Cargando…
Circulating Tumor DNA to Interrogate the Safety of Letrozole-Associated Controlled Ovarian Stimulation for Fertility Preservation in Breast Cancer Patients
BACKGROUND: Current fertility preservation strategies for young breast cancer patients planning a future motherhood include the association of controlled ovarian stimulation with the aromatase inhibitor letrozole (let-COS) to harvest mature oocytes while maintaining low estradiol levels. Despite thi...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370091/ https://www.ncbi.nlm.nih.gov/pubmed/34414109 http://dx.doi.org/10.3389/fonc.2021.686625 |
_version_ | 1783739409375428608 |
---|---|
author | Rothé, Françoise Lambertini, Matteo Goldrat, Oranite Maetens, Marion Bareche, Yacine Blanc, Jeremy Rouas, Ghizlane Larsimont, Denis Sotiriou, Christos Ignatiadis, Michail Demeestere, Isabelle |
author_facet | Rothé, Françoise Lambertini, Matteo Goldrat, Oranite Maetens, Marion Bareche, Yacine Blanc, Jeremy Rouas, Ghizlane Larsimont, Denis Sotiriou, Christos Ignatiadis, Michail Demeestere, Isabelle |
author_sort | Rothé, Françoise |
collection | PubMed |
description | BACKGROUND: Current fertility preservation strategies for young breast cancer patients planning a future motherhood include the association of controlled ovarian stimulation with the aromatase inhibitor letrozole (let-COS) to harvest mature oocytes while maintaining low estradiol levels. Despite this is a widely adopted protocol, the safety of let-COS on breast cancer outcomes has been poorly investigated and its use remains off-label. We assessed the safety of let-COS in breast cancer patients using circulating tumor DNA (ctDNA) as a surrogate biomarker of disease recurrence. METHODS: BROVALE is an interventional non-randomized prospective study designed to evaluate the efficacy and safety of let-COS for fertility preservation in early breast cancer patients before starting (neo)adjuvant chemotherapy. Letrozole was administered throughout the COS cycle, until ovulation triggering. Safety was a secondary endpoint. Data on oncological outcomes were collected during the follow-up as well as plasma and whole blood for evaluation of ctDNA levels at the time of enrollment (i.e. before starting let-COS) and oocyte retrieval (i.e. 48 hours after the last administration of letrozole). Targeted gene sequencing on the primary tumor samples was performed to identify specific mutations used for ctDNA analysis by digital PCR. DNA extracted from whole blood samples was used to discriminate between somatic and germline mutations. RESULTS: From April 2014 to May 2017, 29 young early breast cancer patients enrolled in the BROVALE study who had available tissue samples participated to the ctDNA substudy. Among them, 15 had at least one validated somatic mutation. ctDNA was undetectable neither before nor after let-COS in 9 of them. Six patients had detectable ctDNA in the plasma samples collected before Let-COS. No change in ctDNA level after let-COS was observed in 3 patients and the level decreased (fold-change ≤ 0.5) in two women. One patient experienced an increased (fold-change ≥ 2) in ctDNA level but without disease relapse 34 months after diagnosis. CONCLUSIONS: No increase in ctDNA level was observed in 93% (14/15) of the patients receiving let-COS supporting its use as a safe strategy for young women with early breast cancer interested in fertility preservation before chemotherapy. |
format | Online Article Text |
id | pubmed-8370091 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-83700912021-08-18 Circulating Tumor DNA to Interrogate the Safety of Letrozole-Associated Controlled Ovarian Stimulation for Fertility Preservation in Breast Cancer Patients Rothé, Françoise Lambertini, Matteo Goldrat, Oranite Maetens, Marion Bareche, Yacine Blanc, Jeremy Rouas, Ghizlane Larsimont, Denis Sotiriou, Christos Ignatiadis, Michail Demeestere, Isabelle Front Oncol Oncology BACKGROUND: Current fertility preservation strategies for young breast cancer patients planning a future motherhood include the association of controlled ovarian stimulation with the aromatase inhibitor letrozole (let-COS) to harvest mature oocytes while maintaining low estradiol levels. Despite this is a widely adopted protocol, the safety of let-COS on breast cancer outcomes has been poorly investigated and its use remains off-label. We assessed the safety of let-COS in breast cancer patients using circulating tumor DNA (ctDNA) as a surrogate biomarker of disease recurrence. METHODS: BROVALE is an interventional non-randomized prospective study designed to evaluate the efficacy and safety of let-COS for fertility preservation in early breast cancer patients before starting (neo)adjuvant chemotherapy. Letrozole was administered throughout the COS cycle, until ovulation triggering. Safety was a secondary endpoint. Data on oncological outcomes were collected during the follow-up as well as plasma and whole blood for evaluation of ctDNA levels at the time of enrollment (i.e. before starting let-COS) and oocyte retrieval (i.e. 48 hours after the last administration of letrozole). Targeted gene sequencing on the primary tumor samples was performed to identify specific mutations used for ctDNA analysis by digital PCR. DNA extracted from whole blood samples was used to discriminate between somatic and germline mutations. RESULTS: From April 2014 to May 2017, 29 young early breast cancer patients enrolled in the BROVALE study who had available tissue samples participated to the ctDNA substudy. Among them, 15 had at least one validated somatic mutation. ctDNA was undetectable neither before nor after let-COS in 9 of them. Six patients had detectable ctDNA in the plasma samples collected before Let-COS. No change in ctDNA level after let-COS was observed in 3 patients and the level decreased (fold-change ≤ 0.5) in two women. One patient experienced an increased (fold-change ≥ 2) in ctDNA level but without disease relapse 34 months after diagnosis. CONCLUSIONS: No increase in ctDNA level was observed in 93% (14/15) of the patients receiving let-COS supporting its use as a safe strategy for young women with early breast cancer interested in fertility preservation before chemotherapy. Frontiers Media S.A. 2021-08-03 /pmc/articles/PMC8370091/ /pubmed/34414109 http://dx.doi.org/10.3389/fonc.2021.686625 Text en Copyright © 2021 Rothé, Lambertini, Goldrat, Maetens, Bareche, Blanc, Rouas, Larsimont, Sotiriou, Ignatiadis and Demeestere https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Rothé, Françoise Lambertini, Matteo Goldrat, Oranite Maetens, Marion Bareche, Yacine Blanc, Jeremy Rouas, Ghizlane Larsimont, Denis Sotiriou, Christos Ignatiadis, Michail Demeestere, Isabelle Circulating Tumor DNA to Interrogate the Safety of Letrozole-Associated Controlled Ovarian Stimulation for Fertility Preservation in Breast Cancer Patients |
title | Circulating Tumor DNA to Interrogate the Safety of Letrozole-Associated Controlled Ovarian Stimulation for Fertility Preservation in Breast Cancer Patients |
title_full | Circulating Tumor DNA to Interrogate the Safety of Letrozole-Associated Controlled Ovarian Stimulation for Fertility Preservation in Breast Cancer Patients |
title_fullStr | Circulating Tumor DNA to Interrogate the Safety of Letrozole-Associated Controlled Ovarian Stimulation for Fertility Preservation in Breast Cancer Patients |
title_full_unstemmed | Circulating Tumor DNA to Interrogate the Safety of Letrozole-Associated Controlled Ovarian Stimulation for Fertility Preservation in Breast Cancer Patients |
title_short | Circulating Tumor DNA to Interrogate the Safety of Letrozole-Associated Controlled Ovarian Stimulation for Fertility Preservation in Breast Cancer Patients |
title_sort | circulating tumor dna to interrogate the safety of letrozole-associated controlled ovarian stimulation for fertility preservation in breast cancer patients |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370091/ https://www.ncbi.nlm.nih.gov/pubmed/34414109 http://dx.doi.org/10.3389/fonc.2021.686625 |
work_keys_str_mv | AT rothefrancoise circulatingtumordnatointerrogatethesafetyofletrozoleassociatedcontrolledovarianstimulationforfertilitypreservationinbreastcancerpatients AT lambertinimatteo circulatingtumordnatointerrogatethesafetyofletrozoleassociatedcontrolledovarianstimulationforfertilitypreservationinbreastcancerpatients AT goldratoranite circulatingtumordnatointerrogatethesafetyofletrozoleassociatedcontrolledovarianstimulationforfertilitypreservationinbreastcancerpatients AT maetensmarion circulatingtumordnatointerrogatethesafetyofletrozoleassociatedcontrolledovarianstimulationforfertilitypreservationinbreastcancerpatients AT barecheyacine circulatingtumordnatointerrogatethesafetyofletrozoleassociatedcontrolledovarianstimulationforfertilitypreservationinbreastcancerpatients AT blancjeremy circulatingtumordnatointerrogatethesafetyofletrozoleassociatedcontrolledovarianstimulationforfertilitypreservationinbreastcancerpatients AT rouasghizlane circulatingtumordnatointerrogatethesafetyofletrozoleassociatedcontrolledovarianstimulationforfertilitypreservationinbreastcancerpatients AT larsimontdenis circulatingtumordnatointerrogatethesafetyofletrozoleassociatedcontrolledovarianstimulationforfertilitypreservationinbreastcancerpatients AT sotiriouchristos circulatingtumordnatointerrogatethesafetyofletrozoleassociatedcontrolledovarianstimulationforfertilitypreservationinbreastcancerpatients AT ignatiadismichail circulatingtumordnatointerrogatethesafetyofletrozoleassociatedcontrolledovarianstimulationforfertilitypreservationinbreastcancerpatients AT demeestereisabelle circulatingtumordnatointerrogatethesafetyofletrozoleassociatedcontrolledovarianstimulationforfertilitypreservationinbreastcancerpatients |