NAGIOS: RODERIC FUNCIONANDO

Estudio de las alteraciones genéticas asociadas con la resistencia al tratamiento neoadjuvante de deprivación estrogénica en cáncer de mama

Repositori DSpace/Manakin

IMPORTANT: Aquest repositori està en una versió antiga des del 3/12/2023. La nova instal.lació está en https://roderic.uv.es/

Estudio de las alteraciones genéticas asociadas con la resistencia al tratamiento neoadjuvante de deprivación estrogénica en cáncer de mama

dc.contributor.advisor	Lluch Hernández, Ana
dc.contributor.advisor	Guillem Porta, Vicente
dc.contributor.advisor	López Guerrero, José Antonio
dc.contributor.author	Guerrero Zotano, Angel
dc.contributor.other	Facultat de Medicina i Odontologia	es_ES
dc.date.accessioned	2021-02-09T12:10:30Z
dc.date.available	2021-02-10T05:45:06Z
dc.date.issued	2021	es_ES
dc.date.submitted	15-01-2021	es_ES
dc.identifier.uri	https://hdl.handle.net/10550/77726
dc.description.abstract	With current standard of care adjuvant therapy, approximately 25-30% of women with high risk early stage HR+/HER2- breast cancer experience relapse. The preoperative platform offers an opportunity to interrogate mechanisms of drug resistance that, in turn, could inform the choice of adjuvant therapy. We report herein a study where we performed targeted DNA sequencing and whole transcriptome analysis on whole tumor sections from a cohort of 68 operable ER+ breast cancers treated with the aromatase inhibitor letrozole for a median of 7.2 months before surgery, and a with a median follow up of 5 years. We found that resistant tumors were enriched in clinically actionable mutation and showed an enrichment in expression of genes involved in proliferation. Resistant tumors show a high degree of heterogeneity among them upregulating a variety of transcriptional programs. A common feature among resistant tumors was a co-expression of several genes dependent on the E2F4 transcription factor. We defined an E2F4 activation signature that define ER+ breast cancer with poor prognostic features and is sensitive to treatment with CDK4/6 inhibitors. This signature is of potential use for the identification of patients with ER+ breast cancer candidates for adjuvant therapy with CDK4/6 inhibitors in combination with antiestrogens. Our study also identifies a novel gene, PRR11 (Proline rich 11), as a putative driver of endocrine resistance in ER+ breast cancers and that merits further investigation to understand its mechanisms of action.	es_ES
dc.description.abstract	With current standard of care adjuvant therapy, approximately 25-30% of women with high risk early stage HR+/HER2- breast cancer experience relapse. The preoperative platform offers an opportunity to interrogate mechanisms of drug resistance that, in turn, could inform the choice of adjuvant therapy. We report herein a study where we performed targeted DNA sequencing and whole transcriptome analysis on whole tumor sections from a cohort of 68 operable ER+ breast cancers treated with the aromatase inhibitor letrozole for a median of 7.2 months before surgery, and a with a median follow up of 5 years. We found that resistant tumors were enriched in clinically actionable mutation and showed an enrichment in expression of genes involved in proliferation. Resistant tumors show a high degree of heterogeneity among them upregulating a variety of transcriptional programs. A common feature among resistant tumors was a co-expression of several genes dependent on the E2F4 transcription factor. We defined an E2F4 activation signature that define ER+ breast cancer with poor prognostic features and is sensitive to treatment with CDK4/6 inhibitors. This signature is of potential use for the identification of patients with ER+ breast cancer candidates for adjuvant therapy with CDK4/6 inhibitors in combination with antiestrogens. Our study also identifies a novel gene, PRR11 (Proline rich 11), as a putative driver of endocrine resistance in ER+ breast cancers and that merits further investigation to understand its mechanisms of action.	en_US
dc.format.extent	143 p.	es_ES
dc.language.iso	en	es_ES
dc.subject	cancer de mama	es_ES
dc.subject	hormonoterapia neodayuvante	es_ES
dc.subject	resistencia hormonal	es_ES
dc.subject	E2F	es_ES
dc.title	Estudio de las alteraciones genéticas asociadas con la resistencia al tratamiento neoadjuvante de deprivación estrogénica en cáncer de mama	es_ES
dc.type	doctoral thesis	es_ES
dc.subject.unesco	UNESCO::CIENCIAS MÉDICAS	es_ES
dc.embargo.terms	0 days	es_ES