Browsing by Author "Quan, May Lynn"

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    Determining research priorities for young women with breast cancer: A priority setting partnership
    (2021-09) Keehn, Alysha; Quan, May Lynn; Friedenreich, Christine; Elliott, Meghan
    BACKGROUND: Women under the age of 40 years account for approximately 5-7% of breast cancer cases. Young women with breast cancer (YWBC) often have a biologically distinct disease and unique considerations compared to older women, leading to significant opportunities for research to improve patient outcomes and quality of life. Potential disconnects between research being performed and that deemed meaningful and relevant to patients may impede clinical uptake and knowledge translation. The James Lind Alliance (JLA) brings patients, caregivers and clinicians together in priority setting partnerships (PSPs) to determine key priorities in health research. OBJECTIVE: To determine the top-10 research priorities for YWBC using an established, multi-stakeholder, priority setting methodology. METHODS: An adapted JLA PSP process was used to determine research priorities for YWBC. A balanced, 15-member steering committee composed of patients, caregivers and clinician representatives from across Canada was created to coordinate and implement the activities of the PSP including the creation, approval and dissemination of a nation-wide survey. Survey responses were received in text-based format, sorted and separated into themes, and eventually organized into scientific questions. A raw list of potential uncertainties underwent a reduction process whereby duplicates were combined and out of scope questions were removed. The steering committee voted on a shortlist of 50 questions to be used in the interim prioritization survey. The interim prioritization survey was disseminated back to participants and a reverse ranking process was used to identify the top-30 priorities brought to the final consensus meeting. The final meeting took place through an interactive, virtual, one-day workshop using a nominal group technique with patients, caregivers, clinicians and other stakeholders from across Canada and culminated in consensus on the top-10 priorities for YWBC. RESULTS: One thousand, four hundred and twelve responses were generated from 359 respondents (75% patient generated). A raw list of 423 unique questions were developed once out of scope (n=278) and repeat questions (n=711) were eliminated. Of the remaining questions, 209 were deemed to be gaps in knowledge pertaining specifically to YWBC while the remainder were questions about breast cancer in general. This list was reduced through iterative voting to a Top-50 by the steering committee, Top-30 through the interim prioritization survey and eventual a Top-10 through a final consensus meeting. The priority areas identified include: surgical outcomes, Tamoxifen duration, effect of interruption to hormone blockade, biological markers to detect microscopic disease, long-term consequences of treatment induced menopause, lifestyle and modifiable factors to reduce recurrence, prediction tools for identifying young women at high risk of developing breast cancer, the impact of inflammatory and autoimmune diseases on developing breast cancer in the young, indications for more aggressive treatment and quality improvement to reduce the interval period between diagnostic treatment and diagnosis. CONCLUSION: This work is part of an integrative knowledge translation strategy in partnership with the RUBY study and will inform future research moving forward. Additionally, it be of interest to the broader early onset breast cancer community as well as funding agencies.
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    Examining and predicting outcomes among early-onset breast cancer patients in Alberta using real-world and genomic data
    (2023-11-23) Basmadjian, Robert Barkev; Brenner, Darren; Cheung, Winson; Quan, May Lynn; Lupichuk, Sasha; Xu, Yuan
    Background: It is well accepted patients with early-onset breast cancer (EoBC), defined by a diagnosis <40 years of age, are at greater risks of recurrence and mortality compared to later-onset cases (≥40 years). However, robust evidence of tailored treatment approaches in EoBC is lacking. This thesis intersected causal inference methodology, outcomes prediction research, and bioinformatics to better understand the effectiveness of real-world treatments and decision support tools in EoBC, as well as discover biological drivers of poor prognosis. Methods: Three manuscripts were produced using population-based data of adult breast cancer diagnoses <40 years in Alberta from 2004 to 2020 and whole-exome sequence data from 100 tumour samples in this population. In Manuscript One, we described treatment patterns of ovarian function suppression (OFS) and applied the target trial emulation framework to estimate two treatments effects: 1) 2-year per-protocol effect of tamoxifen alone (TAM) vs. TAM + OFS (T-OFS) vs. aromatase inhibitor + OFS (AI-OFS); and 2) the effect of remaining on hormone therapy + OFS (H-OFS) for ≥2 years vs. <2 years on recurrence-free survival (RFS). In Manuscript Two, we assessed the performance of PREDICT v2.1 for predicting 10-year all-cause mortality in EoBC and developed 10-year mortality prediction models using machine learning. In Manuscript Three, we characterize somatic mutational signatures in 100 EoBC tumour samples and examine their association with clinicopathological variables and survival outcomes. Results: In a target trial that included 2647 premenopausal hormone receptor-positive breast cancer patients, RFS tended to be better in the AI-OFS group (HR=0.76; 95% CI: 0.41-1.37) and T-OFS group (HR=0.87; 95% CI: 0.50-1.45) compared to TAM. Patients on H-OFS for ≥ 2 years had significantly better RFS compared to those on H-OFS for <2 years (HR=0.69; 95% CI:0.54-0.90). In data from 1414 EoBC patients, PREDICT showed good discrimination (AUC=0.76) but tended to overestimate 10-year mortality in patients with high predicted risk. Building a 10-year mortality prediction model on EoBC patient data using penalized multivariable Cox regression showed better discrimination and calibration statistics versus using random survival forests. Among 100 EoBC tumour samples, we extracted five single-base substitution (SBS) and two insertion-deletion signatures. The SBS13-like signature was more common in the HER2 subtype. Higher than median expression of the SBS13-like signature may be associated with better RFS (HR=0.29; 95% CI: 0.08-1.06). Conclusions: These investigations contribute knowledge of tailored approaches in the clinical management of EoBC in Alberta. Our findings provide clearer understandings of the effectiveness of real world treatments and the performance of routinely used prediction models in EoBC. We also provide insights on how additional routinely collected variables and novel mutational variables may improve outcome prediction.
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    Tailoring Ovarian Cancer Strategies to a Sub-Saharan Region: Testing the Developed Country Experience
    (2018-08-16) Rambau, Peter Fabian; Köbel, Martin; Manyama, Mange J.; Benediktsson, Hallgrímur; Hallgrímsson, Benedikt; Lukowiak, Ken D.; Quan, May Lynn
    Ovarian carcinoma is a spectrum of different histotypes which differ in risk factors, precursor lesions, molecular alterations and prognosis. Most of the research focused on high grade serous carcinoma which constitutes the majority of ovarian carcinoma. Endometrioid carcinoma (EC) constitutes 11% of ovarian carcinoma. Studies on EC have been limited by lack of sufficient number of cases for a meaningful conclusion. Seromucinous carcinoma, a newly introduced histotype shows resemblance to EC with no studies on its diagnostic reproducibility and molecular alterations. In developing countries, few studies have addressed the tumor types and histotype distribution of ovarian cancer, which could be useful in resource allocation, in addition the diagnostic accuracy of histotyping is not known. This study utilized immunohistochemical markers in a cohort of EC to study the diagnostic and prognostic biomarkers, as well as histotyping of ovarian cancers from Tanzania to establish diagnostic accuracy. Morphological studies and targeted deep sequencing was applied to seromucinous carcinoma to detect recurrent mutations known to occur in ovarian carcinoma, to justify whether it deserves a separate classification. This study found that, a defect in mismatch repair proteins was restricted to EC, and therefore screening for Lynch syndrome should be restricted to endometrioid histotype. This study also validated the association of hormone receptor (estrogen and progesterone) expression with ovarian cancer specific survival, with limited clinical utility. For seromucinous carcinoma, this study shows that the morphological diagnosis of seromucinous carcinomas is not very reliable. It did not show a distinct immunophenotype or genotype, and molecular features overlaps with endometrioid and low-grade serous carcinomas. Therefore, seromucinous carcinoma can be assigned to one of the major histotypes by ancillary molecular tests. Ovarian cancer in Tanzania shows relatively few cases compared to the Alberta population, with poor diagnostic agreement by using the current WHO criteria and immunohistochemistry. Improvement of H&E staining and adoption of current WHO classification can achieve a reasonable correct histotyping of ovarian carcinoma which can be meaningful in this area where the resource are scarce.
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