Cargando…

Breast cancer survival predicted by TP53 mutation status differs markedly depending on treatment

BACKGROUND: Previous studies on the role of TP53 mutation in breast cancer treatment response and survival are contradictory and inconclusive, limited by the use of different endpoints to determine clinical significance and by small sample sizes that prohibit stratification by treatment. METHODS: We...

Descripción completa

Detalles Bibliográficos
Autores principales: Ungerleider, Nathan A., Rao, Sonia G., Shahbandi, Ashkan, Yee, Douglas, Niu, Tianhua, Frey, Wesley D., Jackson, James G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167800/
https://www.ncbi.nlm.nih.gov/pubmed/30285883
http://dx.doi.org/10.1186/s13058-018-1044-5
_version_ 1783360260900126720
author Ungerleider, Nathan A.
Rao, Sonia G.
Shahbandi, Ashkan
Yee, Douglas
Niu, Tianhua
Frey, Wesley D.
Jackson, James G.
author_facet Ungerleider, Nathan A.
Rao, Sonia G.
Shahbandi, Ashkan
Yee, Douglas
Niu, Tianhua
Frey, Wesley D.
Jackson, James G.
author_sort Ungerleider, Nathan A.
collection PubMed
description BACKGROUND: Previous studies on the role of TP53 mutation in breast cancer treatment response and survival are contradictory and inconclusive, limited by the use of different endpoints to determine clinical significance and by small sample sizes that prohibit stratification by treatment. METHODS: We utilized large datasets to examine overall survival according to TP53 mutation status in patients across multiple clinical features and treatments. RESULTS: Confirming other studies, we found that in all patients and in hormone therapy-treated patients, TP53 wild-type status conferred superior 5-year overall survival, but survival curves crossed at 10 or more years. In contrast, further stratification within the large dataset revealed that in patients receiving chemotherapy and no hormone therapy, wild-type TP53 status conferred remarkably poor overall survival. This previously unrecognized inferior survival is consistent with p53 inducing arrest/senescence instead of apoptosis. Addition of hormone therapy to chemotherapy improved survival notably in patients with TP53 wild-type tumors, but not mutant, suggesting hormone therapy could eradicate arrested/senescent cells. Testing this, we found that estrogen receptor-positive, TP53 wild-type breast cancer cells that were made senescent by doxorubicin treatment were sensitive to tamoxifen. CONCLUSIONS: The poor survival of chemotherapy-treated patients with TP53 wild-type tumors may be improved by strategies to eliminate senescent cells, including the addition of hormone therapy when appropriate. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13058-018-1044-5) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-6167800
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-61678002018-10-09 Breast cancer survival predicted by TP53 mutation status differs markedly depending on treatment Ungerleider, Nathan A. Rao, Sonia G. Shahbandi, Ashkan Yee, Douglas Niu, Tianhua Frey, Wesley D. Jackson, James G. Breast Cancer Res Research Article BACKGROUND: Previous studies on the role of TP53 mutation in breast cancer treatment response and survival are contradictory and inconclusive, limited by the use of different endpoints to determine clinical significance and by small sample sizes that prohibit stratification by treatment. METHODS: We utilized large datasets to examine overall survival according to TP53 mutation status in patients across multiple clinical features and treatments. RESULTS: Confirming other studies, we found that in all patients and in hormone therapy-treated patients, TP53 wild-type status conferred superior 5-year overall survival, but survival curves crossed at 10 or more years. In contrast, further stratification within the large dataset revealed that in patients receiving chemotherapy and no hormone therapy, wild-type TP53 status conferred remarkably poor overall survival. This previously unrecognized inferior survival is consistent with p53 inducing arrest/senescence instead of apoptosis. Addition of hormone therapy to chemotherapy improved survival notably in patients with TP53 wild-type tumors, but not mutant, suggesting hormone therapy could eradicate arrested/senescent cells. Testing this, we found that estrogen receptor-positive, TP53 wild-type breast cancer cells that were made senescent by doxorubicin treatment were sensitive to tamoxifen. CONCLUSIONS: The poor survival of chemotherapy-treated patients with TP53 wild-type tumors may be improved by strategies to eliminate senescent cells, including the addition of hormone therapy when appropriate. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13058-018-1044-5) contains supplementary material, which is available to authorized users. BioMed Central 2018-10-01 2018 /pmc/articles/PMC6167800/ /pubmed/30285883 http://dx.doi.org/10.1186/s13058-018-1044-5 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Ungerleider, Nathan A.
Rao, Sonia G.
Shahbandi, Ashkan
Yee, Douglas
Niu, Tianhua
Frey, Wesley D.
Jackson, James G.
Breast cancer survival predicted by TP53 mutation status differs markedly depending on treatment
title Breast cancer survival predicted by TP53 mutation status differs markedly depending on treatment
title_full Breast cancer survival predicted by TP53 mutation status differs markedly depending on treatment
title_fullStr Breast cancer survival predicted by TP53 mutation status differs markedly depending on treatment
title_full_unstemmed Breast cancer survival predicted by TP53 mutation status differs markedly depending on treatment
title_short Breast cancer survival predicted by TP53 mutation status differs markedly depending on treatment
title_sort breast cancer survival predicted by tp53 mutation status differs markedly depending on treatment
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167800/
https://www.ncbi.nlm.nih.gov/pubmed/30285883
http://dx.doi.org/10.1186/s13058-018-1044-5
work_keys_str_mv AT ungerleidernathana breastcancersurvivalpredictedbytp53mutationstatusdiffersmarkedlydependingontreatment
AT raosoniag breastcancersurvivalpredictedbytp53mutationstatusdiffersmarkedlydependingontreatment
AT shahbandiashkan breastcancersurvivalpredictedbytp53mutationstatusdiffersmarkedlydependingontreatment
AT yeedouglas breastcancersurvivalpredictedbytp53mutationstatusdiffersmarkedlydependingontreatment
AT niutianhua breastcancersurvivalpredictedbytp53mutationstatusdiffersmarkedlydependingontreatment
AT freywesleyd breastcancersurvivalpredictedbytp53mutationstatusdiffersmarkedlydependingontreatment
AT jacksonjamesg breastcancersurvivalpredictedbytp53mutationstatusdiffersmarkedlydependingontreatment