Thousands of women in Canada continue to be diagnosed every year with breast cancer, many undergoing surgical mastectomy as part of their treatment to eradicate or control the spread of disease. At present, the recommendation for breast conserving surgery (BCS) and breast reconstruction dominates discourse in oncological settings, limiting conversations about alternative options for women to consider following the removal of their breast(s). Interesting however is the decision, made by some women in contemporary society, to undertake unconventional practices such as being inscribed with tattoos where breasts once occupied space. Unfortunately, little is known about the experiences of women who have foregone reconstructive surgery and chose to be tattooed post mastectomy. A Gadamerian philosophical hermeneutic approach was used to explore the phenomenon of being tattooed post mastectomy. Six women with mastectomy tattoos were interviewed to learn about the experiences of being tattooed where breast(s) once occupied space. Participants in this study were between 48 and 65 years of age and tattooed from one month to five years after surgery. Meanings about being tattooed post mastectomy surfaced through conversation and photographs. Gadamer’s hermeneutic teachings were engaged to analyze women’s thoughts, feelings, and photographed images of participant tattoos, surfacing meaning about being tattooed where breasts once existed. To establish a passage for understanding, three publishable manuscripts constitute the body of the dissertation. The first manuscript presents my personal narrative [in part] of being diagnosed with breast cancer and undergoing a mastectomy without reconstruction. In the second manuscript, the socio-cultural context of why the mastectomized female body is considered abject in contemporary society is examined. Further, I explore how a mastectomy tattoo may be an emerging alternative for some women following the loss of their breasts(s). In the third manuscript the key interpretive discoveries through hermeneutic analysis of interviews and photographs are presented and include: (1) Feeling sad and damaged post mastectomy (2) Reclaiming self: Taking back power and control; and (3) Transformation: Embodying the tattoo as a novel representation of self. These interpretive findings suggest aesthetic options such as tattooing embolden participants to reclaim power and control lost to cancer and transformed their self perceptions of beauty, femininity, and sexual identity post mastectomy. This dissertation contributes to women’s health, specifically within the field of oncology by offering what I understand to be the first phenomenological study interpreting lived experiences of being tattooed post mastectomy. Understanding how women may feel sad and damaged following surgery opens avenues for empathetic questioning and therapeutic supports from nurses. Sharing experiences of women who found the process of designing and being tattooed transformational and empowering may introduce new options post mastectomy that include aesthetics and beauty. Gaining insight into this unique phenomenon can help make meaning about how aesthetic options such as tattooing can empower some women who may be searching for alternatives to breast reconstruction post mastectomy. Furthermore, challenging dominant discourses specific to how women’s bodies should look can create spaces for discursive conversations and optimistically expand options beyond those currently offered post mastectomy. / Graduate

As immunotherapy grows in popularity as a cancer treatment option, we need to further understand how immune cells interact with the tumor microenvironment and influence tumor progression. The goal of this thesis was to characterize the different immune, cellular, and structural components within the breast tumor tissues of two orthotopic (MCaP0008 and M3C) and one spontaneous (MMTV-PyVT) murine models of immunogenic breast cancer. Identification of the tumor components in question, including CD3+ lymphocytes, CD11b+ myeloid cells, CD31+ endothelial cells, αSMA+ cancer associated fibroblasts, Ki67+ cells, cleaved caspase-3+ cells, collagen-1, and hyaluronan, were done by immunohistochemistry (IHC)-immunofluorescence (IF) staining of frozen tumor tissues with appropriate antibodies and imaging with multispectral confocal microscopy. Quantification and further data analysis were performed using a custom MATLAB program designed by Dr. Mei Rosa Ng. Gaining understanding of these stromal compositions will allow for better utilization of these breast cancer mouse models in future experiments. / 2019-10-31

This project examined the imp act of an expressive writing intervention as compared to a general health in formation control on breast cancer patients' postradiation treatment. It further examined the content of the expressive writing narratives. The sample included women who were completing radiation treatment for breast cancer at the Huntsman Cancer Institute and City of Hope hospital. The measures utilized in this study were self-report instruments targeting psychological distress (PANAS, JES) and general functioning (SIP), as well as demographic questionnaires. Results revealed the expressive writing intervention significantly impacted positive affect over time. Furthermore, participants from both the treatment and control groups evidenced improvements in psychological distress and general functioning over time. Linguistic analyses revealed participants' use of positive affect words increased across writing sessions, whereas the use of negative affect words and cognitive words did not change. Additionally, the use of past tense words decreased across writing sessions, whereas the use of present tense words increased and the use of future tense remained constant. The findings revealed from this study indicate that an expressive writing intervention can positively impact breast cancer patients up to 1 year postradiation treatment. Furthermore, the analysis of writing trends suggests that the use of positive affect words, the decrease in use of past tense words, along with the increase of present tense words across writing sessions, may be important linguistic components in positive outcomes.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20799号 / 医博第4299号 / 新制||医||1025(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 竹内 理, 教授 武藤 学, 教授 河本 宏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Ph.D., Faculty of Health Sciences, University of the Witwatersrand, 2011 / Oestrogen receptor (ER) mutations have been identified for both ERα and ERβ in previous studies. The effects of the deletion variants due to splice mutations on clinical parameters, prognosis and treatment were examined in 61 breast carcinoma patients and 13 control samples from elective reduction mammoplasty procedures, respectively. RNA extracted from fine needle aspirates (FNAs) of breast tissue was reverse transcribed and using nested PCR and sequence analysis the presence of these variants elucidated. Using Χ2 and Fisher’s exact tests their significance with respect to clinical parameters such as tumour size, nodal involvement, stage, presence or absence of metastases, menstrual status and hormone responsiveness was examined. Kaplan-Meier survival analysis was also determined. The T-47D breast cancer cell line was cloned with two clones being selected for further analysis, namely TCA3 (hormone sensitive) and TCC1 (hormone resistant). These clones were treated for ten passages with oestrogen metabolites, 17-β- oestradiol and oestriol; oestrogen precursors, androstenedione and cholesterol; an anti-oestrogen, 4-hydroxy-tamoxifen; and the aromatase inhibitor aminoglutethimide, respectively. RNA was extracted from the cells initially and after the tenth passage and the ERα and ERβ exon profiles were examined using RT-PCR and sequence analysis. After the tenth passage hormone response tests were performed every 24 hours (up to 96 hours) with cell number being determined using the MTT assay. The results indicate that ERα and ERβ variants do not have any affect with respect to menstrual status and nodal involvement (N). Expression of ERα2 and ERα4 are required by the mouse monoclonal antibody (DAKO ® Clone 1D5) in the immunocytochemical assay used for the recognition of the protein in order to assess ER status and therefore show significance. ERαΔ2 and, contrary to previous investigations, the variant ERαΔ3 were not found to play a role in tumourigenesis. ERαΔ5 was observed to be more prevalent in ERα-positive patients and was usually co-expressed with the complete ERα5 indicating heterodimerization. ERαΔ5 showed no significance with respect to progression of disease or response to hormone treatment. An increase in the ratio of ERαΔ4: wild-type ERα4 indicated an increase in metastatic potential of diseased tissue. ERα4 and ERαΔ4 heterodimers were present in both T-47D clones and after 10 passages the TCA3 clone grown in 10-8M aminoglutethimide indicated a complete loss of ERα4 without altering hormone responsiveness. These results suggest that ERαΔ4 may play a role in progression of disease but not in the acquisition of tamoxifen resistance. ERαΔ6 was observed in 15% of patients but not in the T-47D clones or the control samples. An increase in the expression of ERαΔ6 among patient samples significantly increased their metastatic potential (p=0.018). ERαΔ6 was also observed as significant with respect to stage of disease (p=0.023) indicating the possible relevance of ERαΔ6 in progression of the disease. ERαΔ7 was the most frequently observed variant and did not show any significance with regard to any of the clinical parameters examined. The presence of ERαΔ7 did not show significance with regard to hormone response in vivo but in vitro the presence of this variant, expressed as a heterodimer with the wild-type ERα7, conferred greater sensitivity to tamoxifen in the tamoxifen resistant clone TCC1. Multiple exon deletions of ERα were also observed. The two more significant multiple deletion variants were those involving ERαΔ4, namely, ERαΔ2-ERαΔ6 and ERαΔ4-ERαΔ6. The multiple variant ERαΔ4-ERαΔ6 may be involved in tumour progression. ERβ variants were not examined in as much detail as ERα variants due to insufficient material available for analysis. The two domains, the DNA binding domain and the ligand binding domain, of ERβ were analyzed in a few of the patients and in the T-47D clones. They were not found to be significant with respect to the clinical parameters investigated and the ERβ profiles of the TCA3 and TCC1 clones remained unchanged after 10 passages under varying growth conditions.

Indiana University-Purdue University Indianapolis (IUPUI) / Triple-negative breast cancer (TNBC), which accounts for 15-20% of all breast cancers, is highly aggressive and metastatic with the poorest overall rates. While surgery, radiation, and chemotherapy remain the main treatment options, TNBC represents an unmet medical need for better treatment strategies. Tremendous efforts have been made to develop effective therapies over the past years. However, TNBC treatment options are still very limited due to the lack of good drug targets and the low response rate of current therapies. In this study, we developed two different strategies to treat TNBC based on its cancer genomic features: 1) heterozygous loss of chromosome 17p (17p loss) and 2) high mutation load. 17p loss is one of the most frequent genomic events in breast cancer including TNBC, rendering cancer cells vulnerable to the inhibition of POLR2A via α-amanitin (POLR2A-specific inhibitor). Here, we developed a new drug T-Ama (α-amanitin-conjugated trastuzumab) targeting HER2-low TNBC with 17p loss by combining the effects of α-amanitin and trastuzumab (HER2+ breast cancer therapy). Our results showed that T-Ama exhibited superior efficacy in treating HER2-low TNBC with 17p loss in vitro and in vivo, and surprisingly induced immunogenic cell death (ICD) which further enhanced T cell infiltration and cytotoxicity levels and delivered greater efficacy in combination with immune checkpoint blockade therapy. Collectively, the therapeutic window created by 17p loss and HER2 expression will make HER2-low TNBC clinically feasible targets of T-Ama. As another genetic feature of TNBC, the higher genomic instability and mutational burden results in more neoantigens presented on MHC-I, along with the higher level of tumor-infiltrating T cells, making TNBC a perfect model for immunotherapy compared to the other breast cancer subtypes. Here, we designed a deconvolution-algorithm-derived library screening to find new therapeutic targets and identified PIK3C2α as a key player that determines MHC-I turnover and reduces the MHC-I-restricted antigen presentation on tumor cells. In preclinical models, inhibition of PIK3C2α profoundly suppressed breast tumor growth, increased tumor-infiltrating CD8+ T cells, and showed high potential enhancing the efficacy of anti-PD-1 therapy, suggesting that PIK3C2α is a potential therapeutic target for TNBC immunotherapy. / 2025-05-22

No description available.

Breast cancer remains the most commonly diagnosed cancer among women over the age of 20, as recently reported by the Canadian Cancer Society. Studies have shown a strong correlation between early detection and increased survival rates thus it is important to have a means to adequately screen and detect breast cancer. Currently, tests are limited to traditional imaging methods such as ultrasound (US), magnetic resonance imaging (MRI) and standard mammography. There remains a need for a molecular imaging probe that is capable of providing further prognostic information particularly with respect to assessing tumour aggressiveness and the likelihood of a cancer to metastasize. Overexpression of the insulin receptor (IR) has been detailed in patients with breast cancer but there is currently no means of non-invasive and quantifiable detection of the receptor. The goal of the work described here was to prepare an insulin derived nuclear imaging probe via direct coupling of a prosthetic group bearing a radionuclide to the B29 lysine (B29-Lys) residue of the hormone. Benzoic acid bearing halogens were chosen as model compounds. The lead candidate N-[4-fluorobenzoyl]-(B29-Lys) insulin (4) was prepared in 60% overall yield and showed affinity for the IR similar to that of native insulin (IC50=3.6 nM). The 18F analogue (9) was successfully synthesized and showed high stability (up to 4 hours) post formulation in both saline and phosphate buffered solution (PBS). The product represents a promising new probe for assessing the role of the IR in cancer growth and metastasis. A complementary strategy for imaging markers of tumour aggressiveness was investigated through the development of a novel ultrasound probe. A pretargeting approach involving urokinase plasminogen activator receptor (uPAR), which is known to play a role in cancer metastasis, was used to develop the agent of interest. Here an in vivo reaction between tetrazine tagged microbubbles (MBs) and anti-uPAR antibodies conjugated to trans-cyclooctene (TCO) was employed. Following preparation of the antibody conjugate and tetrazine functionalized MBs, preliminary in vitro testing in a flow cell system was conducted. Results showed the ability of the uPAR expressing cells to exclusively capture the tetrazine MBs after they have been previously incubated with the TCO anti-uPAR antibody. No capture was observed when the target and/or the antibody were absent. The contrast agent developed represents the first MB targeted against uPAR and has the potential to impact current diagnostic paradigms particularly given the widespread use of ultrasound in cancer patient management. / Thesis / Master of Science (MSc)

Background and Objectives We investigate three statistical and methodological issues within the context of non-inferiority randomized controlled trials (RCTs), specifically those of radiotherapy regimens for the prevention of local recurrence in patients with early stage breast cancer who have undergone breast conserving surgery. These issues are: (1) the analysis of multiple time-to-event outcomes in non-inferiority RCTs; (2) the interim analysis of a binary outcome that is repeatedly assessed at pre-specified times; and (3) determining the optimal analysis population for dealing with crossovers in non-inferiority RCTs. Methods Issue 1: We investigated and compared the properties of four statistical models (proportional hazards model, competing risk model, marginal model and frailty model) for analyzing radiotherapy non-inferiority RCTs of patients with early stage breast cancer who are at risk for and may experience multiple failure types. We applied the four methods to data from an existing trial in which subjects with breast cancer could experience local recurrence (the primary outcome), distant recurrence, death, or a combination of these events. In addition, we compared these models using simulated examples of similar non-inferiority trials with varying hazards of each failure type. Issue 2: We investigated and compared the properties of three methods for estimating the event proportions for an interim analysis in RCTs with a binary outcome that is repeatedly assessed at pre-specified times. Generally, interim analyses are performed after half or more of the subjects have completed full follow-up. However, depending on the duration of accrual relative to the length of follow-up, this may be inefficient, since there is a possibility that the trial will have completed accrual prior to the interim analysis. We focussed our simulations on situations where delaying the interim analysis until half or more of subjects have completed full follow-up is an inefficient approach. The methods include: 1) estimation of the event proportion based on subjects who have been followed for a pre-specified time (less than the full follow-up duration) or who experienced the outcome; 2) estimation of the event proportion based on all available data from subjects randomized by the time of the interim analysis; and 3) the Kaplan-Meier approach to estimate the event proportion. We varied the risk of the outcome, the treatment effect and the probability of an event occurring at each pre-specified time. We compared the three methods in terms of overall type I and II errors, as well as the probability of stopping early for benefit. Issue 3: We explored the effect of subject crossover from the experimental to the standard radiotherapy arm prior to treatment initiation on the intention-to-treat, per-protocol, as-treated and combined intention-to-treat and per-protocol analysis in non-inferiority RCTs of radiotherapy for the prevention of local recurrence in patients with early stage breast cancer. We varied the non-inferiority margin, the percent of subjects who cross over and evaluated random and non-random crossover. The main comparison of the methods was done using overall type I error. In addition, we compared the methods based on estimate bias and standard error of the estimate. Results and Conclusions Issue 1: All four models produced similar results for the existing trial (i.e. non-inferiority was observed regardless of the method used). Simulations showed that the event-specific methods yielded contrasting results when the distribution of distant recurrence or death differed between treatment groups. We conclude that multiple models should be used as part of a comprehensive analysis. Issue 2: We showed that conducting an interim analysis when a considerable number of subjects have completed a portion of their full follow-up duration is an efficient approach under certain scenarios where event distribution probabilities are similar between treatment groups. Under these specific scenarios, all three methods preserved the type I and II errors. In these cases, we recommend using the Kaplan-Meier method because it incorporates all the available data and has greater probability of early stopping. Issue 3: The as-treated analysis had the best performance in terms of type I error rate. However, it can be recommended only in scenarios where crossover is random. It performed poorly in scenarios with greater than 2% non-random crossover. The intention-to-treat and per-protocol analysis performed poorly under both random and non-random crossover scenarios. / Thesis / Doctor of Philosophy (PhD)