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ObjectiveThe aggressive triple-negative breast cancer (TNBC) subtype disproportionately affects women of African ancestry across the diaspora, but its frequency across Africa has not been widely studied. This study seeks to estimate the frequency of TNBC among African populations.DesignSystematic review and meta-analysis using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.Data sourcesPubMed, EMBASE, African Journals Online and Web of Science were searched on 25 April 2021.Eligibility criteria for selecting studiesWe included studies that use breast cancer tissue samples from indigenous African women with sample size of eligible participants ≥40 and full receptor status for all three receptors (oestrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2)) reported.Data extraction and synthesisTwo independent reviewers extracted data and assessed risk of bias using the modified assessment tool by Hoy et al. (2012) for prevalence studies. A random-effects meta-analysis was performed, and data were pooled using the inverse-variance method and logit transformation. Pooled frequencies were reported with 95% CIs calculated with the Clopper-Pearson method and heterogeneity quantified with I2 statistic. GRADE assessed the certainty of the evidence.Results1808 potentially eligible studies were identified of which 67 were included in the systematic review and 60 were included in the meta- analysis. Pooled TNBC frequency across African countries represented was estimated to be 27.0%; 95% CI: 24.0% to 30.2%, I2=94%. Pooled TNBC frequency was highest across West Africa, 45.7% (n=15, 95% CI: 38.8% to 52.8%, I2=91%) and lowest in Central Africa, 14.9% (n=1, 95% CI: 8.9 % to 24.1%). Estimates for TNBC were higher for studies that used Allred guidelines for ER/PR status compared with American Society of Clinical Oncology(ASCO)/College of American Pathologists(CAP) guidelines, and for studies that used older versions of ASCO/CAP guidelines for assessing HER2 status. Certainty of evidence was assessed to be very low using GRADE approach.ConclusionTNBC frequency was variable with the highest frequency reported in West Africa. Greater emphasis should be placed on establishing protocols for assessing receptor status due to the variability among studies.

PurposeTriple negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately affects women of African ancestry (WAA) and is often associated with poor survival. Although there is a high prevalence of TNBC across West Africa and in women of the African diaspora, there has been no comprehensive genomics study to investigate the mutational profile of ancestrally related women across the Caribbean and West Africa.MethodsThis multisite cross-sectional study used 31 formalin-fixed paraffin-embedded (FFPE) samples from Barbadian and Nigerian TNBC participants. High-resolution whole exome sequencing (WES) was performed on the Barbadian and Nigerian TNBC samples to identify their mutational profiles and comparisons were made to African American, European American and Asian American sequencing data obtained from The Cancer Genome Atlas (TCGA). Whole exome sequencing was conducted on tumors with an average of 382 × coverage and 4335 × coverage for pooled germline non-tumor samples.ResultsVariants detected at high frequency in our WAA cohorts were found in the following genes NBPF12, PLIN4, TP53 and BRCA1. In the TCGA TNBC cases, these genes had a lower mutation rate, except for TP53 (32% in our cohort; 63% in TCGA-African American; 67% in TCGA-European American; 63% in TCGA-Asian). For all altered genes, there were no differences in frequency of mutations between WAA TNBC groups including the TCGA-African American cohort. For copy number variants, high frequency alterations were observed in PIK3CA, TP53, FGFR2 and HIF1AN genes.ConclusionThis study provides novel insights into the underlying genomic alterations in WAA TNBC samples and shines light on the importance of inclusion of under-represented populations in cancer genomics and biomarker studies.

Background Randomized controlled trials (RCTs) are a critical component of evidence-based medicine and the evolution of patient care. However, the costs of conducting a RCT can be prohibitive. A promising approach toward reduction of costs and lessening of the burden of intensive and lengthy patient follow-up is the use of routinely collected healthcare data (RCHD), commonly called real-world data. We propose a scoping review to identify existing RCHD case definitions of breast cancer progression and survival and their diagnostic performance. Methods We will search MEDLINE, EMBASE, and CINAHL to identify primary studies of women with either early-stage or metastatic breast cancer, managed with established therapies, that evaluated the diagnostic accuracy of one or more RCHD-based case definitions or algorithms of disease progression (i.e., recurrence, progression-free survival, disease-free survival, or invasive disease-free survival) or survival (i.e., breast-cancer-free survival or overall survival) compared with a reference standard measure (e.g., chart review or a clinical trial dataset). Study characteristics and descriptions of algorithms will be extracted along with measures of the diagnostic accuracy of each algorithm (e.g., sensitivity, specificity, positive predictive value, negative predictive value), which will be summarized both descriptively and in structured figures/tables. Discussion Findings from this scoping review will be clinically meaningful for breast cancer researchers globally. Identification of feasible and accurate strategies to measure patient-important outcomes will potentially reduce RCT budgets as well as lessen the burden of intensive trial follow-up on patients. Systematic review registration Open Science Framework ( https://doi.org/10.17605/OSF.IO/6D9RS )

Multiparametric assays for risk stratification are widely used in the management of both node negative and node positive hormone receptor positive invasive breast cancer. Recent data from multiple sources suggests that different tests may provide different risk estimates at the individual patient level. The TEAM pathology study consists of 3284 postmenopausal ER+ve breast cancers treated with endocrine therapy Using genes comprising the following multi-parametric tests OncotypeDx®, Prosigna™ and MammaPrint® signatures were trained to recapitulate true assay results. Patients were then classified into risk groups and survival assessed. Whilst likelihood χ2 ratios suggested limited value for combining tests, Kaplan–Meier and LogRank tests within risk groups suggested combinations of tests provided statistically significant stratification of potential clinical value. Paradoxically whilst Prosigna-trained results stratified Oncotype-trained subgroups across low and intermediate risk categories, only intermediate risk Prosigna-trained cases were further stratified by Oncotype-trained results. Both Oncotype-trained and Prosigna-trained results further stratified MammaPrint-trained low risk cases, and MammaPrint-trained results also stratified Oncotype-trained low and intermediate risk groups but not Prosigna-trained results. Comparisons between existing multiparametric tests are challenging, and evidence on discordance between tests in risk stratification presents further dilemmas. Detailed analysis of the TEAM pathology study suggests a complex inter-relationship between test results in the same patient cohorts which requires careful evaluation regarding test utility. Further prognostic improvement appears both desirable and achievable.

Background Response rate (RR), the most common early means of assessing oncology drugs, is not suitable as the sole endpoint for phase II trials of drugs which induce disease stability but not regression. Time to progression (TTP) may be more sensitive to such agents, but induces recruitment delays in multistage studies. Early progressive disease (EPD) is the earliest signal of time to progression, but is less intuitive to investigators, To study drugs with unknown anti-tumour effect, we designed the Combination Stopping Rule (CSR), which allows investigators to establish a hypothesis using RR and TTP, while the program also employs early progressive disease (EPD) to assess for drug inactivity during the first stage of study accrual. Methods A computer program was created to generate stopping rules based on specified error rates, trial size, and RR and median TTP of interest and disinterest for a two-stage phase II trial. Rules were generated for stage II such that the null hypothesis ( H nul ) was rejected if either RR or TTP met desired thresholds, and accepted if both did not. Assuming an exponential distribution for progression, EPD thresholds were determined based on specified TTP values. Stopping rules were generated for stage I such that H nul was accepted and the study stopped if both RR and EPD were unacceptable. Results Patient thresholds were generated for RR, median TTP, and EPD which achieved specified error rates and which allowed early stopping based on RR and EPD. For smaller proportional differences between interesting and disinteresting values of RR or TTP, larger trials are required to maintain alpha error, and early stopping is more common with a larger first stage. Conclusion Stopping rules are provided for phase II trials for drugs which have either a desirable RR or TTP. In addition, early stopping can be achieved using RR and EPD.

Background Response rate (RR) alone may be insensitive to drug activity in phase II trials. Early progressive disease (EPD) could improve sensitivity as well as increase stage I stopping rates. This study compares the previously developed dual endpoint stopping rule (DESR), which incorporates both RR and EPD into a two-stage, phase II trial, with rules using only RR. Methods Stopping rules according to the DESR were compared with studies conducted under the Fleming (16 trials) or Gehan (23 trials) designs. The RR hypothesis for the DESR was consistent with the comparison studies ( r alt = 0.2, r nul = 0.05). Two parameter sets were used for EPD rates of interest and disinterest respectively ( epd alt , epd nul ): (0.4, 0.6) and (0.3, 0.5). Results Compared with Fleming, the DESR was more likely to allow stage two of accrual and to reject the null hypothesis ( H nul ) after stage two, with rejection being more common with EPD parameters (0.4, 0.6) than (0.3, 0.5). Compared with Gehan, both DESR parameter sets accepted H nul in 15 trials after stage I compared with 8 trials by Gehan, with consistent conclusions in all 23 trials after stage II. Conclusions The DESR may reject H nul when EPD rates alone are low, and thereby may improve phase II trial sensitivity to active, cytostatic drugs having limited response rates. Conversely, the DESR may invoke early stopping when response rates are low and EPD rates are high, thus shortening trials when drug activity is unlikely. EPD parameters should be chosen specific to each trial.

BackgroundPrevious studies assessing breast cancer risk in families with Lynch syndrome (LS) have yielded conflicting results. Furthermore, conclusions are limited by small sample size and few breast cancer outcomes. This study assesses breast cancer risk in a large prospectively followed LS cohort.MethodsPedigrees of 325 unrelated families with LS within the Familial Gastrointestinal Cancer Registry in Canada were examined for breast cancer diagnoses. Standardised incidence ratios (SIR) and lifetime cumulative incidence calculations were used to compare the incidence of breast cancer in mutation carriers with the general population.ResultsForty-one mutation carriers diagnosed with breast cancer belonging to 34 unrelated families were identified. Mean age at diagnosis was 54 years. The mutation distribution among the LS patients with breast cancer was statistically different from those without breast cancer (p=0.015), reflecting the predominance of MSH2 mutations among affected patients (74%). Eighty-eight per cent of LS families with breast cancer met Amsterdam criteria, compared with 49% of LS families without breast cancer (p=0.03). Lifetime cumulative incidence of breast cancer in female MSH2 mutation carriers in our cohort was 22% (p<0.001). The SIR for breast cancer of female MSH2 mutation carriers in our cohort was 3.11 (95% CI 1.95 to 4.71).ConclusionsAn increased risk of breast cancer in MSH2 mutation carriers was demonstrated in a Canadian familial cancer registry. Women with breast cancer often had a personal and family history of multiple LS-related malignancies. These results suggest a potential role for intensified breast cancer surveillance among women with LS.

Given that diagnostic, neoadjuvant treatment, and surgical approaches to rectal cancer have changed markedly in the last 25 years, knowledge translation (KT) may be useful to optimize rectal cancer surgery and improve patient outcomes. We sought to evaluate the impact of surgeon-directed KT to improve the quality of rectal cancer surgery on local tumour recurrence in Ontario. Ontario’s 14 health regions were previously categorized into 2 high-intensity and 12 low-intensity KT regions, based on KT methods (e.g., theory, audit, feedback), applied from 2006 to 2012 to improve the quality of rectal cancer surgery. In the high-intensity regions, efforts encouraged preoperative magnetic resonance imaging, appropriate radiation, and optimal surgical technique. We abstracted hospital chart data from across Ontario for a random sample of cases from 2010 to 2012 based on the respective population of a region and the relative hospital case volume within their region. The main study outcome was local tumour recurrence. In the high-intensity and low-intensity KT regions, we reviewed data from 523 (48.6%) and 557 (51.4%) patients, respectively. Descriptive variables (e.g., age, sex, tumour stage) were similar between groups. In the high- and low-intensity regions, the proportion of patients with a permanent stoma was 31.4% and 26.4% (p = 0.08), the proportion with positive radial margins was 8.0% and 6.1% (p = 0.2), and the proportion with local tumour recurrence was 6.3% and 5.2% (p = 0.2), respectively. The adjusted risk of time to local recurrence was similar in the high- and low-intensity KT regions (hazard ratio 0.72, 95% confidence interval 0.50–1.05). The use of resource-intense methods was not associated with improved patient outcomes, including local tumour recurrence. New approaches are needed to optimize the population-level quality of rectal cancer surgery. Étant donné que le diagnostic, le traitement néoadjuvant et les approches chirurgicales au cancer rectal ont beaucoup évolué depuis 25 ans, le processus d’application des connaissances (AC) pourrait sembler utile pour améliorer la chirurgie pour cancer rectal et ses résultats chez les malades. Un processus d’AC destiné aux chirurgiennes et aux chirurgiens pour améliorer la qualité de la chirurgie pour cancer rectal a été déployé, et nous en avons mesuré l’impact sur les récidives locales en Ontario. Les 14 régions sanitaires de l’Ontario ont préalablement été scindées en 2 régions d’AC de forte intensité et 12 régions d’AC de faible intensité selon les modes d’AC (p. ex., théorie, vérification, rétroaction) utilisés de 2006 à 2012 pour améliorer la qualité de la chirurgie pour cancer rectal. Dans les régions de forte intensité, l’accent a été placé sur l’imagerie par résonance magnétique préopératoire, une radiothérapie appropriée et une technique chirurgicale optimale. Nous avons extrait les données des dossiers hospitaliers de tout le territoire ontarien pour créer un échantillon aléatoire des cas pris en charge entre 2010 et 2012, selon la population des différentes régions et le volume relatif de cas dans leurs hôpitaux. Le principal paramètre de l’étude était le taux de récidives locales. Dans les régions de forte et de faible intensité d’AC, nous avons analysé les données concernant 523 (48,6 %) et 557 (51,4 %) malades, respectivement. Les variables descriptives (p. ex., âge, sexe, stade de la tumeur) étaient similaires entre les groupes. Dans les régions de forte et de faible intensité, la proportion de malades porteurs d’une stomie permanente était de 31,4 % et 26,4 % (p = 0,08), la proportion de malades présentant des marges radiales positives était de 8,0 % et 6,1 % (p = 0,2) et la proportion de malades ayant des récidives locales était de 6,3 % et de 5,2 % (p = 0,2), respectivement. Le risque ajusté en ce qui concerne l’intervalle précédant une récidive locale a été similaire dans les régions de forte et de faible intensité d’AC (rapport de risque 0,72, intervalle de confiance de 95 % 0,50–1,05). L’utilisation de méthodes qui mobilisent beaucoup de ressources n’a pas été associée à une amélioration des résultats chez les malades, y compris au plan des récidives locales. De nouvelles approches sont nécessaires pour optimiser la qualité de la chirurgie rectale à l’échelle de la population.