TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer

Abstract Background Whereas the genomic landscape of endocrine‐resistant breast cancer has been intensely characterized in previously treated cases with local or distant recurrence, comparably little is known about genomic alterations conveying primary non‐responsiveness to endocrine treatment in lu...

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Autores principales:	Isabel Grote, Stephan Bartels, Leonie Kandt, Laura Bollmann, Henriette Christgen, Malte Gronewold, Mieke Raap, Ulrich Lehmann, Oleg Gluz, Ulrike Nitz, Sherko Kuemmel, Christine zuEulenburg, Michael Braun, Bahriye Aktas, Eva‐Maria Grischke, Claudia Schumacher, Kerstin Luedtke‐Heckenkamp, Ronald Kates, Rachel Wuerstlein, Monika Graeser, Nadia Harbeck, Matthias Christgen, Hans Kreipe
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	breast cancer endocrine proliferative response Ki67 preoperative endocrine therapy TP53 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/2c544d649b024c5bbd721b91d7f7c740
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spelling	oai:doaj.org-article:2c544d649b024c5bbd721b91d7f7c7402021-12-01T04:49:16ZTP53 mutations are associated with primary endocrine resistance in luminal early breast cancer2045-763410.1002/cam4.4376https://doaj.org/article/2c544d649b024c5bbd721b91d7f7c7402021-12-01T00:00:00Zhttps://doi.org/10.1002/cam4.4376https://doaj.org/toc/2045-7634Abstract Background Whereas the genomic landscape of endocrine‐resistant breast cancer has been intensely characterized in previously treated cases with local or distant recurrence, comparably little is known about genomic alterations conveying primary non‐responsiveness to endocrine treatment in luminal early breast cancer. Methods In this study, 622 estrogen receptor‐expressing breast cancer cases treated with short‐term preoperative endocrine therapy (pET) from the WSG‐ADAPT trial (NCT01779206) were analyzed for genetic alterations associated with impaired endocrine proliferative response (EPR) to 3‐week pET with tamoxifen or aromatase inhibitors. EPR was categorized as optimal (post‐pET Ki67 <10%) versus slightly, moderately, and severely impaired (post‐pET Ki67 10%–19%, 20%–34%, and ≥35%, respectively). Recently described gene mutations frequently found in previously treated advanced breast cancer were analyzed (ARID1A, BRAF, ERBB2, ESR1, GATA3, HRAS, KRAS, NRAS, PIK3CA, and TP53) by next‐generation sequencing. Amplifications of CCND1, FGFR1, ERBB2, and PAK1 were determined by digital PCR or fluorescence in situ hybridization. Results ERBB2 amplification (p = 0.0015) and mutations of TP53 (p < 0.0001) were significantly associated with impaired EPR. Impaired EPR in TP53‐mutated breast cancer cases was independent from the Oncotype DX Recurrence Score group and was seen both with tamoxifen‐ and aromatase inhibitor‐based pET (p = 0.0005 each). Conclusion We conclude that impaired EPR to pET is suitable to identify cases with primary endocrine resistance in early luminal breast cancer and that TP53‐mutated luminal cancers might not be sufficiently treated by endocrine therapy alone.Isabel GroteStephan BartelsLeonie KandtLaura BollmannHenriette ChristgenMalte GronewoldMieke RaapUlrich LehmannOleg GluzUlrike NitzSherko KuemmelChristine zuEulenburgMichael BraunBahriye AktasEva‐Maria GrischkeClaudia SchumacherKerstin Luedtke‐HeckenkampRonald KatesRachel WuerstleinMonika GraeserNadia HarbeckMatthias ChristgenHans KreipeWileyarticlebreast cancerendocrine proliferative responseKi67preoperative endocrine therapyTP53Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancer Medicine, Vol 10, Iss 23, Pp 8581-8594 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	breast cancer endocrine proliferative response Ki67 preoperative endocrine therapy TP53 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	breast cancer endocrine proliferative response Ki67 preoperative endocrine therapy TP53 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Isabel Grote Stephan Bartels Leonie Kandt Laura Bollmann Henriette Christgen Malte Gronewold Mieke Raap Ulrich Lehmann Oleg Gluz Ulrike Nitz Sherko Kuemmel Christine zuEulenburg Michael Braun Bahriye Aktas Eva‐Maria Grischke Claudia Schumacher Kerstin Luedtke‐Heckenkamp Ronald Kates Rachel Wuerstlein Monika Graeser Nadia Harbeck Matthias Christgen Hans Kreipe TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer
description	Abstract Background Whereas the genomic landscape of endocrine‐resistant breast cancer has been intensely characterized in previously treated cases with local or distant recurrence, comparably little is known about genomic alterations conveying primary non‐responsiveness to endocrine treatment in luminal early breast cancer. Methods In this study, 622 estrogen receptor‐expressing breast cancer cases treated with short‐term preoperative endocrine therapy (pET) from the WSG‐ADAPT trial (NCT01779206) were analyzed for genetic alterations associated with impaired endocrine proliferative response (EPR) to 3‐week pET with tamoxifen or aromatase inhibitors. EPR was categorized as optimal (post‐pET Ki67 <10%) versus slightly, moderately, and severely impaired (post‐pET Ki67 10%–19%, 20%–34%, and ≥35%, respectively). Recently described gene mutations frequently found in previously treated advanced breast cancer were analyzed (ARID1A, BRAF, ERBB2, ESR1, GATA3, HRAS, KRAS, NRAS, PIK3CA, and TP53) by next‐generation sequencing. Amplifications of CCND1, FGFR1, ERBB2, and PAK1 were determined by digital PCR or fluorescence in situ hybridization. Results ERBB2 amplification (p = 0.0015) and mutations of TP53 (p < 0.0001) were significantly associated with impaired EPR. Impaired EPR in TP53‐mutated breast cancer cases was independent from the Oncotype DX Recurrence Score group and was seen both with tamoxifen‐ and aromatase inhibitor‐based pET (p = 0.0005 each). Conclusion We conclude that impaired EPR to pET is suitable to identify cases with primary endocrine resistance in early luminal breast cancer and that TP53‐mutated luminal cancers might not be sufficiently treated by endocrine therapy alone.
format	article
author	Isabel Grote Stephan Bartels Leonie Kandt Laura Bollmann Henriette Christgen Malte Gronewold Mieke Raap Ulrich Lehmann Oleg Gluz Ulrike Nitz Sherko Kuemmel Christine zuEulenburg Michael Braun Bahriye Aktas Eva‐Maria Grischke Claudia Schumacher Kerstin Luedtke‐Heckenkamp Ronald Kates Rachel Wuerstlein Monika Graeser Nadia Harbeck Matthias Christgen Hans Kreipe
author_facet	Isabel Grote Stephan Bartels Leonie Kandt Laura Bollmann Henriette Christgen Malte Gronewold Mieke Raap Ulrich Lehmann Oleg Gluz Ulrike Nitz Sherko Kuemmel Christine zuEulenburg Michael Braun Bahriye Aktas Eva‐Maria Grischke Claudia Schumacher Kerstin Luedtke‐Heckenkamp Ronald Kates Rachel Wuerstlein Monika Graeser Nadia Harbeck Matthias Christgen Hans Kreipe
author_sort	Isabel Grote
title	TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer
title_short	TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer
title_full	TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer
title_fullStr	TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer
title_full_unstemmed	TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer
title_sort	tp53 mutations are associated with primary endocrine resistance in luminal early breast cancer
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/2c544d649b024c5bbd721b91d7f7c740
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TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer

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