Publications by authors named "Alexandra Desnoyers"

10 Publications

  • Page 1 of 1

Fragility index of trials supporting approval of anti-cancer drugs in common solid tumours.

Cancer Treat Rev 2021 Mar 16;94:102167. Epub 2021 Feb 16.

Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Electronic address:

Background: The Fragility Indexquantifies the reliability of positive trials by estimating the number of events, which would change statistically significant results to non-significant results.

Methods: We identified randomized trials supporting drug approvals by the US FDA between 2009 and 2019 in lung, breast, prostate, and colon cancers and in melanoma. We reconstructed survival tablesand calculated the number of events, which would result in a non-significant result for the primary endpoint. The FI was then compared to the number of patients in each trial who withdrew consent or were lost to follow-up. Regression analyses were used to explore associations between RCT characteristics and FI and trials in which FI was lower or equal to number of participants who withdrew consent or were lost to follow-up.

Results: Among 81 RCTs, the median FI was 28. The median number of patients who withdrew consent or were lost to follow up was 27. FI was equal or lower than the number of patients who withdrew consent or were lost to follow-up in 47 trials (58%). There was a modest increase in FI over time (p = 0.02). Trials with overall survival as the primary endpoint (p = 0.006) and those in the palliative setting (p < 0.001) had lower FI. There was no association with trial sample size or duration of follow-up.

Findings: Statistical significance of RCTs in common solid tumours can be reversed often with a small number of additional events. Post-approval RCTs or real-world data analyses should be performed to ensure results of registration trials are robust.
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http://dx.doi.org/10.1016/j.ctrv.2021.102167DOI Listing
March 2021

Implementing DPYD*2A Genotyping in Clinical Practice: The Quebec, Canada, Experience.

Oncologist 2021 Apr 23;26(4):e597-e602. Epub 2020 Dec 23.

Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Quebec, Canada.

Background: Fluoropyrimidines are used in chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life-threatening toxicities. DPYD*2A polymorphism is one of the most studied variants. The study objective was to document the impact of implementing this test in routine clinical practice.

Methods: We retrospectively performed chart reviews of all patients who tested positive for a heterozygous or homozygous DPYD*2A mutation in samples obtained from patients throughout the province of Quebec, Canada.

Results: During a period of 17 months, 2,617 patients were tested: 25 patients tested positive. All were White. Twenty-four of the 25 patients were heterozygous (0.92%), and one was homozygous (0.038%). Data were available for 20 patients: 15 were tested upfront, whereas five were identified after severe toxicities. Of the five patients confirmed after toxicities, all had grade 4 cytopenias, 80% grade ≥3 mucositis, 20% grade 3 rash, and 20% grade 3 diarrhea. Eight patients identified with DPYD*2A mutation prior to treatment received fluoropyrimidine-based chemotherapy at reduced initial doses. The average fluoropyrimidine dose intensity during chemotherapy was 50%. No grade ≥3 toxicities were observed. DPYD*2A test results were available in an average of 6 days, causing no significant delays in treatment initiation.

Conclusion: Upfront genotyping before fluoropyrimidine-based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. The administration of chemotherapy at reduced doses appears to be safe in patients heterozygous for DPYD*2A.

Implications For Practice: Fluoropyrimidines are part of chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life-threatening toxicities. This retrospective analysis demonstrates that upfront genotyping of DPYD before fluoropyrimidine-based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. This approach was reported previously, but insufficient data concerning its application in real practice are available. This is likely the first reported experience of systematic DPYD genotyping all over Canada and North America as well.
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http://dx.doi.org/10.1002/onco.13626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018309PMC
April 2021

Comparison of treatment-related adverse events of different Cyclin-dependent kinase 4/6 inhibitors in metastatic breast cancer: A network meta-analysis.

Cancer Treat Rev 2020 Nov 17;90:102086. Epub 2020 Aug 17.

Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: Palbociclib, ribociclib and abemaciclib have all been approved in combination with endocrine therapy in hormone-receptor positive, HER2 negative metastatic breast cancer. While the efficacy of these drugs appears similar, differences in safety and tolerability are apparent.

Methods: We searched PubMed and ASCO, ESMO and SABCS proceedings to identify randomized trials of palbociclib, ribociclib and abemaciclib. Data on common and serious adverse events (AE) were extracted for each approved drug. The odds ratio for each AE and the hazard ratio for progression-free survival were calculated relative to endocrine therapy alone. A network meta-analysis was then performed for each endocrine therapy backbone (aromatase inhibitor (AI) or fulvestrant) to compare ribociclib and abemaciclib to palbociclib.

Results: 8 trials were included in the analysis and comprised 2799 patients receiving cyclin-dependent kinase 4/6 inhibitors palbociclib: 873 patients; ribociclib: 1153 patients; abemaciclib: 773 patients. In 5 trials (1524 patients), the endocrine therapy backbone was an AI and in 3 trials (1275 patients) it was fulvestrant. Compared to palbociclib, ribociclib and abemaciclib showed significantly lower grade 3-4 neutropenia, but significantly higher GI toxicity. Treatment discontinuation was higher with abemaciclib than other drugs. Efficacy of the 3 drugs was similar. Compared to palbociclib, for AI backbone, the HR for PFS for ribociclib was 0.98 and for abemaciclib 1.02. For fulvestrant backbone, the HR were 0.88 and 0.93 respectively.

Conclusions: Palbociclib, ribociclib and abemaciclib have comparable efficacy, but differences in safety and tolerability. Abemaciclib has worse tolerability with significantly higher treatment discontinuation likely due to GI toxicity.
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http://dx.doi.org/10.1016/j.ctrv.2020.102086DOI Listing
November 2020

Evolution in the risk of adverse events of adjuvant endocrine therapy in postmenopausal women with early-stage breast cancer.

Breast Cancer Res Treat 2020 Jul 1;182(2):259-266. Epub 2020 Jun 1.

Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, 39 Jabotinsky st., 4941492, Petah Tikva, Israel.

Background: Adjuvant endocrine therapy is a gold standard in early-stage, hormone receptor positive breast cancer. In postmenopausal women, aromatase inhibitors (AIs) are associated with improved outcome compared to tamoxifen monotherapy. Differences in the toxicity profiles of these drugs are described; however, little is known about whether the risk of adverse events changes over time.

Methods: Sequential reports of large, randomized, adjuvant endocrine therapy trials comparing AIs to tamoxifen were reviewed. Data on pre-specified adverse events were extracted including cardiovascular events, bone fractures, cerebrovascular disease, endometrial cancer, secondary malignancies excluding breast cancer, venous thrombosis and death without recurrence. Odds ratios (ORs) were calculated for each adverse event at each time over the course of follow-up. The change in the ORs for adverse events over time was evaluated using weighted linear regression.

Results: Analysis included 21 reports of 7 trials comprising 30,039 patients and reporting outcomes between 28 and 128 months of follow-up. Compared to tamoxifen, AIs use was associated with a significant reduction in the magnitude of increased odds of bone fracture over time (β = - 0.63, p = 0.013). There was a non-significant decrease in the magnitude of reduced odds of secondary malignancies over time (β = 0.448, p = 0.094). The differences in other toxicity profiles between AIs and tamoxifen did not change significantly over time.

Conclusions: The increased risk of bone fractures associated with adjuvant AIs falls over time and after discontinuation of treatment. Differences in other toxicities between AIs and tamoxifen do not change significantly over time including a persistently elevated risk of cardiovascular events.
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http://dx.doi.org/10.1007/s10549-020-05715-1DOI Listing
July 2020

Influence of Competing Risks on Estimates of Recurrence Risk and Breast Cancer-specific Mortality in Analyses of the Early Breast Cancer Trialists Collaborative Group.

Sci Rep 2020 03 5;10(1):4091. Epub 2020 Mar 5.

Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, Ontario, Canada.

Early-stage breast cancer (BC) is a curable disease with many patients dying of causes other than BC. The influence of non-BC death and other competing risks on the interpretation of Kaplan-Meier (KM)-based analyses for BC-specific outcomes are unknown. We searched the Oxford University website to identify all meta-analyses published by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) between 2005 and 2018. The potential influence of competing risks was estimated using a validated multivariable linear model that predicts the difference between KM and cumulative incidence function (CIF) on estimates of BC-specific outcomes. The initial search identified 14 EBCTCG papers, 10 (71%) reported data on BC and competing events. Eight (80%) had a relative difference between KM and the competing risk adjusted estimates exceeding 10%. The median relative difference was 28.4% for local-recurrence; 16.8% for distant-recurrence, and 6.7% for BC-specific mortality. There was a 18.9% relative difference between KM and CIF adjusted analyses beyond 10 years. The use of KM-based methods when competing risks are present biases risk estimates in studies of early BC especially for uncommon outcomes such as local recurrence. The use of CIF to calculate BC-specific outcomes may be preferable in this setting.
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http://dx.doi.org/10.1038/s41598-020-61093-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058037PMC
March 2020

Integrin ανβ6 Protein Expression and Prognosis in Solid Tumors: A Meta-Analysis.

Mol Diagn Ther 2020 04;24(2):143-151

Experimental Therapeutics Unit, Medical Oncology Department, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain.

Background And Objective: Integrins are a family of adhesion receptor proteins that provide signaling from the extracellular matrix to the cytoplasm. They have been associated with cancer by promoting migration, invasion, metastasis, and survival. ανβ6 integrin is upregulated in several tumors. Here, we evaluate the prognostic impact of ανβ6 integrin protein expression in solid tumors.

Methods: A systematic search of electronic databases identified publications exploring the effect of ανβ6 integrin on overall survival (OS). Hazard ratios (HRs) were pooled in a meta-analysis using generic inverse variance and random effects modeling. Subgroup analyses were conducted based on tumor site, tumor stage, antibody used for immunohistochemistry (IHC) and method for extraction of the HR. A meta-regression explored the influence of clinical variables on the magnitude of effect of ανβ6 integrins on OS.

Results: Seventeen studies comprising 5795 patients met the inclusion criteria. High ανβ6 integrin expression in tumors was associated with worse OS (HR 1.65, 95% confidence interval [CI] 1.32-2.06; Cochran's Q p < 0.001, I = 81%). Adverse outcomes were similar in all tumor sites (subgroup difference p = 0.10), with the strongest association between ανβ6 integrins and OS in gastric cancer (HR 2.20, 95% CI 1.71-2.83) and the lowest in head and neck cancer (HR 1.21, 95% CI 0.79-1.83). There was no significant difference between early-stage and metastatic cancer, type of IHC antibodies, and analysis methods.

Conclusions: High expression of ανβ6 integrins is associated with adverse survival outcome in several tumors. Prospective studies evaluating the prognostic impact of ανβ6 integrin and its role as a therapeutic target are warranted.
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http://dx.doi.org/10.1007/s40291-020-00450-1DOI Listing
April 2020

A critique of the fragility index.

Lancet Oncol 2019 10 30;20(10):e552. Epub 2019 Sep 30.

Division of Medical Oncology, Princess Margaret Cancer Centre and the University of Toronto, Toronto ON, M5G 2M9, Canada. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(19)30583-2DOI Listing
October 2019

The Effect of Exercise on Quality of Life, Fatigue, Physical Function, and Safety in Advanced Solid Tumor Cancers: A Meta-analysis of Randomized Control Trials.

J Pain Symptom Manage 2019 11 15;58(5):899-908.e7. Epub 2019 Jul 15.

Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, Ontario, Canada.

Background: People with metastatic cancers experience poor quality of life (QoL), fatigue, and decreased physical function. Exercise improves these symptoms in the curative setting, but the efficacy and safety of exercise in the metastatic setting is uncertain.

Methods: Prospective, randomized trials of moderate/high-intensity aerobic exercise or resistance training vs. control in patients with advanced/metastatic solid cancers were identified from prior reviews and updated using a search of PubMed. The mean and SD for validated outcome measures (QoL, physical function, and fatigue) were extracted for intervention and control groups at baseline and postintervention. The Mann-Whitney test was used to evaluate the effect of exercise on the pooled change between baseline and postintervention. Safety was evaluated qualitatively.

Results: Sixteen trials were analyzed. Among patients with scores at the mean or 2SD above, exercise was not associated with significant or clinical difference in QoL or fatigue. In patients with baseline scores 2SD below mean, exercise was associated with nonsignificant difference meeting minimal clinical important difference in QoL (-2.8 vs. 4.6, P = 0.28). For function, patients at the mean had nonstatistically significant, but clinically meaningful difference in the six-minute walk test (6-MWT) (14.7 vs. 29.0 m, P = 0.44). In patients 2 SD below the mean, there was a clinically meaningful difference in two patient-reported functional subscales (0.1 vs. 5.3, P = 0.076 and 0.44 vs. 8.5, P = 0.465) and a clinically meaningful improvement in the 6-MWT (-7.5 vs. 27.0 m, P = 0.34), although none of these associations met statistical significance. There were no differences in falls, fractures, or pain.

Discussion: Exercise is associated with clinically meaningful improvements in QoL, function, and 6-MWT in some patients with metastatic cancer. Despite poor reporting of safety, there was no signal of increased harm from exercise in this setting.
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http://dx.doi.org/10.1016/j.jpainsymman.2019.07.005DOI Listing
November 2019

Retrospective Study of High Hemoglobin Levels in 56 Young Adults.

J Hematol 2018 May 10;7(2):43-50. Epub 2018 May 10.

Sherbrooke University Hospital Center, Sherbrooke, QC, Canada.

Background: Erythrocytosis is a frequent request for consultation in the hematologic field. The diagnostic approach is well established in the general population but in a young adult, finding the etiology of erythrocytosis can be a real diagnostic challenge.

Methods: This is an observational retrospective unicentric study made at the Sherbrooke University Hospital Center, over a period of 20 years (1995 - 2015). Every patient aged between 16 and 35 years old with a significant elevation of hemoglobin or hematocrit was included (hemoglobin > 185 g/L and/or hematocrit > 0.52 in men; hemoglobin > 165 g/L and/or hematocrit > 0.48 in women).

Results: Totally, 426 patients met the inclusion criteria (over a total of 113,453 complete blood counts) but only 56 entered the study for investigations. The majority of patients were of male gender, 43% of the patients were obese, 59% were smokers and 38% used excess alcohol or recreational drugs. Twenty-five patients had the diagnosis of absolute erythrocytosis. Seven patients had the diagnosis of relative erythrocytosis and no cause could be identified in 24 patients. No primary erythrocytosis was found in this cohort. Among the 25 patients with secondary erythrocytosis, hypoxia was the most frequent etiology identified. Less than half of the patients in the cohort had long term follow-up. Search for mutation and serum EPO dosage were performed in 17.9% and 23.2% of cases respectively. Seven patients were treated with aspirin and five patients had phlebotomies.

Conclusions: This retrospective study reveals an actual clinical management that is often discordant with the current recommendations and a frequent lack of follow-up after initial investigations. Harmonization of management of erythrocytosis appears to be highly desirable.
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http://dx.doi.org/10.14740/jh375wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155863PMC
May 2018

Preconditioning of stem cells by oxytocin to improve their therapeutic potential.

Endocrinology 2012 Nov 28;153(11):5361-72. Epub 2012 Sep 28.

Centre de Recherche, Department of Medicine, Université de Montréal, Québec, Canada.

Principal limitation of cell therapy is cell loss after transplantation because of the interplay between ischemia, inflammation, and apoptosis. We investigated the mechanism of preconditioning of mesenchymal stem cells (MSCs) with oxytocin (OT), which has been proposed as a novel strategy for enhancing therapeutic potential of these cells in ischemic heart. In this study, we demonstrate that rat MSCs express binding sites for OT receptor and OT receptor transcript and protein as detected by RT-PCR and immunofluorescence, respectively. In response to OT (10(-10) to 10(-6) M) treatment, MSCs respond with rapid calcium mobilization and up-regulation of the protective protein kinase B (PKB or Akt) and phospho-ERK1/2 proteins. In OT-stimulated cells, phospho-Akt accumulates intracellularly close to the mitochondrial marker cytochrome c oxidase subunit 4. Functional analyses reveal the involvement of Akt/ERK1/2 pathways in cell proliferation, migration, and protection against the cytotoxic and apoptotic effects of hypoxia and serum deprivation. In addition, OT preconditioning increases MSC glucose uptake. Genes with angiogenic, antiapoptotic, and cardiac antiremodeling properties, such as heat shock proteins (hsps) HSP27, HSP32, HSP70, vascular endothelial growth factor, thrombospondin, tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, TIMP-3, and matrix metalloproteinase-2, were also up-regulated upon OT exposure. Moreover, coculture with OT-preconditioned MSC reduces apoptosis, as measured using terminal transferase dUTP nick end labeling assay in newborn rat cardiomyocytes exposed to hypoxia and reoxygenation. In conclusion, these results indicate that OT treatment evokes MSC protection through both intrinsic pathways and secretion of cytoprotective factors. Ex vivo cellular treatment with OT represents an attractive strategy aimed to maximize the biological and functional properties of effector cells.
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http://dx.doi.org/10.1210/en.2012-1402DOI Listing
November 2012