of mortality in women, with a survival from 8.8 to 34.4 months [1], depending on metastasis distribution and histological sub-type. Brain metastases are associated with the poorest survival (median under 15 months) [2] They occur in the progression of 15 to 40% of metastatic breast cancers. Primary breast cancers are heterogeneous [10, 11], and metastases derive from selected aggressive clones that have acquired resistance to first line treatment [12]. These clones, which may be a minority in the primary tumor [13], are precisely those on which genomic analyses need to be performed to guide targeted therapies

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