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. 2017 Jun 6;8(23):37332-37341.
doi: 10.18632/oncotarget.16953.

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

Elise Furet  1   2 , Morad El Bouchtaoui  2 , Jean-Paul Feugeas  3   4 , Catherine Miquel  1   2   5 , Christophe Leboeuf  1   2 , Clémentine Beytout  2 , Philippe Bertheau  1   2   5 , Emilie Le Rhun  6   7   8 , Jacques Bonneterre  6   9 , Anne Janin  1   2   5 , Guilhem Bousquet  1   2   10   11
Affiliations

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

Elise Furet et al. Oncotarget. .

Abstract

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.

Keywords: brain metastases; breast cancer; p16.

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Conflict of interest statement

CONFLICTS OF INTEREST

Emilie Le Rhun has Research Fundings with MUNDIPHARMA and AMGEN Companies.

Jacques Bonneterre has honoraria to disclose with PHARMAMAR Company.

The other authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1
(A) Using immunostainings on metastatic lymph-nodes, p16 score and the percentage of Ki67-expressing cells were significantly higher in women with brain metastases than in women without brain metastases. **p < 0.01, *p < 0.05 (B) There is a correlation between p16 score and the percentage of Ki67-expressing tumor cells (R Pearson coefficient of 0.58, p < 0.01).
Figure 2
Figure 2. multivariate analyses
Multivariate analysis of p16 score, percentage of Ki67-expressing cells, HER2 status, estrogen receptor (ER) and progesterone receptor (PR) status of metastatic lymph-nodes, and metastatic distribution other than in lymph-node shows that only the p16 score is significantly associated with the risk of brain metastases. *p < 0.01.
Figure 3
Figure 3. Survival analyses according to p16 score
(A) Survival according to p16 score level in the series of 28 women with transcriptomic analyses. (B) Survival according to p16 score level in the validation series of 24 women. Survival according to p16 score level of the 52 women in the two series combined. In all three analyses, a p16 score over 5 is associated with a significantly shorter median survival.
See this image and copyright information in PMC

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