Publications by authors named "Marguerite Ennis"

56 Publications

Association of Obesity with Breast Cancer Outcome in Relation to Cancer Subtypes: A Meta-Analysis.

J Natl Cancer Inst 2021 Feb 23. Epub 2021 Feb 23.

Institute of Health Policy Management and Evaluation, University of Toronto, Ontario, Canada.

Background: Obesity at breast cancer (BC) diagnosis has been associated with poor outcome, although the magnitude of effect in different BC subtypes is uncertain. We report on the association of obesity/overweight at diagnosis of non-metastatic BC with disease-free (DFS) and overall survival (OS) in the following defined subtypes: hormone receptor positive/HER2 negative (HR+HER2-), HER2 positive (HER2+), and triple negative (TNBC).

Methods: We searched MEDLINE, EMBASE and COCHRANE databases until January 1, 2019. Study eligibility were performed independently by two authors. Studies reporting hazard ratios (HR) of OS and/or DFS for obesity/overweight in BC subtypes were included. Pooled HR were computed and weighted using generic inverse variance and random effects models.

Results: 27 studies were included. Obese, compared to non-obese, women, had worse DFS in all subtypes: the hazard ratios were 1.26 (95% confidence interval [CI] = 1.13 to 1.41, P < .001) for HR+HER2-BC, 1.16 (95%CI = 1.06 to 1.26, P < .001) for HER2+ BC, and 1.17 (95%CI = 1.06 to 1.29, P = .001) for TNBC. OS was also worse in obese vs non-obese women (HR+HER2-BC HR = 1.39, 95%CI = 1.20 to 1.62, P < .001; HER2+BC HR = 1.18, 95%CI = 1.05 to 1.33, P = .006 and TNBC HR = 1.32, 95%CI = 1.13 to 1.53, P < .001). As opposed to obesity, overweight was not associated with either DFS or OS in HER2+BC (HR = 1.02, 95%CI = 0.81 to 1.28, P = .85; and HR = 0.96, 95%CI = 0.76 to 1.21, P = .99, respectively) or TNBC (HR = 1.04, 95%CI = 0.93 to 1.18, P = .49; and HR = 1.08, 95%CI = 0.81 to 1.44, P = .17), respectively. In HR+HER2-BC, being overweight was associated with worse OS (HR = 1.14, 95%CI = 1.07 to 1.22, P < .001).

Conclusions: Obesity was associated with modestly worse DFS and OS in all BC subtypes.
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http://dx.doi.org/10.1093/jnci/djab023DOI Listing
February 2021

The Effect of Metformin vs Placebo on Sex Hormones in Canadian Cancer Trials Group MA.32.

J Natl Cancer Inst 2021 Feb;113(2):192-198

Lunenfeld Tanenbaum Research Institute at Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.

Background: Metformin has been associated with lower breast cancer (BC) risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones. We evaluated the effect of metformin on sex hormones in MA.32, a phase III trial of nondiabetic BC subjects who were randomly assigned to metformin or placebo.

Methods: We studied the subgroup of postmenopausal hormone receptor-negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after being randomly assigned. Sex hormone-binding globulin, bioavailable testosterone, and estradiol levels were assayed using electrochemiluminescence immunoassay. Change from baseline to 6 months between study arms was compared using Wilcoxon sum rank tests and regression models.

Results: 312 women were eligible (141 metformin vs 171 placebo); the majority of subjects in each arm had T1/2, N0, HER2-negative BC and had received (neo)adjuvant chemotherapy. Mean age was 58.1 (SD=6.9) vs 57.5 (SD=7.9) years, mean body mass index (BMI) was 27.3 (SD=5.5) vs 28.9 (SD=6.4) kg/m2 for metformin vs placebo, respectively. Median estradiol decreased between baseline and 6 months on metformin vs placebo (-5.7 vs 0 pmol/L; P < .001) in univariable analysis and after controlling for baseline BMI and BMI change (P < .001). There was no change in sex hormone-binding globulin or bioavailable testosterone.

Conclusion: Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen sensitive cancers.
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http://dx.doi.org/10.1093/jnci/djaa082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850529PMC
February 2021

Prognostic associations of plasma hepcidin in women with early breast cancer.

Breast Cancer Res Treat 2020 Dec 22;184(3):927-935. Epub 2020 Sep 22.

Lunenfeld-Tanenbaum Research Institute, Department of Medicine, Mount Sinai Hospital, Toronto, ON, Canada.

Purpose: Iron is essential to energy metabolism, cell proliferation and DNA synthesis, and sufficient iron availability may be required for tumor growth. The hormone hepcidin is a systemic regulator of iron concentration in plasma. Intra-tumor RNA expression of hepcidin has been linked to shorter metastasis-free survival in women with early breast cancer, but the prognostic implications of this inflammatory marker and iron-regulating plasma peptide in the blood are unknown.

Methods: Using an ELISA assay, hepcidin was measured in the banked blood of 518 women who were recruited from 1989 to 1996 for a prospective cohort study of diet and lifestyle factors in breast cancer. Blood samples were obtained 4-12 weeks post-operatively, prior to treatment with chemotherapy or tamoxifen.

Results: Hepcidin was not associated with time to distant breast cancer recurrence (primary outcome) nor time to death from any cause. However, a pre-planned interaction test of body mass index (BMI) was statistically significant (p < 0.01). Among obese women (BMI > 30 kg/m), higher hepcidin was associated with a shorter time to distant breast cancer recurrence in both uni- and multivariable analyses (adjusted HR 1.84; 95% CI 1.04-3.25). For overall survival, a similar pattern was seen in the univariable model but the effect was diminished in a multivariable analysis. Plasma hepcidin was not associated with high-sensitivity C-reactive protein, but it was significantly associated (r ≥ 0.32) with iron indices, including total iron (p < 0.01), transferrin (p < 0.01) and soluble transferrin receptor (p < 0.01).

Conclusions: Hepcidin may be associated with poor breast cancer outcome in obese women, however, replication is required. The biologic basis for this prognostic association requires further research.
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http://dx.doi.org/10.1007/s10549-020-05903-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883934PMC
December 2020

Association between BMI, vitamin D, and estrogen levels in postmenopausal women using adjuvant letrozole: a prospective study.

NPJ Breast Cancer 2020 12;6:22. Epub 2020 Jun 12.

Princess Margaret Cancer Centre, Toronto, Canada.

Studies have suggested that women with elevated BMI or 25-OH vitamin D levels may derive less benefit from AIs versus tamoxifen. We prospectively investigated whether high BMI or 25-OH vitamin D levels were associated with higher estrogen levels in post-menopausal women receiving standard adjuvant letrozole (2.5 mg/day). Furthermore, we evaluated whether an increased dose of letrozole resulted in lower serum estrogens in women with BMI > 25 kg/m. Correlation between entry BMI and day 29 serum biomarkers (estrogens, 25-OH vitamin D, insulin, CRP, leptin) was assessed in all patients. On day 29, participants with BMI > 25 kg/m switched to letrozole 5 mg/day for 4-weeks and blood was drawn upon completion of the study. The change in serum estrogen levels was assessed in these patients (BMI > 25 kg/m). 112 patients completed days 1-28. The Pearson correlations of estradiol and estrone with BMI or serum 25-OH vitamin D levels were near zero (-0.04 to 0.07,  = 0.48-0.69). Similar results were obtained for correlation with markers of obesity (insulin, CRP, and leptin) with estradiol and estrone (-0.15 to 0.12;  = 0.11-0.82). Thirty-one patients (BMI > 25 kg/m) completed the interventional component; Increasing the dose of letrozole did not further reduce estradiol or estrone levels (change 0.1 and 0.4 pmol/L respectively;  = 0.74 and 0.36). There was no observed association between markers of obesity (BMI, insulin, leptin, and CRP), serum 25-OH vitamin D levels and estradiol or estrone levels. Additionally, an increased dose of letrozole did not further reduce estradiol or estrone levels compared to the standard dose.
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http://dx.doi.org/10.1038/s41523-020-0166-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293309PMC
June 2020

The effect of metformin vs placebo on sex hormones in CCTG MA.32.

J Natl Cancer Inst 2020 Jun 4. Epub 2020 Jun 4.

Lunenfeld Tanenbaum Research Institute at Mount Sinai Hospital, University of Toronto, Canada.

Background: Metformin has been associated with lower breast cancer risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones (SHs). We evaluated the effect of metformin on SHs in MA.32, a phase III trial of nondiabetic BC subjects randomized to metformin or placebo.

Methods: We studied the subgroup of post-menopausal hormone receptor negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after randomization. Sex hormone binding globulin (SHBG), bioavailable testosterone (BT) and estradiol levels were assayed using ECLIA (electrochemiluminescense immunoassay). Change from baseline to 6 months between study arms was compared using Wilcoxon sum rank tests and regression models.

Results: 312 women were eligible (141 metformin vs 171 placebo); the majority of subjects in each arm had T1/2, N0, HER2 negative BC and had received (neo)adjuvant chemotherapy. Mean age ± SD was 58.1±6.9 vs 57.5±7.9 years, mean BMI was 27.3±5.2 vs 28.9±6.4 kg/m2 for metformin vs placebo respectively. Median estradiol decreased between baseline and 6 months on metformin vs placebo (-5.7 vs 0 pmol/L; p < 0.001) in univariable analysis and after controlling for baseline BMI and BMI change (p < 0.001). There was no change in SHBG or BT.

Conclusion: Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen sensitive cancers.
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http://dx.doi.org/10.1093/jnci/djaa082DOI Listing
June 2020

Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 1: Late Recurrence: Current Understanding, Clinical Considerations.

JNCI Cancer Spectr 2019 Dec 10;3(4):pkz050. Epub 2019 Aug 10.

Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Sinai Health System, Toronto, ON, Canada.

Disease recurrence (locoregional, distant) exerts a significant clinical impact on the survival of estrogen receptor-positive breast cancer patients. Many of these recurrences occur late, more than 5 years after original diagnosis, and represent a major obstacle to the effective treatment of this disease. Indeed, methods to identify patients at risk of late recurrence and therapeutic strategies designed to avert or treat these recurrences are lacking. Therefore, an international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. In this article, the major issues surrounding late recurrence are defined and current approaches that may be applicable to this challenge are discussed. Specifically, diagnostic tests with potential utility in late-recurrence prediction are described as well as a variety of patient-related factors that may influence recurrence risk. Clinical and therapeutic approaches are also reviewed, with a focus on patient surveillance and the implementation of extended endocrine therapy in the context of late-recurrence prevention. Understanding and treating late recurrence in estrogen receptor-positive breast cancer is a major unmet clinical need. A concerted effort of basic and clinical research is required to confront late recurrence and improve disease management and patient survival.
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http://dx.doi.org/10.1093/jncics/pkz050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049988PMC
December 2019

Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 2: Approaches to Predict and Identify Late Recurrence, Research Directions.

JNCI Cancer Spectr 2019 Dec 10;3(4):pkz049. Epub 2019 Aug 10.

Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Sinai Health System, Toronto, ON, Canada.

Late disease recurrence (more than 5 years after initial diagnosis) represents a clinical challenge in the treatment and management of estrogen receptor-positive breast cancer (BC). An international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. The underlying biological causes of late recurrence are complex, with the processes governing cancer cell dormancy, including immunosurveillance, cell proliferation, angiogenesis, and cellular stemness, being integral to disease progression. These critical processes are described herein as well as their role in influencing risk of recurrence. Moreover, observational and interventional clinical trials are proposed, with a focus on methods to identify patients at risk of recurrence and possible strategies to combat this in patients with estrogen receptor-positive BC. Because the problem of late BC recurrence of great importance, recent advances in disease detection and patient monitoring should be incorporated into novel clinical trials to evaluate approaches to enhance patient management. Indeed, future research on these issues is planned and will offer new options for effective late recurrence treatment and prevention strategies.
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http://dx.doi.org/10.1093/jncics/pkz049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050024PMC
December 2019

A phase II randomized clinical trial of the effect of metformin versus placebo on progression-free survival in women with metastatic breast cancer receiving standard chemotherapy.

Breast 2019 Dec 22;48:17-23. Epub 2019 Aug 22.

Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Ontario, Canada.

Objectives: Pre-clinical data suggest metformin might enhance the effect of chemotherapy in breast cancer (BC). We conducted a Phase II randomized trial of chemotherapy plus metformin versus placebo in metastatic breast cancer (MBC).

Material And Methods: In this double blind phase II trial we randomly assigned non-diabetic MBC patients on 1st to 4th line chemotherapy to receive metformin 850 mg po bid or placebo bid. Primary outcome was progression-free survival (PFS); secondary outcomes included overall survival (OS), response rate (RR), toxicity and quality of life (QOL). With 40 subjects and a type-one error of 0.2 (one-sided), a PFS hazard ratio (HR) of 0.58 could be detected with 80% power.

Results: 40 patients were randomized (22 metformin, 18 placebo) with a mean age of 55 vs 57 years and ER/PR positive BC in 86.4% vs 83.3% off metformin vs placebo, respectively. Mean BMI was 27kg/m2 in both arms. The majority of patients were on 1st line chemotherapy. Grade 3-4 toxicity occurred in 31.8% (metformin) vs 58.8% (placebo). Best response: Partial response 18.2% metformin vs 25% placebo, stable disease 36.4% metformin vs 18.8% placebo, progressive disease 45.4% metformin vs 56.2% placebo. Mean PFS was 5.4 vs 6.3 months (metformin vs placebo), HR 1.2 (95% CI 0.63-2.31). Mean OS was 20.2 (metformin) vs 24.2 months (placebo), HR 1.68 (95% CI 0.79-3.55).

Conclusion: In this population metformin showed no significant effect on RR, PFS or OS. These results do not support the use of metformin with chemotherapy in non-diabetic MBC patients.
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http://dx.doi.org/10.1016/j.breast.2019.08.003DOI Listing
December 2019

Association of Metabolic, Inflammatory, and Tumor Markers With Circulating Tumor Cells in Metastatic Breast Cancer.

JNCI Cancer Spectr 2018 Apr 12;2(2):pky028. Epub 2018 Jul 12.

Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System.

Background: Circulating tumor cells (CTCs) are associated with worse prognosis in metastatic breast cancer (BC). We evaluated the association of metabolic, inflammatory, and tumor markers with CTCs in women with metastatic BC before commencing a new systemic therapy.

Methods: Ninety-six patients with newly diagnosed or progressing metastatic BC without current diabetes or use of anti-inflammatory agents were recruited from four Ontario hospitals. Women provided fasting blood for measurement of metabolic, inflammatory, and tumor markers and CTCs. CTCs were assayed within 72 hours of collection using CellSearch. Other blood was frozen at -80°C, and assays were performed in a single batch. Associations between CTC counts with study factors were evaluated using Spearman correlation, and the chi-square or Fisher exact test. All statistical tests were two-sided and value ≤ .05 was considered statistically significant.

Results: The median age was 60.5 years; 90.6% were postmenopausal. The cohort included hormone receptor-positive (87.5%), HER2-positive (15.6%), and triple-negative (10.4%) BCs. Patients were starting firstline (35.5%), second-line (26.0%), or third-or-later-line therapy (38.5%). CTC counts (per 7.5 mL of blood) ranged from 0 to 1238 (median 2); an elevated CTC count, defined as five or more CTCs, was detected in 42 (43.8%) patients. Those with liver metastases (vs not) more frequently had an elevated CTC count (59.0% vs 33.3%, = .02). CTCs were significantly associated with C-reactive protein ( = .22, = .02), interleukin (IL)-6 ( = .25, = .01), IL-8 ( = .38, = .0001), plasminogen activator inhibitor 1 ( = .31, = .001), carcinoembryonic antigen ( = .31, = .002), and cancer antigen 15-3 ( = .40, = .0001) and inversely associated with body mass index ( = -.23, = .02) and leptin ( = -.26, = .01).

Conclusions: CTC counts were positively associated with tumor and inflammatory markers and inversely associated with some metabolic markers, potentially reflecting tumor burden and cachexia.
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http://dx.doi.org/10.1093/jncics/pky028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044231PMC
April 2018

Sexual health in long-term breast cancer survivors.

Breast Cancer Res Treat 2018 Nov 19;172(1):159-166. Epub 2018 Jul 19.

Division of Medical Oncology and Hematology, Division of Clinical Epidemiology, Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada.

Purpose: Sexual dysfunction is reported in women with breast cancer (BC). It is unclear whether symptoms persist over time as data comparing long-term survivors to controls are lacking. We compared sexual functioning in long-term breast cancer survivors (BCS) to controls and determined the impact of adjuvant therapy on sexual health.

Methods: A cohort of women with localized BC (1989-1996) was prospectively followed. BCS and controls (2005-2007) completed self-reported questionnaires. Sexual health was measured with the Sexual Activity Questionnaire (SAQ). Vasomotor, gynecological, and bladder symptoms were scored using the Menopausal Symptom Scale. Regression analysis was used to compare groups, with adjustment for age and secondly menopausal status.

Results: BCS (n = 248, 87%) and controls (n = 159, 95%) completed the SAQ at a median time from diagnosis of 12.5 years. BCS were older (62 vs 59 years, p = 0.0004) and more likely to be menopausal (94 vs 86%, p = 0.0025). Sexual activity did not differ significantly between BCS and controls, but when adjusted for menopausal status, pre/peri-menopausal BCS were less likely to be sexually active than pre/peri-controls (odds ratio OR 0.12, p = 0.012). In those sexually active, no significant differences were noted on the SAQ Pleasure, Discomfort, and Habit scales. BCS reported worse gynecological symptoms and pre/peri-menopausal patients had more bladder complaints (standardized effect size 0.36 p = 0.002 and 1.11, p = 0.011). Adjuvant treatments were not significantly associated with sexual function, but BCS treated with chemotherapy reported worse gynecological symptoms.

Conclusion: Sexual health and uro-genital symptom counseling should be provided to BCS, particularly pre/peri-menopausal patients, even at long-term follow-up.
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http://dx.doi.org/10.1007/s10549-018-4894-8DOI Listing
November 2018

Metabolic factors, anthropometric measures, diet, and physical activity in long-term breast cancer survivors: change from diagnosis and comparison to non-breast cancer controls.

Breast Cancer Res Treat 2017 Jul 25;164(2):451-460. Epub 2017 Apr 25.

Division of Medical Oncology and Hematology; Division of Clinical Epidemiology, Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, 1284-600 University Ave, Toronto, ON, M5G 1X5, Canada.

Purpose: We studied metabolic factors, diabetes, and anthropometric measurements at diagnosis and long-term follow-up (LTFU), mean 12.5 years post-diagnosis, in breast cancer (BC) survivors, and compared their status at LTFU to that of age-matched women without BC. Diet and physical activity were also assessed.

Method: 535 non-diabetic BC patients treated at three University of Toronto hospitals were followed prospectively; 285 surviving patients, without distant recurrence, participated in a LTFU study. A control group of 167 age-matched women without BC was recruited from a mammogram screening program at one of the hospitals. Change over time was analyzed using paired t tests, and comparisons between BC survivors and controls used age and education (AE)-adjusted regression models.

Results: Median weight gain in BC survivors was 2.00 kg (p < 0.0001); BMI, glucose, insulin, homeostasis model assessment (HOMA), and total cholesterol increased modestly but significantly. Waist circumference, glucose, and triglycerides were higher in LTFU BC survivors versus controls. BC survivors had significantly greater prevalence of diabetes/pre-diabetes versus controls (33 vs. 20.4%, AE-adjusted odds ratio (OR) 1.59, p = 0.050). This effect was restricted to those with lower levels of physical activity (<56 metabolic equivalent (MET)-hours/week: OR 2.70 versus 0.94 for those with higher physical activity, interaction p = 0.034). At LTFU, BC survivors were more physically active than at diagnosis (median increase 28 MET-hours/week interquartile range -14.8 to 82), and compared to controls (median 68.2 vs. 44 MET-hours/week, p < 0.0001).

Conclusion: The prevalence of the metabolic syndrome and diabetes/pre-diabetes was significantly higher in BC survivors than in controls group, notably in those with lower levels of physical activity. Enhanced diabetes/metabolic syndrome screening and promotion of physical activity may be warranted in BC survivors.
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http://dx.doi.org/10.1007/s10549-017-4263-zDOI Listing
July 2017

The effect of object size on the sensitivity of single photon emission computed tomography: comparison of two CZT cardiac cameras and an Anger scintillation camera.

EJNMMI Phys 2014 Dec 31;1(1):97. Epub 2014 Dec 31.

Applied Statistician, 9227 Kennedy Rd, Markham, ON, Canada, L3R 6H9.

Background: Heart sizes vary greatly across the spectrum of patients referred for myocardial perfusion imaging. We therefore performed a phantom study to explore under controlled circumstances how count rates change when different volumes containing the same amount of activity are scanned. Two dedicated cadmium-zinc-telluride cameras, the D-SPECT (Spectrum Dynamics, Caesarea, Israel) and Discovery 530c (D530c, GE Healthcare, Haifa, Israel), and the conventional SPECT Anger (A-SPECT, GE Healthcare, Haifa, Israel) camera are included in the study.

Methods: Different heart sizes were represented by syringes of various column heights mimicking a range of cardiac diameters. Syringes with fixed activity were scanned at five different volumes by successively adding non-radioactive water to the syringes. This procedure was repeated five times on each of the three cameras. Raw count rates were recorded for each scan to determine whether count rates changed with syringe column height.

Results: Using mixed-effect regression modeling, a linear relationship was found between count rate and water column height. For the D-SPECT, D530c, and A-SPECT, the changes in count rate for each centimeter increase in water column height were -1.75, +0.28, and -0.022 kilocounts per min per MBq, respectively (95% confidence intervals -1.89 to -1.61, 0.19 to 0.36, and -0.035 to -0.009); all effects are significantly different from each other and significantly different from zero. Average coefficients of variation were 0.080, 0.028, and 0.009.

Conclusions: The D-SPECT demonstrated a significant progressive increase in count rate related to decreasing size of the imaged object. D530c count rate increased slightly with increasing column height. The Anger SPECT showed minimally increased count rates with decreasing column height, an order of magnitude smaller than the D-SPECT based on their relative coefficients of variation.
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http://dx.doi.org/10.1186/s40658-014-0097-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545452PMC
December 2014

Prophylactic cranial irradiation (PCI). Still a no-brainer?

Lung Cancer 2015 Jul 25;89(1):4-7. Epub 2015 Apr 25.

Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Medical Imaging, University of Toronto.

Although prophylactic cranial irradiation (PCI) has been the standard of practice for patients successfully treated for limited stage small cell lung cancer for decades, subsequent changes in patient selection, updated brain imaging guidelines, an increased understanding of the mechanisms underlying the deleterious effects of whole brain irradiation as well as ongoing investigations into improving radiation treatment delivery have begun to question the current role of PCI. Who should be treated and how? This review attempts to gather together evidence for improving patient selection and describe potential improvements in treatment delivery.
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http://dx.doi.org/10.1016/j.lungcan.2015.04.006DOI Listing
July 2015

Changes in insulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective window of opportunity neoadjuvant study.

Breast Cancer Res 2015 Mar 3;17:32. Epub 2015 Mar 3.

Introduction: The antidiabetic drug metformin exhibits potential anticancer properties that are believed to involve both direct (insulin-independent) and indirect (insulin-dependent) actions. Direct effects are linked to activation of AMP-activated protein kinase (AMPK) and an inhibition of mammalian target of rapamycin mTOR signaling, and indirect effects are mediated by reductions in circulating insulin, leading to reduced insulin receptor (IR)-mediated signaling. However, the in vivo impact of metformin on cancer cell signaling and the factors governing sensitivity in patients remain unknown.

Methods: We conducted a neoadjuvant, single-arm, "window of opportunity" trial to examine the clinical and biological effects of metformin on patients with breast cancer. Women with untreated breast cancer who did not have diabetes were given 500 mg of metformin three times daily for ≥2 weeks after diagnostic biopsy until surgery. Fasting blood and tumor samples were collected at diagnosis and surgery. Blood glucose and insulin were assayed to assess the physiologic effects of metformin, and immunohistochemical analysis of tumors was used to characterize cellular markers before and after treatment.

Results: Levels of IR expression decreased significantly in tumors (P = 0.04), as did the phosphorylation status of protein kinase B (PKB)/Akt (S473), extracellular signal-regulated kinase 1/2 (ERK1/2, T202/Y204), AMPK (T172) and acetyl coenzyme A carboxylase (S79) (P = 0.0001, P < 0.0001, P < 0.005 and P = 0.02, respectively). All tumors expressed organic cation transporter 1, with 90% (35 of 39) exhibiting an Allred score of 5 or higher.

Conclusions: Reduced PKB/Akt and ERK1/2 phosphorylation, coupled with decreased insulin and IR levels, suggest insulin-dependent effects are important in the clinical setting. These results are consistent with beneficial anticancer effects of metformin and highlight key factors involved in sensitivity, which could be used to identify patients with breast cancer who may be responsive to metformin-based therapies.

Trial Registration: ClinicalTrials.gov identifier: NCT00897884. Registered 8 May 2009.
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http://dx.doi.org/10.1186/s13058-015-0540-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381495PMC
March 2015

Concordance between transrectal ultrasound guided biopsy results and radical prostatectomy final pathology: Are we getting better at predicting final pathology?

Can Urol Assoc J 2014 Jan-Feb;8(1-2):47-52

Division of Urology, Department of Surgical Oncology, University Health Network, Toronto, ON;

Introduction: Inaccuracy in biopsy Gleason scoring poses a risk to men who may then receive inappropriate treatment. We assess whether there was a change in discordance rates between biopsy and radical prostatectomy at our institution in recent years, while considering the implementation of active surveillance and the shift in biopsy scores caused by the 2005 International Society of Urologic Pathology update to the Gleason scoring protocol.

Methods: We reviewed patients who underwent radical prostatectomy at our institution between May 2004 and April 2011. We analyzed clinical and pathological correlates of upgrading in 3 subgroups: Gleason sum (GS) 6/6, GS6/7 and GS7/7, where the sum preceding the dash was determined from biopsy and the subsequent sum was determined from the radical prostatectomy specimen. We applied the log-rank test and Cox model to a Kaplan Meier analysis of biochemical recurrence in the subgroups, and also mapped GS6/7 discordance over time.

Results: In total, 1717 patients met our inclusion criteria. The 3 subgroups had significantly different mean prostate-specific antigen, patient age, tumour volume, margin status, pathologic stage, prostate weight, transrectal ultrasound volume and rate of progression (p < 0.05). We noted a multiphasic trend with a fall in discordance after 2005. However, there was no sustained trend over the study period taken as a whole (p = 0.06).

Conclusions: Although no sustained trend was observed, the falling discordance after 2005 may reflect the accommodation to the Gleason scoring update, while the gradual adoption of active surveillance may have led to the otherwise increasing trends. However, our observations may also be spurious biopsy sampling errors.
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http://dx.doi.org/10.5489/cuaj.751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929481PMC
February 2014

Clinical parameters associated with pressure ulcer healing in patients with advanced illness.

J Pain Symptom Manage 2014 Jun 23;47(6):1035-42. Epub 2013 Oct 23.

McMaster University, Hamilton, Ontario, Canada.

Context: Pressure ulcers are the most prevalent wounds affecting patients with advanced illness. Although complete wound healing is the most desired outcome, it remains unlikely in the setting of patients with limited life expectancy. Realistic goal setting may be enabled using objective clinical parameters.

Objectives: To identify clinical parameters associated with complete healing of Stage II pressure ulcers.

Methods: Univariable and multivariable competing risk analyses were used to assess the association of complete healing with the following six clinical parameters, namely gender, age, total number of pressure ulcers, total number of other wounds, number of failing organ systems, and Palliative Performance Scale (PPS) scores.

Results: A total of 147 patients with 245 Stage II pressure ulcers were followed until death; 9.4% of Stage II pressure ulcers achieved complete healing. Univariable analyses showed hazard ratios (HRs) for complete healing in favor of higher levels of PPS scores (HR 1.82-5.99, P<0.001) and age younger than 80 years (HR 3.28, P=0.031). Multivariable analyses showed HRs for complete healing in favor of higher levels of PPS scores (HR 1.49-3.34, P=0.003).

Conclusion: Higher levels of PPS scores are associated with complete healing of Stage II pressure ulcers in patients with advanced illness.
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http://dx.doi.org/10.1016/j.jpainsymman.2013.07.005DOI Listing
June 2014

Blood levels of vitamin D and early stage breast cancer prognosis: a systematic review and meta-analysis.

Breast Cancer Res Treat 2013 Oct 9;141(3):331-9. Epub 2013 Oct 9.

Faculty of Medicine, McGill University, McIntyre Medical Building, 3655 Sir William Osler, Montreal, QC, H3G 1Y6, Canada.

Vitamin D regulates expression of genes important in development and progression of breast cancer. The association of vitamin D with breast cancer outcomes among breast cancer patients is controversial. We conducted a systematic review and meta-analysis of this association in early stage breast cancer outcome. We searched MEDLINE (1982-May 1, 2013), the American Society of Clinical Oncology (2009-2012), and the San Antonio Breast Cancer Symposium (2010-2012) for abstracts, using the following keywords: "breast cancer" and "prognosis" or "survival", and "vitamin D" or" calcitriol" to identify studies reporting the associations of blood vitamin D levels (drawn close to diagnosis) with breast cancer outcomes. Meta-analyses were performed using an inverse-variance weighted fixed-effects model with Stata Version 12. Eight studies including 5,691 patients were identified. Vitamin D deficiency was variably categorized across studies; a median of 36.8 % of patients were classified as deficient. Low vitamin D levels were associated with a pooled hazard ratio of 2.13 (95 % CI 1.64-2.78) and 1.76 (95 % CIs 1.35-2.30) for recurrence (six studies) and death (four studies), respectively, with no evidence of significant heterogeneity across studies. There was potential evidence of a publication bias in studies examining associations with death (but not in those examining associations with recurrence). These findings support an association of low levels of vitamin D with increased risk of recurrence and death in early stage breast cancer patients. Given the observational nature of the included studies, it cannot be concluded that this association is causal. Further research is warranted to investigate the potential beneficial effects of vitamin D in breast cancer.
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http://dx.doi.org/10.1007/s10549-013-2713-9DOI Listing
October 2013

Post-surgical highly sensitive C-reactive protein and prognosis in early-stage breast cancer.

Breast Cancer Res Treat 2013 Oct 27;141(3):485-93. Epub 2013 Sep 27.

Division of Medical Oncology and Hematology, Department of Medicine, Mount Sinai Hospital, 1284-600 University Avenue, Toronto, ON, M5G 1X5, Canada.

Obesity, associated with inflammation, has been linked to poor prognosis in breast cancer. Research investigating the potential role of C-reactive protein (CRP), an obesity-associated systemic marker of inflammation, as a mediator of adverse prognostic effects of obesity has yielded inconsistent results. We examined the association of highly sensitive CRP (hsCRP) with obesity-related factors and breast cancer outcome. A cohort of 535 non-diabetic women diagnosed with T1-3, N0-1, M0 breast cancer, was assembled between 1989 and 1996 and followed prospectively. Circulating levels of hsCRP were analyzed on blood obtained postoperatively, prior to systemic therapy, in 501 women. Correlations and prognostic associations were analyzed using one-way analysis of variance, Spearman's rank correlation coefficients (r) and Cox models. hsCRP was significantly correlated with body mass index (r = 0.60), insulin (r = 0.44), leptin (r = 0.54), and lipids, but not T or N stage, grade or estrogen receptor/progesterone receptor. At a median follow-up of 12 years, hsCRP was not associated with distant disease-free survival or overall survival in univariable [Q4 vs. Q1 hazard ratio (HR) 1.03, 95 % confidence interval (CI) 0.69-1.52, P = 0.9 and HR 1.27, 95 % CI 0.86-1.86, P = 0.24, respectively] or multivariable [Q4 vs Q1 HR 1.02, 95 % CI 0.66-1.59, P = 0.93 and HR 1.17, 95 % CI 0.76-1.81, P = 0.48 respectively] analyses. hsCRP was associated with age, comorbidities, and the insulin resistance syndrome but not with breast cancer outcome.
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http://dx.doi.org/10.1007/s10549-013-2694-8DOI Listing
October 2013

Quality of life in long-term breast cancer survivors.

J Clin Oncol 2013 Oct 26;31(28):3540-8. Epub 2013 Aug 26.

Tina Hsu and Pamela J. Goodwin, University of Toronto; Nicky Hood, Margaret Graham, and Pamela J. Goodwin, Samuel Lunenfeld Research Institute; Pamela J. Goodwin, Mount Sinai Hospital, Toronto; and Marguerite Ennis, Applied Statistician, Markham, Ontario, Canada.

Purpose: There is considerable interest in the quality of life (QOL) of long-term breast cancer (BC) survivors. We studied changes in QOL from time of BC diagnosis to long-term survivorship and compared QOL in long-term survivors to that of age-matched women with no history of BC.

Patients And Methods: In all, 535 women with localized BC (T1-3N0-1M0) were recruited from 1989 to 1996 and followed prospectively, completing QOL questionnaires at diagnosis and 1 year postdiagnosis. Between 2005 and 2007, those alive without distant recurrence were recontacted to participate in a long-term follow-up (LTFU) study. A control group was recruited from women presenting for screening mammograms, and both groups completed LTFU QOL questionnaires. Longitudinal change in BC survivors and differences between BC survivors and controls were assessed in eight broad categories with clinically significant differences set at 5% and 10% of the breadth of each QOL scale.

Results: A total of 285 patients with BC were included in the study, on average 12.5 years postdiagnosis. Longitudinally, clinically significant improvements were observed in overall QOL by 1 year postdiagnosis with further improvements by LTFU. Some clinically significant improvements over time were seen in all categories. A total of 167 controls were recruited. Deficits were observed in self-reported cognitive functioning (5.3% difference) and financial impact (6.3% difference) in BC survivors at LTFU compared with controls.

Conclusion: Long-term BC survivors show improvement in many domains of QOL over time, and they appear to have similar QOL in most respects to age-matched noncancer controls, although small deficits in cognition and finances were identified.
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http://dx.doi.org/10.1200/JCO.2012.48.1903DOI Listing
October 2013

Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study.

Breast Cancer Res Treat 2012 Oct 30;135(3):821-30. Epub 2012 Aug 30.

Division of Medical Oncology and Hematology, Department of Medicine, Mount Sinai Hospital and Princess Margaret Hospital, University of Toronto, 1284-600 University Avenue, Toronto, ON M5G 1X5, Canada.

Metformin may exert anti-cancer effects through indirect (insulin-mediated) or direct (insulin-independent) mechanisms. We report results of a neoadjuvant "window of opportunity" study of metformin in women with operable breast cancer. Newly diagnosed, untreated, non-diabetic breast cancer patients received metformin 500 mg tid after diagnostic core biopsy until definitive surgery. Clinical (weight, symptoms, and quality of life) and blood [fasting serum insulin, glucose, homeostasis model assessment (HOMA), C-reactive protein (CRP), and leptin] attributes were compared pre- and post-metformin as were terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Ki67 scores (our primary endpoint) in tumor tissue. Thirty-nine patients completed the study. Mean age was 51 years, and metformin was administered for a median of 18 days (range 13-40) up to the evening prior to surgery. 51 % had T1 cancers, 38 % had positive nodes, 85 % had ER and/or PgR positive tumors, and 13 % had HER2 overexpressing or amplified tumors. Mild, self-limiting nausea, diarrhea, anorexia, and abdominal bloating were present in 50, 50, 41, and 32 % of patients, respectively, but no significant decreases were seen on the EORTC30-QLQ function scales. Body mass index (BMI) (-0.5 kg/m(2), p < 0.0001), weight (-1.2 kg, p < 0.0001), and HOMA (-0.21, p = 0.047) decreased significantly while non-significant decreases were seen in insulin (-4.7 pmol/L, p = 0.07), leptin (-1.3 ng/mL, p = 0.15) and CRP (-0.2 mg/L, p = 0.35). Ki67 staining in invasive tumor tissue decreased (from 36.5 to 33.5 %, p = 0.016) and TUNEL staining increased (from 0.56 to 1.05, p = 0.004). Short-term preoperative metformin was well tolerated and resulted in clinical and cellular changes consistent with beneficial anti-cancer effects; evaluation of the clinical relevance of these findings in adequately powered clinical trials using clinical endpoints such as survival is needed.
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http://dx.doi.org/10.1007/s10549-012-2223-1DOI Listing
October 2012

Feasibility of a randomized controlled trial of vitamin D vs. placebo in women with recently diagnosed breast cancer.

Breast Cancer Res Treat 2012 Jul 16;134(2):759-67. Epub 2012 Jun 16.

Mount Sinai Hospital, 1284-600 University Avenue, Toronto, ON, M5G 1X5, Canada.

Low serum vitamin D levels have been associated with poor outcomes in women diagnosed with early breast cancer. However, no randomized controlled trials (RCTs) have been performed to determine whether vitamin D supplementation might be an effective intervention in this population. We prospectively evaluated vitamin D adequacy and supplementation rates in a contemporary cross-sectional sample of breast cancer patients from 2 large urban centers and examined the feasibility of an RCT of vitamin D supplementation. Women with recently diagnosed early breast cancer were prospectively identified and recruited in Toronto and Los Angeles between March 2009 and January 2010. Anthropometric measurements, dietary, lifestyle, and medication histories were obtained by means of structured questionnaires and interviews. Tumor and treatment characteristics were abstracted from clinical records and blood samples were collected for analysis of 25-OH vitamin D. 173 eligible patients (median age 57) were enrolled. Clinical and treatment characteristics were similar between centres. 84.4 % of women reported use of vitamin D-containing supplements with median daily doses of 1,400 IU. Median 25-OH vitamin D levels were 85.5 and 98.5 nmol/L (P = 0.1), and levels of deficiency (<50 nmol/L), insufficiency (50-72 nmol/L), and adequacy (>72 nmol/L) were 3.8, 23.8, 72.5 % (Toronto) and 4.3, 20.7, 75 % (Los Angeles). 25-OH vitamin D levels were strongly correlated with vitamin D supplement use (r = 0.41, P < 0.0001). 68 % of women expressed willingness to participate in a vitamin D supplementation RCT; however, only 12.7 % of the study population met the pre-specified feasibility criteria (25-OH vitamin D <72 nmol/L, willing to participate, and taking ≤1,000 IU vitamin D supplement/day). Both vitamin D levels and supplementation rates are higher than in previous reports. While the majority of women would be willing to participate in an RCT of vitamin D supplementation, low levels of deficiency/insufficiency and high rates of supplement use would limit the feasibility of such a study.
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http://dx.doi.org/10.1007/s10549-012-2120-7DOI Listing
July 2012

Body size and breast cancer prognosis in relation to hormone receptor and menopausal status: a meta-analysis.

Breast Cancer Res Treat 2012 Jul 5;134(2):769-81. Epub 2012 May 5.

Mount Sinai Hospital and Princess Margaret Hospital, Toronto, ON, Canada.

Obesity is associated with poor survival after breast cancer diagnosis in individual studies and meta-analyses. Evidence regarding associations of obesity with breast cancer-specific survival (BCSS) and overall survival (OS) in relation to hormone receptor status, or BCSS in relation to menopausal status has not been evaluated in a previous meta-analysis. In this study, we conducted a meta-analysis of the association of obesity with OS and BCSS in relation to hormone receptor status and menopausal status. MEDLINE, EMBASE, and COCHRANE databases from the first record to December 2011 and presentations made at major international meetings in the last 5 years were searched. We included observational or interventional studies reporting hazard ratios (HRs) of obesity with OS and/or BCSS in relation to hormone receptor and/or menopausal status. Twenty-one studies qualified, meeting the above criteria. The pooled HR for OS in heavier versus lighter women was 1.31 (95 % CI 1.17-1.46) for estrogen receptor/progesterone receptor (ER/PgR) positive cancers; 1.18 (95 % CI 1.06-1.31) for ER/PgR negative cancers; and the difference between the two groups was not significant (p = 0.31). The pooled HR for OS in heavier versus lighter women was 1.23 (95 % CI 1.07-1.42) for premenopausal women and 1.15 (95 % CI 1.06-1.26) for post-menopausal women, and the difference between the two groups was not significant (p = 0.57). Comparable pooled HRs for BCSS were 1.36 (95 % CI 1.20-1.54) for ER/PgR positive cancers and 1.46 (95 % CI 0.98-2.19) for ER/PgR negative cancers; and 1.18 (95 % CI 0.82-1.70) for pre-menopausal women and 1.38 (95 % CI 1.11-1.71) for post-menopausal women, also without significant group differences. Results were similar after adjustment for BMI measurement technique, years of follow-up, or study design. These findings led us to conclude that there is no evidence showing that the association of obesity with breast cancer outcome differs by hormone receptor or menopausal status. This has implications for studies of weight loss interventions in the adjuvant BC setting.
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http://dx.doi.org/10.1007/s10549-012-2073-xDOI Listing
July 2012

Wound outcomes in patients with advanced illness.

Int Wound J 2012 Dec 2;9(6):683-92. Epub 2012 Feb 2.

University of Toronto, ON, Canada.

A prospective case series was studied to assess the potential for complete healing of wounds among patients with advanced illness referred to a regional palliative care program in Toronto, Canada. Two hundred and eighty-two patients, of which 148 were primarily diagnosed with cancer and 134 with non cancer advanced illness, were assessed and followed until their deaths. On the baseline initial referral date, 823 wounds were documented. The wound classes assessed included pressure ulcers, malignant wounds, skin tears, venous leg ulcers, diabetic foot ulcers and arterial leg/foot ulcers. Proportions of patients showing complete healing of at least one wound were calculated, stratified by patient's survival time post-baseline (1 week, 1 month, 3 months and 6 months). Proportions of patients showing complete healing of at least one wound increased the longer patients lived and ranged between 12·9% and 43·5% for stage I pressure ulcers, 0% and 60% for stage II pressure ulcers, 2·4% and 100% for skin tears, 10% and 100% for venous leg ulcers and 0% and 50% for diabetic foot ulcers. Only one person showed complete healing of a stage III pressure ulcer and no complete healing was observed with stage IV pressure ulcers, unstageable pressure ulcers, malignant wounds and arterial leg/foot ulcers.
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http://dx.doi.org/10.1111/j.1742-481X.2012.00939.xDOI Listing
December 2012

Insulin- and obesity-related variables in early-stage breast cancer: correlations and time course of prognostic associations.

J Clin Oncol 2012 Jan 12;30(2):164-71. Epub 2011 Dec 12.

Mount Sinai Hospital, 1284-600 University Ave, Toronto, Ontario M5G 1X5, Canada.

Purpose: To investigate patterns of prognostic associations over time of insulin- and obesity-related variables measured at diagnosis of early breast cancer (BC), focusing on whether the prognostic associations with distant recurrence and death changed over time.

Patients And Methods: Five hundred thirty-five nondiabetic women with T1-3, N0-1, M0 invasive BC diagnosed from 1989 to 1996 were included in the study. Insulin-related variables included fasting insulin, Homeostasis Model Assessment, C-peptide, and glucose. Obesity-related variables included weight, body mass index (BMI), waist and hip circumference, and leptin. Correlations were examined using the Pearson correlation coefficient and prognostic associations using the Cox model.

Results: There was evidence that associations of baseline insulin-related variables with distant recurrence and death were not constant over time; univariable adverse prognostic associations were significant only during the first 5 years (eg, insulin quartile 4 v 1: hazard ratio [HR], 2.32; 95% CI, 1.39 to 3.86; P < .001 for distant disease-free survival [DDFS]; and HR, 2.85; 95% CI, 1.48 to 5.50; P = .002 for overall survival [OS], with little attenuation of this pattern in multivariable analyses). In contrast, obesity-related variables (BMI, weight, leptin) exerted significant adverse univariable associations that were constant over time (eg, BMI quartile 4 v 2: HR, 1.40; 95% CI, 1.07 to 1.82 for DDFS; P = .014; and HR, 1.50; 95% CI, 1.16 to 1.93; P < .001 for OS); prognostic associations of leptin remained significant in multivariable analyses.

Conclusion: Baseline insulin- and obesity-related variables exert different patterns of prognostic associations over time in early BC.
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http://dx.doi.org/10.1200/JCO.2011.36.2723DOI Listing
January 2012

Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers: an International Prospective Breast Cancer Family Registry population-based cohort study.

J Clin Oncol 2012 Jan 5;30(1):19-26. Epub 2011 Dec 5.

Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario.

Purpose: To compare breast cancer prognosis in BRCA1 and BRCA2 mutation carriers with that in patients with sporadic disease.

Patients And Methods: An international population-based cohort study was conducted in Canada, the United States, and Australia of 3,220 women with incident breast cancer diagnosed between 1995 and 2000 and observed prospectively. Ninety-three had BRCA1 mutations; 71, BRCA2 mutations; one, both mutations; 1,550, sporadic breast cancer; and 1,505, familial breast cancer (without known BRCA1 or BRCA2 mutation). Distant recurrence and death were analyzed.

Results: Mean age at diagnosis was 45.3 years; mean follow-up was 7.9 years. Risks of distant recurrence and death did not differ significantly between BRCA1 mutation carriers and those with sporadic disease in univariable and multivariable analyses. Risk of distant recurrence was higher for BRCA2 mutation carriers compared with those with sporadic disease in univariable analysis (hazard ratio [HR], 1.63; 95% CI, 1.02 to 2.60; P = .04). Risk of death was also higher in BRCA2 carriers in univariable analysis (HR, 1.81; 95% CI, 1.15 to 2.86; P = .01). After adjustment for age, tumor stage and grade, nodal status, hormone receptors, and year of diagnosis, no differences were observed for distant recurrence (HR, 1.00; 95% CI, 0.62 to 1.61; P = 1.00) or death (HR, 1.12; 95% CI, 0.70 to 1.79; P = .64).

Conclusion: Outcomes of BRCA1 mutation carriers were similar to those of patients with sporadic breast cancer. Worse outcomes in BRCA2 mutation carriers in univariable analysis seem to reflect the presence of more adverse tumor characteristics in these carriers. Similar outcomes were identified in BRCA2 carriers and those with sporadic disease in multivariable analyses.
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http://dx.doi.org/10.1200/JCO.2010.33.0068DOI Listing
January 2012

Significance of abnormal sonographic findings in postmenopausal women with and without bleeding.

J Obstet Gynaecol Can 2011 Sep;33(9):944-51

Department of Obstetrics and Gynaecology, University of Toronto, Toronto ON.

Objective: We sought to determine the incidence of cancer and to compare pathologic outcomes in bleeding and non-bleeding postmenopausal patients who underwent hysteroscopy.

Methods: We conducted a retrospective chart review of 294 postmenopausal women with abnormal uterine bleeding and 142 postmenopausal women without symptoms who underwent hysteroscopy. An 11 mm cut-off for asymptomatic women was applied to determine whether this endometrial thickness threshold would differentiate women with and without endometrial cancer in the asymptomatic group.

Results: In symptomatic patients, 14 were found to have endometrial cancer and 10 were found to have endometrial hyperplasia. In the asymptomatic group, two women (1.4%) were found to have endometrial cancer with average thickness 17.5 mm, and one (0.71%) was found to have endometrial hyperplasia. Logistic regression models showed the risk of a bleeding patient developing endometrial cancer at an endometrial thickness of 4 mm was the same as the risk in a non-bleeding patient at a thickness of 15 mm.

Conclusion: Asymptomatic postmenopausal women have a low risk of having significant endometrial pathology. Cancer was approximately four times more prevalent in women with bleeding than in women with no bleeding.
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http://dx.doi.org/10.1016/s1701-2163(16)35020-4DOI Listing
September 2011

Multicenter, randomized, cross-over clinical trial of venlafaxine versus gabapentin for the management of hot flashes in breast cancer survivors.

J Clin Oncol 2010 Dec 8;28(35):5147-52. Epub 2010 Nov 8.

Department of Oncology, Juravinski Cancer Centre, 699 Concession St, Hamilton, Ontario, Canada L8V 5C2.

Purpose: Nonhormonal pharmacologic interventions are recommended for the treatment of hot flashes in breast cancer survivors. Antidepressants and gabapentin have been shown to be both effective and well tolerated; however, it is not clear which is preferred.

Patients And Methods: This was a group-sequential, open-label, randomized, cross-over trial of 4 weeks of venlafaxine (37.5 mg daily for 7 days followed by 75 mg daily for 21 days) versus gabapentin (300 mg once per day for 3 days, then 300 mg twice per day for 3 days, then 300 mg three times per day for 22 days), with patient preference as the primary outcome. Postmenopausal women with at least 14 bothersome hot flashes per week for the prior month were eligible. A 2-week baseline period and a 2-week tapering/washout time was used before the first and second treatment periods, respectively. Diaries were used to measure hot flashes and potential toxicities throughout the study. Participants completed a preference questionnaire at the end of the study. A predefined Pocock stopping rule was applied. Patient preference and hot flash and toxicity outcomes were compared between treatments.

Results: Sixty-six patients were randomly assigned, 56 of whom provided a preference (eight dropped out and two had no preference); 18 (32%) preferred gabapentin and 38 (68%) preferred venlafaxine (P = .01). Both agents reduced hot flash scores to a similar extent (66% reduction). Venlafaxine was associated with increased nausea, appetite loss, constipation, and reduced negative mood changes compared with gabapentin, whereas gabapentin was associated with increased dizziness and appetite compared with venlafaxine (all P < .05).

Conclusion: Breast cancer survivors prefer venlafaxine over gabapentin for treating hot flashes.
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http://dx.doi.org/10.1200/JCO.2010.29.9230DOI Listing
December 2010

Preferences for active and aggressive intervention among patients with advanced cancer.

BMC Cancer 2010 Oct 28;10:592. Epub 2010 Oct 28.

Division of Palliative Medicine, William Osler Health System, Toronto, Ontario, Canada.

Background: Intrinsic to "Patient-Centered Care" is being respectful and responsive to individual patient preferences, expressed needs, and personal values. Establishing a patient's preferences for active and aggressive intervention is imperative and foundational to the development of advance care planning. With the increasing awareness and acceptance of palliative philosophies of care, patients with advanced cancer are increasingly transitioning from active and aggressive medical management (AAMM) to conservative palliative management (CPM).

Methods: A cross-sectional study based on a prospective and sequential case series of patients referred to a regional palliative medicine consultative program was assembled between May 1, 2005 and June 30, 2006. Patients and/or their substitute decision makers (SDM) completed a questionnaire, at baseline, that assessed their preferences for AAMM en route to their eventual deaths. Seven common interventions constituting AAMM were surveyed: cardiopulmonary resuscitation (CPR) & mechanical ventilation (MV), chemotherapy, antibiotics, anticoagulants, blood transfusions, feeding tubes, and artificial hydration. Multivariable analyses were conducted on the seven interventions individually as well as on the composite score that summed preferences for the seven interventions.

Results: 380 patients with advanced cancer agreed to participate in the study. A trend to desire a mostly conservative palliative approach was noted as 42% of patients desired one or fewer interventions. At baseline, most patients and their SDM's were relatively secure about decisions pertaining to the seven interventions as the rates of being "undecided" ranged from a high of 23.4% for chemotherapy to a low of 3.9% for feeding tubes. Multivariable modeling showed that more AAMM was preferred by younger patients (P < 0.0001), non-Caucasians (P = 0.042), patients with higher baseline Palliative Performance Scale scores (P = 0.0002) and where a SDM was involved in the decision process (p = 0.027). Non-statistically significant trends to prefer more AAMM was observed with male gender (p = 0.077) and higher levels of the Charlson Comorbidity index (p = 0.059). There was no association between treatment preferences and cancer class.

Conclusions: Although the majority of patients with advanced cancer in this study expressed preferences for CPM, younger age, higher baseline PPSv2, and involvement of SDMs in the decision process were significantly associated with preferences for AAMM.
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http://dx.doi.org/10.1186/1471-2407-10-592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988029PMC
October 2010

Wounds and survival in noncancer patients.

J Palliat Med 2010 Apr;13(4):453-9

Division of Palliative Medicine, William Osler Health System, University of Toronto, Toronto, Ontario, Canada.

Background: Currently available prognostic models for noncancer patients lack high levels of discrimination. Therefore, the quest for additional prognostic factors must continue. To date, none have utilized the occurrence of wounds as a prognostic factor.

Methods: As a prospective observational study, based on a sequential case series of 189 advanced noncancer patients, all wounds were documented. One hundred seventy patients were followed until their deaths. Univariate and multivariate survival analyses were performed using hazard ratios (HRs) derived from Cox proportional hazard models.

Results: Seventy-eight percent of patients presented with at least one wound at referral. Patients with wounds displayed worse overall survival than those without wounds (p = 0.009). Survival analysis for the full postreferral period revealed a violation of the proportional hazards assumption for pressure ulcers and the Palliative Performance Scale version 2 (PPSv2). In order to address this finding, early deaths (within 14 days of referral) were assessed separately from later deaths (more than 14 days after referral). After controlling for the co-occurrence of wounds, age, gender, Charlson comorbidity index, and PPSv2, pressure ulcers were associated with statistically significant increased risk of death for patients of sufficient health to survive at least 2 weeks after referral (HR 2.42, p = 0.003), while other wounds were associated with greater levels of mortality over the full postreferral period (HR 1.96, p = 0.0001).

Discussion: The occurrence of pressure ulcers and other wounds are correlated with reduced survival in patients with advanced noncancer illness. These data merit incorporation into existing prognostic models or used in conjunction with them to enhance prognostic accuracy.
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http://dx.doi.org/10.1089/jpm.2009.0260DOI Listing
April 2010