Demà 4 de Març de 2021 el sistema estarà en manteniment des de les 7:15 fins a les 9:15 hores. Disculpeu les molèsties.
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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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Guerrero Zotano, Angel
Lluch Hernández, Ana (dir.);
Guillem Porta, Vicente (dir.);
López Guerrero, José Antonio (dir.)
Facultat de Medicina i Odontologia
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This document is a tesisDate2021
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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.
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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.
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