Background: Inflammatory breast cancer (IBC) is a rare form of breast cancer associated with a poor prognosis. This study describes the incidence, survival, and management of IBC in the province of Ontario. Methods: We conducted a retrospective, population-based, cohort study using data systems held at the Division of Cancer Care and Epidemiology at Queen’s University in Kingston, Ontario. Using the Ontario Cancer Registry (OCR), we identified all primary, pathologically confirmed cases of breast cancer. IBC cases were identified using the unique histology code ‘85303’. OCR records were linked to Statistics Canada data, Canadian Institutes of Health Information (CIHI) records of surgical procedures, and cancer centre records detailing radiotherapy and chemotherapy administration. We calculated age-adjusted incidence rates of IBC for cases diagnosed between 1984 and 2005. Using the Kaplan Meier product-limit method and log-rank statistics we compared overall survival for IBC and non-IBC, and assessed temporal and regional variations in IBC survival. We described the management of IBC for patients diagnosed between 1984 and 2004, and assessed variations over time and across cancer centres. Results: Age-adjusted incidence rates of IBC increased from 0.57/105 women-years in 1984-1987 to 1.15/105 women-years in 2003-2005 (p<0.0001). 10-year survival was 21.5% for IBC compared to 61.7% for non-IBC (p<0.0001). For IBC, 10-year survival increased from 12.0% (95% CI: 8.3–16.3) for those diagnosed between 1984-1994 to 24.0% (95% CI: 20.1–28.2) for those diagnosed between 1995-2005. The utilization of combined mastectomy and postoperative radiotherapy increased from 28.9% in 1984-1994 to 46.1% in 1995-2004 (p<0.0001). We observed no statistically significant difference in the utilization of chemotherapy over time. Differences in the utilization of combined mastectomy and postoperative radiotherapy were observed across cancer centres (29.8% at centre C vs. 54.7% at centre A, p<0.0001). We also observed wide variations in the estimates of survival across cancer centres. Discussion: Rates of IBC have increased over time in Ontario and we observed an improvement in the long-term survival. Management has shifted over time towards increased use of mastectomy and postoperative radiotherapy. Additional prognostic information is needed to determine how variations in practice may be related to variations in outcome. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2009-09-24 16:15:10.068

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer, with a particularly poor prognosis. Identification of epidemiologic risk factors for IBC might shed light on causes of the disease, and guide screening and perhaps treatment. Previous studies have suggested that race, geographic location, body mass index (BMI), menopausal status, age at menarche, parity, duration of lactation, and exposure to mouse mammary tumor virus may be key risk factors in the development of IBC. This retrospective epidemiologic study examines the risk factors for IBC in predominantly Caucasian patients treated at the Dana Farber Cancer Institute (DFCI) in Boston, MA. The risk factors that were examined in this study include the following: BMI, family history of having breast cancer, comorbidities, duration of symptoms associated with IBC prior to diagnosis, season of diagnosis, and molecular subtypes of breast cancer. Additionally, the descriptive statistics for the mean age of diagnosis, race, menopausal status, genetic predisposition, and the presence of metastases in distant organs were also determined. This study showed that there is some evidence of a hereditary component and seasonal variation to the disease. Furthermore, this study reiterates the association of high body mass index (BMI) and IBC. The data collected from the DFCI IBC patient population suggest that modifiable lifestyle factors, perhaps due to a lack of awareness of the disease, might be crucial in the development of IBC. Further research is needed to explore the unique risk factors in developing IBC elucidated in this study in order to better understand and prevent such an aggressive disease.

<p>Inflammatory breast cancer (IBC) is a rare and highly aggressive form of breast cancer that is characterized by survival signaling through overexpression and/or activation of the epidermal growth factor receptors EGFR/ErbB1 and Her2/ErbB2 and defects in the apoptotic program. The development of therapeutic resistance is a significant barrier to successful treatment in IBC, and thus, strategies targeting the mechanisms that drive drug resistance could prevent or reverse therapeutic resistance, significantly improving patient prognosis. Based on analysis of previously developed models of therapeutic resistant IBC, we hypothesized that apoptotic dysregulation and redox adaptive mechanisms were central to the drug resistant phenotype in IBC cells, and that targeting of these mechanisms could overcome therapeutic resistance. Our objectives to address this hypothesis were: 1. to develop and characterize an isotype-matched IBC cellular model to investigate the mechanisms of acquired therapeutic resistance; 2. to characterize IAP-specific small molecule inhibitors as a means of targeting the mechanism of apoptotic dysregulation in IBC; and 3. to characterize a novel redox modulatory combination as a means of targeting redox adaptive mechanisms in IBC.</p><p>Analysis of cell viability, proliferation, and growth parameters, evaluation of protein expression and signaling via western immunoblot, and measurement of reactive oxygen species (ROS), antioxidants, and apoptosis in patient-derived IBC cell lines and isogenic derivatives revealed that resistance to the ErbB1/2 inhibitor lapatinib was protective against other targeted agents and chemotherapeutics. Additionally, reversal of resistance was associated with enhanced ability to accumulate ROS and downregulation of anti-apoptotic and antioxidant proteins. Targeting of resistance mechanisms using small molecule IAP inhibitors and a redox modulatory strategy both effectively induced apoptosis in therapy resistant IBC cells. Together, these results confirm XIAP and the redox adaptive phenotype as promising therapeutic targets for IBC and demonstrate the feasibility of targeting those mechanisms in order to reverse therapeutic resistance.</p> / Dissertation

Le cancer du sein inflammatoire (CSI) est l’une des formes la plus agressive en raison de son potentiel métastatique élevé. Le diagnostic est basé sur des signes cliniques avec une émergence rapide, mais en réalité ces signes sont subjectifs et non spécifiques. Malgré le traitement multidisciplinaire, le pronostic reste mauvais avec une survie à 5 ans inférieure à 50% vs 90% dans le cancer du sein non inflammatoire (CSNI). Les CSI sont rares en Europe et aux Etats-Unis, représentant moins de 2% du CS. En Afrique du Nord et en particulier en Tunisie, ils représentent plus de 5% des CS. Notre équipe a trouvé des gènes significativement plus sur-exprimés dans CSI dans une signature moléculaire indépendante des sous-types moléculaires et était composé de 79 gènes. Nous nous sommes intéressés particulièrement à MARCKS qui code pour le substrat majeur de la protéine kinase C. Dans le cadre de cette thèse, nous avons tenté de mieux comprendre les aspects épidémiologiques et cliniques des CSI associés à une distribution géographique différente. Nous analyserons les caractéristiques histo-cliniques et de pronostic sur une série de 219 patientes de CSI traitées à l'Institut Salah Azaiez (Tunis) de 2008 à 2013. Les résultats de cette série historique tunisienne ont été comparés à ceux de la littérature. Évaluer si la protéine MARCKS pourrait être un nouveau marqueur spécifique du CSI par une analyse IHC sur des échantillons de tumeurs CSI et CSNI de patientes française et tunisiennes (N = 502). Les corrélations entre l'expression de MARCKS et les critères cliniques et biologiques ont été établies. / Inflammatory Breast Cancer (IBC is one of the most aggressive breast cancers due its high metastatic potential. The diagnostic is based on clinical signs with rapid emergence but in reality these signs are subjective and non-specific. Despite the multi-modality treatment, the prognosis remains poor with survival in 5-year inferior to 50% vs 90% in non-Inflammatory Breast Cancers (non-IBC). IBC were rare in Europe and USA, represented at least 2% of breast cancer (BC), more frequent in North Africa and particularly in Tunisia which they present more than 5% of BC. Our team has found genes most significantly over-expressed in IBC given a molecular signature independent from the molecular subtypes and was composed of 79 genes. We were interested particularly to MARCKS gene that encodes for the major substrate of protein kinase C. As part of this thesis, we have attempted to better understand the epidemiological and clinical aspects of IBCs associated with a different geographical distribution. We will analyze the histo-clinical characteristics and the prognosis on a series of 219 patients with IBC treated at the Salah Azaiez Institute (Tunis) from 2008 to 2013. The results of this historical Tunisian series were compared with those of literature. Evaluate whether MARCKS protein could be a new specific marker for IBC by an IHC analysis on IBC and non-IBC tumor samples of French and Tunisian patients (N=502). Correlations between the expression of MARCKS and clinical and biological criteria were established.

Autoimmune hemolytic anemia (AIHA) is a disease process that involves the destruction of red blood cells mediated by the humoral immune system. It can be characterized as a cold agglutinin syndrome, paroxysmal cold hemoglobinuria, and warm, mixed type, and drug-induced AIHA. Although a well-established relationship exists between the presence of AIHA and lymphoproliferative malignancy, AIHA rarely presents in association with solid malignancies. An analysis of the limited number of published cases of AIHA in association with solid malignancies performed showed that AIHA may present before the diagnosis of a solid malignancy, concurrently with the presence of a solid malignancy, or even on resolution of a solid malignancy. Few cases of solid cancers associated with AIHA have been reported. AIHA rarely presents as a paraneoplastic syndrome indicating existence of a solid cancer. We report a case of inflammatory breast cancer with AIHA.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13218号 / 論医博第2165号 / 新制||医||1033(附属図書館) / 京都大学大学院医学研究科内科系専攻 / (主査)教授 溝脇 尚志, 教授 黒田 知宏, 教授 鈴木 実 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM