Examining breast cancer screening recommendations in Canada: The projected resource impact of screening among women aged 40-49.

OBJECTIVE: To quantify the resource use of revising breast cancer screening guidelines to include average-risk women aged 40-49 years across Canada from 2024 to 2043 using a validated microsimulation model. SETTING: OncoSim-Breast microsimulation platform was used to simulate the entire Canadian population in 2015-2051. METHODS: We compared resource use between current screening guidelines (biennial screening ages 50-74) and alternate screening scenarios, which included annual and biennial screening for ages 40-49 and ages 45-49, followed by biennial screening ages 50-74. We estimated absolute and relative differences in number of screens, abnormal screening recalls without cancer, total and negative biopsies, screen-detected cancers, stage of diagnosis, and breast cancer deaths averted. RESULTS: Compared with current guidelines in Canada, the most intensive screening scenario (annual screening ages 40-49) would result in 13.3% increases in the number of screens and abnormal screening recalls without cancer whereas the least intensive scenario (biennial screening ages 45-49) would result in a 3.4% increase in number of screens and 3.8% increase in number of abnormal screening recalls without cancer. More intensive screening would be associated with fewer stage II, III, and IV diagnoses, and more breast cancer deaths averted. CONCLUSIONS: Revising breast cancer screening in Canada to include average-risk women aged 40-49 would detect cancers earlier leading to fewer breast cancer deaths. To realize this potential clinical benefit, a considerable increase in screening resources would be required in terms of number of screens and screen follow-ups. Further economic analyses are required to fully understand cost and budget implications.

The Association between Mutational Signatures and Clinical Outcomes among Patients with Early-Onset Breast Cancer.

Early-onset breast cancer (EoBC), defined by a diagnosis <40 years of age, is associated with poor prognosis. This study investigated the mutational landscape of non-metastatic EoBC and the prognostic relevance of mutational signatures using 100 tumour samples from Alberta, Canada. The MutationalPatterns package in R/Bioconductor was used to extract de novo single-base substitution (SBS) and insertion-deletion (indel) mutational signatures and to fit COSMIC SBS and indel signatures. We assessed associations between these signatures and clinical characteristics of disease, in addition to recurrence-free (RFS) and overall survival (OS). Five SBS and two indel signatures were extracted. The SBS13-like signature had higher relative contributions in the HER2-enriched subtype. Patients with higher than median contribution tended to have better RFS after adjustment for other prognostic factors (HR = 0.29; 95% CI: 0.08-1.06). An unsupervised clustering algorithm based on absolute contribution revealed three clusters of fitted COSMIC SBS signatures, but cluster membership was not associated with clinical variables or survival outcomes. The results of this exploratory study reveal various SBS and indel signatures may be associated with clinical features of disease and prognosis. Future studies with larger samples are required to better understand the mechanistic underpinnings of disease progression and treatment response in EoBC.

Adjuvant Ovarian Function Suppression in Premenopausal Hormone Receptor-Positive Breast Cancer.

Importance: Few oncology studies have assessed the effectiveness of adjuvant ovarian function suppression (OFS) in observational settings for premenopausal hormone receptor-positive breast cancer. Target trial emulation is increasingly used for estimating treatment outcomes in observational cohorts. Objectives: To describe hormone therapy and OFS treatment patterns (aim 1), examine the association between adding OFS to tamoxifen (TAM) or aromatase inhibitor (AI) and survival (aim 2), and examine the association between duration of hormone treatment (TAM or AI) plus OFS (H-OFS) and survival (aim 3). Design, Setting, and Participants: This population-based cohort study included all premenopausal, early-stage breast cancer diagnoses between 2010 and 2020 in Alberta, Canada. Target trial emulation was conducted. Eligibility criteria were directly modeled after the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT). Participants were followed up for a maximum of 5 years. Data were analyzed from July 2022 through March 2023. Exposures: For aim 2, exposures were receiving the following baseline treatments for 2 years: AI + OFS (AI-OFS), TAM + OFS (T-OFS), and TAM alone. For aim 3, exposures were a 2-year or greater and a less than 2-year duration of H-OFS. Main Outcomes and Measures: Recurrence-free survival was the primary outcome of interest. Marginal structural Cox models with inverse probability treatment and censoring weights were used to estimate hazard ratios (HRs), adjusted for baseline and time-varying confounding variables. Results: Among 3434 female patients with premenopausal, early-stage breast cancer diagnoses (median [IQR] age, 45 [40-48] years), 2647 individuals satisfied SOFT and TEXT eligibility criteria. There were 2260 patients who initiated TAM, 232 patients who initiated T-OFS, and 155 patients who initiated AI-OFS; 192 patients received H-OFS for 2 or more years, and 195 patients received H-OFS for less than 2 years. The 5-year recurrence risks were not significantly lower in AI-OFS vs TAM (HR, 0.76; 95% CI, 0.38-1.33) or T-OFS vs TAM (HR, 0.87; 95% CI, 0.50-1.45) groups. Patients receiving H-OFS for 2 or more years had significantly better 5-year recurrence-free survival compared with those receiving H-OFS for less than 2 years (HR, 0.69; 95% CI, 0.54-0.90). Conclusions and Relevance: This study found no significant reductions in recurrence risk for AI-OFS and T-OFS compared with TAM alone. H-OFS duration for at least 2 years was associated with significantly improved recurrence-free survival.

Exploring the Future of Cancer Impact in Alberta: Projections and Trends 2020-2040.

The impact of cancer in Alberta is expected to grow considerably, largely driven by population growth and aging. The Future of Cancer Impact (FOCI) initiative offers an overview of the present state of cancer care in Alberta and highlights potential opportunities for research and innovation across the continuum. In this paper, we present a series of detailed projections and analyses regarding cancer epidemiological estimates in Alberta, Canada. Data on cancer incidence and mortality in Alberta (1998-2018) and limited-duration cancer prevalence in Alberta (2000-2019) were collected from the Alberta Cancer Registry. We used the Canproj package in the R software to project these epidemiological estimates up to the year 2040. To estimate the direct management costs, we ran a series of microsimulations using the OncoSim All Cancers Model. Our findings indicate that from 2020, the total number of annual new cancer cases and cancer-related deaths are projected to increase by 56% and 49% by 2040, respectively. From 2019, the five-year prevalence of all cancers in Alberta is projected to increase by 86% by 2040. In line with these trends, the overall direct cost of cancer management is estimated to increase by 53% in 2040. These estimates and projections are integral to future strategic planning and investment.

The Association between Early-Onset Diagnosis and Clinical Outcomes in Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis.

Early-onset diagnosis, defined by age <40 years, has historically been associated with inferior outcomes in breast cancer. Recent evidence suggests that this association is modified by molecular subtype. We performed a systematic review and meta-analysis of the literature to synthesize evidence on the association between early-onset diagnosis and clinical outcomes in triple-negative breast cancer (TNBC). Studies comparing the risk of clinical outcomes in non-metastatic TNBC between early-onset patients and later-onset patients (≥40 years) were queried in Medline and EMBASE from inception to February 2023. Separate meta-analyses were performed for breast cancer specific survival (BCSS), overall survival (OS), and disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), distant recurrence-free survival (DRFS), and pathological complete response (pCR). In total, 7581 unique records were identified, and 36 studies satisfied inclusion criteria. The pooled risk of any recurrence was significantly greater in early-onset patients compared to later-onset patients. Better BCSS and OS were observed in early-onset patients relative to later-onset patients aged >60 years. The pooled odds of achieving pCR were significantly higher in early-onset patients. Future studies should evaluate the role of locoregional management of TNBC and the implementation of novel therapies such as PARP inhibitors in real-world settings, and whether they improve outcomes.

Reporting of Model Performance and Statistical Methods in Studies That Use Machine Learning to Develop Clinical Prediction Models: Protocol for a Systematic Review.

BACKGROUND: With the growing excitement of the potential benefits of using machine learning and artificial intelligence in medicine, the number of published clinical prediction models that use these approaches has increased. However, there is evidence (albeit limited) that suggests that the reporting of machine learning-specific aspects in these studies is poor. Further, there are no reviews assessing the reporting quality or broadly accepted reporting guidelines for these aspects. OBJECTIVE: This paper presents the protocol for a systematic review that will assess the reporting quality of machine learning-specific aspects in studies that use machine learning to develop clinical prediction models. METHODS: We will include studies that use a supervised machine learning algorithm to develop a prediction model for use in clinical practice (ie, for diagnosis or prognosis of a condition or identification of candidates for health care interventions). We will search MEDLINE for studies published in 2019, pseudorandomly sort the records, and screen until we obtain 100 studies that meet our inclusion criteria. We will assess reporting quality with a novel checklist developed in parallel with this review, which includes content derived from existing reporting guidelines, textbooks, and consultations with experts. The checklist will cover 4 key areas where the reporting of machine learning studies is unique: modelling steps (order and data used for each step), model performance (eg, reporting the performance of each model compared), statistical methods (eg, describing the tuning approach), and presentation of models (eg, specifying the predictors that contributed to the final model). RESULTS: We completed data analysis in August 2021 and are writing the manuscript. We expect to submit the results to a peer-reviewed journal in early 2022. CONCLUSIONS: This review will contribute to more standardized and complete reporting in the field by identifying areas where reporting is poor and can be improved. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42020206167; https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=206167. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/30956.

Developing a Prediction Model for Pathologic Complete Response Following Neoadjuvant Chemotherapy in Breast Cancer: A Comparison of Model Building Approaches.

PURPOSE: The optimal characteristics among patients with breast cancer to recommend neoadjuvant chemotherapy is an active area of clinical research. We developed and compared several approaches to developing prediction models for pathologic complete response (pCR) among patients with breast cancer in Alberta. METHODS: The study included all patients with breast cancer who received neoadjuvant chemotherapy in Alberta between 2012 and 2014 identified from the Alberta Cancer Registry. Patient, tumor, and treatment data were obtained through primary chart review. pCR was defined as no residual invasive tumor at surgical excision in breast or axilla. Two types of prediction models for pCR were built: (1) expert model: variables selected on the basis of oncologists' opinions and (2) data-driven model: variables selected by trained machine. These model types were fit using logistic regression (LR), random forests (RF), and gradient-boosted trees (GBT). We compared the models using area under the receiver operating characteristic curve and integrated calibration index, and internally validated using bootstrap resampling. RESULTS: A total of 363 cases were included in the analyses, of which 86 experienced pCR. The RF and GBT fits yielded higher optimism-corrected area under the receiver operating characteristic curves compared with LR for the expert (RF: 0.70; GBT: 0.69; LR: 0.65) and data-driven models (RF: 0.71; GBT: 0.68; LR: 0.64). The LR fit yielded the lowest integrated calibration indices for the expert (LR: 0.037; GBT: 0.05; RF: 0.10) and data-driven models (LR: 0.026; GBT: 0.06; RF: 0.099). CONCLUSION: Our models demonstrated predictive ability for pCR using routinely collected clinical and demographic variables. We show that machine learning fit methods can be used to optimize models for pCR prediction. We also show that additional variables beyond clinical expertise do not considerably improve predictive ability and may not be of value on the basis of the burden of data collection.

Examining the etiology of early-onset breast cancer in the Canadian Partnership for Tomorrow's Health (CanPath).

PURPOSE: Breast cancer incidence among younger women (under age 50) has increased over the past 25 years, yet little is known about the etiology among this age group. The objective of this study was to investigate relationships between modifiable and non-modifiable risk factors and early-onset breast cancer among three prospective Canadian cohorts. METHODS: A matched case-control study was conducted using data from Alberta's Tomorrow Project, BC Generations Project, and the Ontario Health Study. Participants diagnosed with breast cancer before age 50 were identified through provincial registries and matched to three control participants of similar age and follow-up. Conditional logistic regression was used to examine the association between factors and risk of early-onset breast cancer. RESULTS: In total, 609 cases and 1,827 controls were included. A body mass index ≥ 30 kg/m2 was associated with a lower risk of early-onset breast cancer (OR 0.65; 95% CI 0.47-0.90), while a waist circumference ≥ 88 cm was associated with an increased risk (OR 1.58; 95% CI 1.18-2.11). A reduced risk was found for women with ≥ 2 pregnancies (OR 0.76; 95% CI 0.59-0.99) and a first-degree family history of breast cancer was associated with an increased risk (OR 1.95; 95% CI 1.47-2.57). CONCLUSIONS: In this study, measures of adiposity, pregnancy history, and familial history of breast cancer are important risk factors for early-onset breast cancer. Evidence was insufficient to conclude if smoking, alcohol intake, fruit and vegetable consumption, and physical activity are meaningful risk factors. The results of this study could inform targeted primary and secondary prevention for early-onset breast cancer.

Risk of Depression in Patients With Psoriatic Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Previous systematic reviews have assessed the prevalence and odds ratio (OR) of depression for patients with psoriatic disease. Due to probable bidirectional effects, prevalence and prevalence ORs are difficult to interpret. No prior reviews have quantified the relative risk (RR) of depression following a diagnosis of psoriatic disease. OBJECTIVE: To estimate the RR of depression in individuals with psoriasis and in psoriatic arthritis (PsA), clear-to-moderate psoriasis, and moderate-to-severe psoriasis subgroups. METHODS: Observational studies investigating the risk of depression in adults with psoriatic disease were systematically searched for in Medline, EMBASE, PsycINFO, and CINAHL databases; 4989 unique references were screened. Studies that reported measures of incident depression in psoriasis patients were included. Thirty-one studies were included into the systematic review, of which 17 were meta-analyzed. Random effects models were employed to synthesize relevant data. Sources of heterogeneity were explored with subgroup analysis and meta-regression. RESULTS: Seventeen studies were included in meta-analyses. The pooled RR of depression in psoriasis patients compared to nonpsoriasis controls was 1.48 (95% CI: 1.16-1.89). Heterogeneity was high (I2 = 99.8%). Subgroup analysis and meta-regression did not indicate that PsA status or psoriasis severity (clear-to-mild, moderate-to-severe) were sources of heterogeneity. No evidence of publication bias was found. CONCLUSIONS: This review demonstrates that the risk of depression is greater in patients with psoriasis and PsA. Future research should focus on developing strategies to address the mental health needs of this patient population for depression, including primary prevention, earlier detection, and treatment strategies.