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Discrimination between Complete versus Non-Complete Pathologic Response to Neoadjuvant Therapy Using Ultrasensitive Mutation Analysis: A Proof-of-Concept Study in BRCA1-Driven Breast Cancer Patients
Neoadjuvant chemotherapy (NACT) for breast cancer (BC) often results in pathologic complete response (pCR), i.e., the complete elimination of visible cancer cells. It is unclear whether the use of ultrasensitive genetic methods may still detect residual BC cells in complete responders. Breast carcin...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9914941/ https://www.ncbi.nlm.nih.gov/pubmed/36768191 http://dx.doi.org/10.3390/ijms24031870 |
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author | Sokolenko, Anna P. Moiseyenko, Fedor V. Iyevleva, Aglaya G. Ivantsov, Alexandr O. Dolmatov, Georgiy D. Shelekhova, Ksenia V. Gulo, Elizaveta V. Topal, Anastasya X. Artemieva, Elizaveta V. Abduloeva, Nuriniso H. Rysev, Nikita A. Barsova, Daria A. Levchenko, Natalia V. Volkov, Nikita M. Egorenkov, Vitaliy V. Moiseyenko, Vladimir M. Imyanitov, Evgeny N. |
author_facet | Sokolenko, Anna P. Moiseyenko, Fedor V. Iyevleva, Aglaya G. Ivantsov, Alexandr O. Dolmatov, Georgiy D. Shelekhova, Ksenia V. Gulo, Elizaveta V. Topal, Anastasya X. Artemieva, Elizaveta V. Abduloeva, Nuriniso H. Rysev, Nikita A. Barsova, Daria A. Levchenko, Natalia V. Volkov, Nikita M. Egorenkov, Vitaliy V. Moiseyenko, Vladimir M. Imyanitov, Evgeny N. |
author_sort | Sokolenko, Anna P. |
collection | PubMed |
description | Neoadjuvant chemotherapy (NACT) for breast cancer (BC) often results in pathologic complete response (pCR), i.e., the complete elimination of visible cancer cells. It is unclear whether the use of ultrasensitive genetic methods may still detect residual BC cells in complete responders. Breast carcinomas arising in BRCA1 mutation carriers almost always carry alterations of the TP53 gene thus providing an opportunity to address this question. The analysis of consecutive BC patients treated by NACT revealed a higher pCR rate in BRCA1-driven vs. BRCA1-wildtype BCs (13/24 (54%) vs. 29/192 (15%), p < 0.0001). Twelve pre-/post-NACT tissue pairs obtained from BRCA1 mutation carriers were available for the study. While TP53 mutation was identified in all chemonaive tumors, droplet digital PCR (ddPCR) analysis of the post-NACT tumor bed revealed the persistence of this alteration in all seven pCR-non-responders but in none of five pCR responders. Eleven patients provided to the study post-NACT tissue samples only; next-generation sequencing (NGS) analysis revealed mutated TP53 copies in all six cases without pCR but in none of five instances of pCR. In total, TP53 mutation was present in post-NACT tissues in all 13 cases without pCR, but in none of 10 patients with pCR (p < 0.000001). Therefore, the lack of visible tumor cells in the post-NACT tumor bed is indeed a reliable indicator of the complete elimination of transformed clones. Failure of ultrasensitive methods to identify patients with minimal residual disease among pCR responders suggests that the result of NACT is a categorical rather than continuous variable, where some patients are destined to be cured while others ultimately fail to experience tumor eradication. |
format | Online Article Text |
id | pubmed-9914941 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-99149412023-02-11 Discrimination between Complete versus Non-Complete Pathologic Response to Neoadjuvant Therapy Using Ultrasensitive Mutation Analysis: A Proof-of-Concept Study in BRCA1-Driven Breast Cancer Patients Sokolenko, Anna P. Moiseyenko, Fedor V. Iyevleva, Aglaya G. Ivantsov, Alexandr O. Dolmatov, Georgiy D. Shelekhova, Ksenia V. Gulo, Elizaveta V. Topal, Anastasya X. Artemieva, Elizaveta V. Abduloeva, Nuriniso H. Rysev, Nikita A. Barsova, Daria A. Levchenko, Natalia V. Volkov, Nikita M. Egorenkov, Vitaliy V. Moiseyenko, Vladimir M. Imyanitov, Evgeny N. Int J Mol Sci Article Neoadjuvant chemotherapy (NACT) for breast cancer (BC) often results in pathologic complete response (pCR), i.e., the complete elimination of visible cancer cells. It is unclear whether the use of ultrasensitive genetic methods may still detect residual BC cells in complete responders. Breast carcinomas arising in BRCA1 mutation carriers almost always carry alterations of the TP53 gene thus providing an opportunity to address this question. The analysis of consecutive BC patients treated by NACT revealed a higher pCR rate in BRCA1-driven vs. BRCA1-wildtype BCs (13/24 (54%) vs. 29/192 (15%), p < 0.0001). Twelve pre-/post-NACT tissue pairs obtained from BRCA1 mutation carriers were available for the study. While TP53 mutation was identified in all chemonaive tumors, droplet digital PCR (ddPCR) analysis of the post-NACT tumor bed revealed the persistence of this alteration in all seven pCR-non-responders but in none of five pCR responders. Eleven patients provided to the study post-NACT tissue samples only; next-generation sequencing (NGS) analysis revealed mutated TP53 copies in all six cases without pCR but in none of five instances of pCR. In total, TP53 mutation was present in post-NACT tissues in all 13 cases without pCR, but in none of 10 patients with pCR (p < 0.000001). Therefore, the lack of visible tumor cells in the post-NACT tumor bed is indeed a reliable indicator of the complete elimination of transformed clones. Failure of ultrasensitive methods to identify patients with minimal residual disease among pCR responders suggests that the result of NACT is a categorical rather than continuous variable, where some patients are destined to be cured while others ultimately fail to experience tumor eradication. MDPI 2023-01-18 /pmc/articles/PMC9914941/ /pubmed/36768191 http://dx.doi.org/10.3390/ijms24031870 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Sokolenko, Anna P. Moiseyenko, Fedor V. Iyevleva, Aglaya G. Ivantsov, Alexandr O. Dolmatov, Georgiy D. Shelekhova, Ksenia V. Gulo, Elizaveta V. Topal, Anastasya X. Artemieva, Elizaveta V. Abduloeva, Nuriniso H. Rysev, Nikita A. Barsova, Daria A. Levchenko, Natalia V. Volkov, Nikita M. Egorenkov, Vitaliy V. Moiseyenko, Vladimir M. Imyanitov, Evgeny N. Discrimination between Complete versus Non-Complete Pathologic Response to Neoadjuvant Therapy Using Ultrasensitive Mutation Analysis: A Proof-of-Concept Study in BRCA1-Driven Breast Cancer Patients |
title | Discrimination between Complete versus Non-Complete Pathologic Response to Neoadjuvant Therapy Using Ultrasensitive Mutation Analysis: A Proof-of-Concept Study in BRCA1-Driven Breast Cancer Patients |
title_full | Discrimination between Complete versus Non-Complete Pathologic Response to Neoadjuvant Therapy Using Ultrasensitive Mutation Analysis: A Proof-of-Concept Study in BRCA1-Driven Breast Cancer Patients |
title_fullStr | Discrimination between Complete versus Non-Complete Pathologic Response to Neoadjuvant Therapy Using Ultrasensitive Mutation Analysis: A Proof-of-Concept Study in BRCA1-Driven Breast Cancer Patients |
title_full_unstemmed | Discrimination between Complete versus Non-Complete Pathologic Response to Neoadjuvant Therapy Using Ultrasensitive Mutation Analysis: A Proof-of-Concept Study in BRCA1-Driven Breast Cancer Patients |
title_short | Discrimination between Complete versus Non-Complete Pathologic Response to Neoadjuvant Therapy Using Ultrasensitive Mutation Analysis: A Proof-of-Concept Study in BRCA1-Driven Breast Cancer Patients |
title_sort | discrimination between complete versus non-complete pathologic response to neoadjuvant therapy using ultrasensitive mutation analysis: a proof-of-concept study in brca1-driven breast cancer patients |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9914941/ https://www.ncbi.nlm.nih.gov/pubmed/36768191 http://dx.doi.org/10.3390/ijms24031870 |
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