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The Human Epidermal Growth Factor Receptor 2 (HER2) in the Breast Cancer: from Measurement to Targeted Treatment

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The Human Epidermal Growth Factor Receptor 2 (HER2) in the Breast Cancer: from Measurement to Targeted Treatment The human epidermal growth factor receptor 2 (HER2) in the breast cancer: from measurement to targeted treatment Thèse Daniela Furrer Soliz Urrutia Doctorat en médecine expérimentale Philosophiæ doctor (Ph. D.) Québec, Canada © Daniela Furrer Soliz Urrutia, 2017 The human epidermal growth factor receptor 2 (HER2) in breast cancer: from measurement to targeted treatment Thèse Daniela Furrer Soliz Urrutia Sous la direction de : Caroline Diorio, directrice de recherche Résumé La surexpression du récepteur 2 du facteur de croissance épidermique humain (HER2) et/ou l’amplification du gène HER2 sont des facteurs prédictifs du cancer du sein. Avec l’introduction du traitement ciblé au trastuzumab, l’évaluation fiable d’HER2 est devenue essentielle. Malheureusement, jusqu’à 50% des patientes HER2-positives développent une résistance envers ce médicament. Les objectifs étaient : 1) déterminer la façon la plus fiable et économique pour évaluer le statut HER2 (cohorte de 521 cas consécutifs de cancer du sein); 2) examiner l’association entre deux polymorphismes d’HER2 (Ile655Val et Ala1170Pro), la consommation de tabac et d’alcool et la réponse au trastuzumab (cohorte de 236 patientes HER2-positives traitées au trastuzumab). De plus, dans une étude pilote, nous avons examiné l’association entre les patrons de méthylation d’ADN dans la tumeur et la réponse au trastuzumab (cohorte de 12 patientes HER2-positives traitées au trastuzumab). Le statut HER2 a été évalué par immunohistochimie (IHC), hybridation fluorescente in situ (FISH) et essai TaqMan. Nous avons comparé le statut HER2 déterminé par FISH sur lame complète (LC, un tissu par lame) et par matrice tissulaire (TMA, 60 tissus par lame), ainsi que le statut HER2 évalué par IHC et FISH sur le bloc ayant servi pour le diagnostic (bloc diagnostique) et sur un bloc choisi aléatoirement (bloc aléatoire). Les informations cliniques ont été obtenues dans les dossiers médicaux, celles sur la consommation de tabac et d’alcool par des questionnaires validés. Le patron de méthylation d’ADN a été évalué en utilisant la micropuce Illumina Infinium HumanMethylation450 BeadChip. La concordance générale entre le statut HER2 déterminé par FISH sur LC et TMA était de 98,2%, et celle entre les blocs diagnostiques et aléatoires était de 98,0% au FISH et de 93,6% à l’IHC. La consommation de tabac et l’allèle Val étaient associés à une moins bonne réponse, tandis que la consommation d’alcool était associée à une meilleure réponse. Le patron de méthylation dans les tumeurs de patientes atteintes d’un cancer du sein HER2- positif qui ont développé une résistance au trastuzumab diffère de celui des patientes qui répondent au traitement. Cependant, ces résultats semblent dépendre de la méthode bioinformatique d’analyse utilisée. Nous concluons que l’évaluation d’HER2 par FISH sur TMA représente une méthode fiable et économique. Les taux de concordances obtenus par FISH, mais pas ceux observés à iii l’IHC, satisfont l’exigence du Collège des pathologistes américains d’au moins 95% de concordance entre les résultats obtenus avec la méthode de référence et la nouvelle méthode. Le tabagisme, la consommation d’alcool et le polymorphisme HER2 Ile655Val pourraient influencer la réponse au traitement au trastuzumab. iv Abstract The overexpression of the human epidermal growth factor receptor 2 (HER2) and/or HER2 gene amplification are predictive factors in breast cancer. Following the HER2-targeted treatment with trastuzumab, the reliable evaluation of HER2 has become essential. Unfortunately, up to 50% of HER2-positive breast cancer patients develop resistance towards this drug. The objectives were: 1). To determine the most reliable and economical method to evaluate HER2 status (cohort of 521 consecutive breast cancer cases); 2). To examine the association between tobacco and alcohol consumption, and two HER2 polymorphisms (Ile655Val and Ala1170Pro), and the response to trastuzumab (cohort of 236 HER2-positive breast cancer patients treated with trastuzumab). Moreover, in a pilot study, we explored the association between genome-wide DNA methylation patterns in breast cancer tissues and the response to trastuzumab (cohort of 12 breast cancer patients treated with trastuzumab). HER2 status was evaluated by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and TaqMan assay. We compared HER2 status determined by FISH on whole tissue (WT, one tissue per slide) section and tissue microarray (TMA, 60 tissues per slide) section, and HER2 status evaluated by IHC and FISH on the block used for diagnostic (diagnostic block) and on a randomly chosen additional block (random block). Clinicopathological information were assessed by review of medical records, tobacco and alcohol consumption by an administered validated questionnaire. DNA methylation patterns were evaluated using the Illumina Infinium HumanMethylation450 BeadChip. Overall concordance between HER2 status determined by FISH on WT and TMA sections was 98.2% and that between diagnostic and random blocks was 98.0% for FISH and 93.6% for IHC. Tobacco consumption and the Val allele were associated with a worse response, whereas alcohol consumption was associated with a better response. Methylation pattern in tumor tissues of HER2-positive breast cancer patients who acquired resistance to trastuzumab treatment differed from that of HER2-positive breast cancer patients who responded to trastuzumab treatment. However, this observation seemed to depend upon the method of bioinformatics analysis used. We conclude that FISH performed on TMA section represents a reliable and economical method for the evaluation of HER2. Results obtained by FISH, but not those obtained by v IHC, fulfill the recommendations of the College of American Pathologists of concordance greater than 95% between the reference method and the new method. Tobacco use, alcohol consumption and Ile655Val HER2 polymorphism might influence the response to trastuzumab treatment. vi Table of contents Résumé .............................................................................................................................................................. iii Abstract ................................................................................................................................................................ v Table of contents ............................................................................................................................................... vii Tables index ..................................................................................................................................................... xiii Figures index ..................................................................................................................................................... xv List of abbreviations .......................................................................................................................................... xvi Acknowledgments ............................................................................................................................................ xxii Foreword ......................................................................................................................................................... xxiv Chapter 1: Introduction ................................................................................................................................... - 1 - Literature overview ..................................................................................................................................... - 2 - 1.1. Breast cancer intrinsic subtypes .......................................................................................................... - 2 - 1.1.1. Molecular classification of breast cancer ...................................................................................... - 2 - 1.1.2. Molecular classification of breast cancer subtypes using immunohistochemical surrogates ....... - 5 - 1.1.3. HER2-enriched subtype vs. breast cancer clinically evaluated as HER2-positive ....................... - 7 - 1.1.4. Breast cancer clinically evaluated as HER2-positive ................................................................... - 8 - 1.2. Methods for the evaluation of HER2 status in breast cancer specimens............................................. - 9 - 1.2.1. Immunohistochemistry (IHC) and in situ hybridization (ISH) methods ......................................... - 9 - 1.2.2. Methodological worries related to HER2 testing ........................................................................ - 11 - 1.2.3. Concordance of HER2 status determined by IHC, FISH, CISH and SISH in the literature ........ - 13 - 1.3. HER2 biology..................................................................................................................................... - 14 - 1.3.1. HER2 structure and function ...................................................................................................... - 14 - 1.3.2. Consequences of constitutive HER2 receptor activation............................................................ - 18 - 1.4. Treatment of HER2-positive breast cancer patients .......................................................................... - 19 - 1.4.1. Anti-HER2 agents ...................................................................................................................... - 19 - 1.4.2. Endocrine therapy .....................................................................................................................
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