Chemotherapy and adjuvant endocrine treatment for breast cancer has been associated with varying degrees of cognitive dysfunction, with 15-50% of women reported to experience subtle cognitive decline. While these treatments may have direct adverse consequences on neurological functioning, cancer diagnosis and treatment is also associated with many health and psychosocial factors that may decrease performance on neuropsychological tests. However, despite a growing body of literature on affected cognitive domains and observable neurological changes after chemotherapy, there has not been a thorough investigation into potentially important psychosocial and physical health mechanisms that may underlie the observed cognitive dysfunction. Therefore, the primary aim of this thesis was to evaluate the relationship between health/ treatment, psychosocial, and endocrine-related factors and cognitive dysfunction after breast cancer treatment. In addition, a smaller secondary aim was to assess the appropriateness of different methods of individual change. Chapter 1 provides a brief overview of the structure and content of the thesis. Chpaters 2 and 3 are review papers that evaluate whether there is evidence that variations in psychosocial adjustment, health and treatment factors result in cognitive changes after chemotherapy. Based on previous research, the mechanisms evaluated are endocrine-related changes (use of adjuvant endocrine treatment and chemotherapy-induced menopause); chemotherapy-induced anaemia; depression; anxiety; fatigue; quality of life; and other treatment factors (e.g. treatment duration, time since treatment, tumour stage, use of concomitant medications and co-morbid medical conditions). The impact of confounding variables such as age of participants, level of baseline functioning and methodological limitations are also considered. These two chapters have been published (refer to Appendix A for a complete list of presentations and publications arising from this thesis). The fourth and fifth chapters are methodological in nature. Chapter 4 describes methods, while Chapter 5 is a brief paper (under review) which examines methodological considerations regarding analysis of individual change in neuropsychological performance over time and across domains for women undergoing treatment for breast cancer. The sixth and seventh chapters involve empirical analyses of the data collected as part of the Cognition in Breast Cancer (CBC) study, a longitudinal study examining the causes of variation in cognitive functioning, health and well-being in women up to 2 years post-chemotherapy. Chapter 6 was an experimental study designed to investigate the acute effects of psychosocial mechanisms on cognitive functioning after chemotherapy in a sample of 157 breast cancer patients. Many of the methodological limitations identified in the review studies were addressed and the neuropsychological performance of two groups was compared, namely recently diagnosed breast cancer patients scheduled for chemotherapy (n = 136) or other forms of treatment (n = 21). Participants were assessed prior to commencing treatment and approximately one month post completion of chemotherapy (or 6 months after the first assessment). Individual cognitive impairment was examined using the Reliable Change Index, while Pearson correlations were utilised in order to investigate the effect of psychosocial and health factors on cognitive change. The results indicated that decline in haemoglobin levels and increased anxiety over the course of chemotherapy significantly predicted impairment in multiple cognitive measures, while change in specific cognitive measures was significantly associated with baseline measures of fatigue, depression and functional well-being. The impact of these findings on rehabilitation strategies for women after chemotherapy was discussed. Chapter 7 investigated whether endocrine-related changes, namely chemotherapy-induced menopause and adjuvant endocrine treatment, resulted in increased cognitive dysfunction. One hundred and thirty-six breast cancer patients were assessed using a comprehensive neuropsychological assessment over three time-points, namely pre-chemotherapy, one month and six months post chemotherapy (or at similar time-points). Linear mixed models evaluated the effects of these two factors, with little evidence found to suggest that endocrine-related factors contribute to cognitive dysfunction in breast cancer patients. Chapter 8 comprises a brief summary and overview of the entire thesis and offers overarching conclusions, strengths and weaknesses, and directions for future research. The findings of the present investigations attempt to elucidate the contributions of potentially important psychosocial and health/ treatment-related mechanisms for cognitive dysfunction after breast cancer treatment. While there was little evidence to suggest endocrine-related changes impacted on cognition, the findings linking chemotherapy-induced anaemia and baseline psychosocial measures may play an important role in identifying and treating at-risk individuals. These findings have potential research implications for the ways data is collected, analysed and presented in empirical research as well as clinical ramifications for how women are affected cognitively as well as psychologically by treatment for breast cancer.

The primary purpose of this research was to examine the effects of HRT in women with acute estrogen deficiency from surgically induced menopause. The secondary purpose was to evaluate how HRT improves symptoms of acute estrogen deficiency and quality of life (QOL) in women using hormone supplementation. Peer reviewed articles published from 2000 to 2017 that were written in the English language with a focus on the use of HRT in women with acute estrogen deficiency after surgical menopause were evaluated for relevance. Evidence suggests the primary reason for decreased use of HRT is the associated risks outweighing the benefits; however, this is not reflected in health care provider's (HCP's) clinical experience. HCP's were more likely to prescribe HRT for themselves or family members if they were experiencing the negative side effects of estrogen deficiency due to surgical menopause, but not to women in their care with similar clinical manifestations of menopause. Additionally, serious risks associated with HRT for acute estrogen deficiency remain incongruent with HRT for women experiencing natural menopause; although risk for breast cancer due to HRT was a universal concern. Risks of HRT related to thromboembolism, stroke and heart disease, were discussed with comparison to the undesirable clinical manifestations of menopause. Results indicate further education and research is needed that explores the risks and benefits for HRT in women with sudden onset of estrogen deficiency from surgical menopause.

Le cancer du sein est le cancer le plus fréquent chez la femme et malgré une baisse de la mortalité ces dernières années, attribuable à une détection précoce et une meilleure prise en charge, il reste la première cause de mortalité par cancer et demeure donc un problème majeur de santé publique. La mortalité par cancer du sein s’avère être plus élevée dans le cas des cancers dits agressifs ou de mauvais pronostic tels que le cancer du sein de la femme jeune et le cancer du sein triple négatif (CSTN). Mes travaux de thèse portent sur ces deux types de cancer du sein avec comme objectifs l’étude des conséquences de la ménopause chimio-induite (MCI) chez les femmes jeunes atteintes d’un cancer du sein non métastatique d’une part et l’analyse des facteurs pronostiques de la rechute du cancer du sein triple négatif d’autre part. Le premier axe de ma thèse concerne l’étude clinique MENOCOR dont le but est d’évaluer chez les femmes jeunes atteintes d’un cancer du sein non métastatique l’impact de la MCI sur la qualité de vie (QdV). L’incidence de la MCI et l’étude des variations hormonales font également partie des objectifs secondaires. Dans le cadre de cette thèse, l’analyse intermédiaire, prévue dans le protocole, a été réalisée sur 59 patientes avec un recul de 18 mois post-chimiothérapie. Ces premiers résultats ont tendance à montrer une altération de la QdV évaluée par le QLQ-BR23 chez les patientes ménopausées vs les non ménopausées (p=0.17). A ce stade de l’essai, le QLQ-BR23 semble donc être plus adapté que le QLQ-C30 pour évaluer la QdV dans le contexte de cette étude. Nous avons également observé une prédiction possible de la MCI par le dosage de l’AMH initial et l’âge des patientes. Ainsi, ces résultats doivent être comparés à ceux de l’analyse finale et nous supposons qu’avec une puissance plus importante (effectif total prévu de 240 patientes et suivi de 30 mois post-traitement) les résultats concernant la QdV pourraient être significatifs.Le deuxième axe de ma thèse a consisté à la création d’une base de données sur le CSTN. Cette étude rétrospective s’inscrit dans la continuité des travaux réalisés au Centre Jean PERRIN et a pour but d’évaluer la dynamique et les facteurs prédictifs de la rechute du CSTN. Les analyses ont montré que l’atteinte ganglionnaire, la présence d’emboles et la taille tumorale sont les principaux facteurs pronostiques de la rechute. Les résultats présentés dans cette thèse confirment également l’hétérogénéité des CSTN avec l’existence d’une disparité des réponses à la CTNA (allant de la réponse complète à la chimiorésistance) et d’une diversité des rechutes (précoces (< 1 an), standards (1 à 5 ans) et tardives (> 5 ans)) soulignant la nécessité de poursuivre la recherche de nouveaux biomarqueurs pouvant prédire la réponse ou encore permettant de prévenir les rechutes afin d’améliorer la prise en charge des patientes. En conclusion, ces résultats permettent d’ouvrir de nombreuses perspectives de recherches. Nous prévoyons de comparer les résultats finaux de l’étude MENOCOR à ceux de l’analyse intermédiaire présentés dans cette thèse. A l’issu de l’essai, nous espérons avoir une meilleure compréhension de la MCI, de son impact sur la QdV et du rôle de l’AMH dans la prédiction de la ménopause. Concernant le CSTN, il est prévu de mener une autre étude rétrospective sur une cohorte plus large, avec cette fois-ci, l’analyse des paramètres hématologiques. En fonction des résultats, une étude prospective pourra être mise en place afin d’étudier le rôle du microenvironnement tumoral ainsi que des paramètres hématologiques et génétiques dans la rechute des CSTN. / Breast cancer is the most common cancer among women and despite a decline in mortality in recent years, due to early detection and better treatment management, it remains a major public health issue. Breast cancer mortality has been found to be higher in the case of aggressive or poor prognostic cancers such as breast cancer in young women and the triple negative subtype of breast cancer (TNBC).This PhD focuses on these two types of breast cancer and aims to study the consequences of chemotherapy-induced menopause (CIM) in young women with non metastatic breast cancer and evaluate the prognostic factors of TNBC relapse. One of the aspect of my PhD is based on the clinical study MENOCOR. The main objective of this study is to evaluate the impact of CIM on the quality of life (QoL) of young women with non metastatic breast cancer. The incidence of CIM and the study of hormonal variations are also a part of the secondary objectives. As a part of this PhD work, the interim analysis planned in the study protocol was conducted on 59 patients with a follow-up of 18 months post-chemotherapy. These first results tend to show a QoL decrease, evaluted by the QLQ-BR23, in menopausal women vs non menopausal women (p=0.17). At this stage of the trial, the QLQ-BR23 seems to be more appropriate than the QLQ-C30 to evaluate QoL. We also underline the possible prediction of CIM by the inital AMH level and age. Thus, these results should be compared to the final analysis and we expect that with a greater power (240 patients and a follow-up of 30 months post-chemotherapy) the QoL results will reach significance.The second axis consists of a database on TNBC. This retrospective study follows the work carried out in Jean PERRIN Cancer Center and aims to evaluate dynamics and pronostic factors of TNBC relapse. The analysis showed that the main pronostic factors are the node metastasis, the presence of emboli and the tumor size. The variability of response to chemotherapy (pCR to chemoresistance) and the diversity of relapses (early relapse (<1 year), standard relapse (1 to 5 years) and late relpase (> 5 years)) confirmed the heterogeneity of TNBC highlighting the need to continue the research of new biomarkers. In conclusion, these results open up many research perspectives. We plan to compare the final results of the MENOCOR study with those of the interim analysis presented in this PhD work. At the end of the study, we expect to have a better knowledge of CIM, its impact on QoL and the role of AMH in predicting menopause. Regarding the TNBC, it is planned to conduct another larger retrospective study focused in hematologic parameters evaluating the role of hematologic and genetic parameters. Depending on the results, a prospective study could be promoted in order to evaluate the role of tumoral micro-environment, and hematologic and genetic parameters in TNBC relapse.