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

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

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

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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.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 info:eu-repo/semantics/doctoralThesis es_ES
dc.subject.unesco UNESCO::CIENCIAS MÉDICAS es_ES
dc.description.abstractenglish 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.embargo.terms 0 days es_ES

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