Josée-Lyne Ethier

Sunnybrook Health Science Centre

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Eitan Amir

University of Toronto

Amit M. Oza

Princess Margaret Cancer Centre

Alberto Ocaña

Centro de Investigación Biomédica en Red de Cáncer

Stéphanie Lheureux

Princess Margaret Cancer Centre

BŠ

Boštjan Šeruga

Institute of Oncology Ljubljana

Helen Mackay

Sunnybrook Health Science Centre

Neesha C. Dhani

Princess Margaret Cancer Centre

Arnoud J. Templeton

St. Claraspital

Amirrtha Srikanthan

Ottawa Hospital

Blaise Clarke

University Health Network

Cooperative Institutions

Princess Margaret Cancer Centre

University of Toronto

University Health Network

Queen's University

GEICAM – Spanish Breast Cancer Group

Memorial Sloan Kettering Cancer Center

The University of Texas MD Anderson Cancer Center

Gynecologic Oncology Group

Dana-Farber Cancer Institute

Centro de Investigación Biomédica en Red de Cáncer

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Cardiovascular Toxicity of Multi-Tyrosine Kinase Inhibitors in Advanced Solid Tumors: A Population-Based Observational Study

PLoS ONE (2015)

Amirrtha Srikanthan Josée-Lyne Ethier Alberto Ocaña Boštjan Šeruga Monika K. Krzyzanowska

Background Treatment with small molecule tyrosine kinase inhibitors (TKIs) has improved survival in many cancers, yet has been associated with an increased risk of adverse events. Warnings of cardiovascular events are common in drug labels of many TKIs. Despite these warnings, cardiovascular toxicity of patients treated with TKIs remains unclear. Here, we evaluate the cardiovascular outcomes of advanced cancer patients treated with small molecule tyrosine kinase inhibitors. Methods A population based cohort study was undertaken involving adults aged >18 years in Ontario, Canada, diagnosed with any advanced malignancy between 2006 and 2012. Data were extracted from linked administrative governmental databases. Adults with advanced cancer receiving TKIs were identified and followed throughout the time period. The main outcomes of interest were rates of hospitalization for ischemic heart disease (acute myocardial infarction and angina) or cerebrovascular accidents and death. Results 1642 patients with a mean age of 62.5 years were studied; 1046 were treated with erlotinib, 166 with sorafenib and 430 with sunitinib. Over the 380 day median follow-up period (range 6-1970 days), 1.1% of all patients had ischemic heart events, 0.7% had cerebrovascular accidents and 72.1% died. Rates of cardiovascular events were similar to age and gender-matched individuals without cancer. In a subgroup analysis of treatment patients with a prior history of ischemic heart disease, 3.3% had ischemic heart events while 1.2% had cerebrovascular accidents. Conclusions TKIs do not appear to increase the cause-specific hazard of ischemic heart disease and cerebrovascular accidents compared to age and gender-matched individuals without advanced cancer.

Stroke

10.1371/journal.pone.0122735

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Citations (17)

Clinical outcome and biomarker assessments of a multi-centre phase II trial assessing niraparib with or without dostarlimab in recurrent endometrial carcinoma

Nature Communications (2023)

Ainhoa Madariaga Swati Garg Nairi Tchrakian Neesha C. Dhani Waldo Jiménez

Abstract This multi-centre, non-randomized, open-label, phase II trial (NCT03016338), assessed niraparib monotherapy (cohort 1, C1), or niraparib and dostarlimab (cohort 2, C2) in patients with recurrent serous or endometrioid endometrial carcinoma. The primary endpoint was clinical benefit rate (CBR), with ≥5/22 overall considered of interest. Secondary outcomes were safety, objective response rate (ORR), duration of response, progression free survival and overall survival. Translational research was an exploratory outcome. Potential biomarkers were evaluated in archival tissue by immunohistochemistry and next generation sequencing panel. In C1, 25 patients were enrolled, and CBR was 20% (95% CI: 9–39) with median clinical benefit duration of 5.3 months. The ORR was 4% (95% CI: 0–20). In C2, 22 patients were enrolled, and the CBR was 31.8% (95% CI: 16–53) with median clinical benefit duration of 6.8 months. The ORR was 14% (95% CI: 3–35). No new safety signals were detected. No significant association was detected between clinical benefit and IHC markers (PTEN, p53, MMR, PD-L1), or molecular profiling ( PTEN , TP53 , homologous recombination repair genes). In conclusion, niraparib monotherapy did not meet the efficacy threshold. Niraparib in combination with dostarlimab showed modest activity.

Clinical endpoint

10.1038/s41467-023-37084-w

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Study Design Solutions for Adjuvant and Maintenance Therapy in Cancer: Ovarian Cancer as an Example

SN Comprehensive Clinical Medicine (2022)

Xiaomei Yao Raymond Poon Laurie Elit Josée-Lyne Ethier Sarah E. Ferguson

Guideline

Soundness

Maintenance therapy

Adjuvant Therapy

Research Design

10.1007/s42399-022-01265-3

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A phase Ib trial of pembrolizumab (Pembro) following adoptive cell therapy (ACT) in patients with platinum-resistant ovarian cancer; The ACTIVATE (Adoptive Cell Therapy InVigorated to Augment Tumor Eradication) trial.

Journal of Clinical Oncology (2018)

Josée-Lyne Ethier Luisa Bonilla Sarah Boross-Harmer Geneviève Bouchard‐Fortier Jane Cipollone

TPS5611 Background: ACT is based on the in vitro expansion of T cells with anti-tumor activity, followed by transfer of large numbers of T cells back to the patient. T cells for ACT can be obtained from tumor-infiltrating lymphocytes (TILs), which represent a source of tumor-specific T cells. Evidence supports that epithelial ovarian carcinoma (OC) is immunogenic and has the potential to respond to immunotherapy. Pembro, a PD-1 monoclonal antibody, was shown to have activity in metastatic ovarian cancer with a response rate of 11.5% (Varga, ASCO 2015;33:5510). There is limited data regarding the efficacy of combining ACT with PD-1/PD-L1 inhibitors. However, ACT may synergize with checkpoint inhibitors to overcome immunosuppression within the tumor microenvironment, and dramatic clinical responses have been observed anecdotally. Based on these observations, a Phase 1b study of ACT followed by Pembro in advanced OC was initiated. Methods: This is a single-centre, non-randomized trial of Pembro following ACT using TILs in platinum-resistant OC. Key inclusion criteria include progression within 6 months of last platinum dose and tumor suitable for harvest. Patients undergo preparative lymphodepleting chemotherapy, followed by a single TIL infusion. Therapy with Pembro 200 mg q3 weeks is initiated once toxicities grade 2 or higher have resolved. The primary objective is safety, and the regimen will be deemed feasible if at least 80% of enrolled patients receive ACT with TILs and ≥2 doses of Pembro without unacceptable toxicity. Secondary objectives include evaluation of response rate, overall and progression free survival. The study will enroll 12 patients to determine whether the proportion of patients in whom the treatment regimen is tolerable, P, is less than or equal to 0.50 or is greater than or equal to 0.80. If the number of patients for whom treatment is feasible is 8 or more, the hypothesis that P ≤ 0.50 is rejected with a target error rate of 0.20. Enrollment is currently ongoing, with TIL preparation underway for 10 patients and plan to initiate treatment in 3 of these over the next 3 months. Clinical trial information: NCT03158935.

Tumor-infiltrating lymphocytes

Adoptive Cell Transfer

10.1200/jco.2018.36.15_suppl.tps5611

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Neoadjuvant and adjuvant systemic therapy for newly diagnosed stage II- IV epithelial ovary, fallopian tube, or primary peritoneal carcinoma: A systematic review

Critical Reviews in Oncology/Hematology (2021)

Hal W. Hirte Raymond Poon Xiaomei Yao Taymaa May Josée-Lyne Ethier

Fallopian tube

Adjuvant Therapy

10.1016/j.critrevonc.2021.103324

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How to optimize and evaluate diversity in gynecologic cancer clinical trials: statements from the GCIG Barcelona Meeting

International Journal of Gynecological Cancer (2024)

Jalid Sehouli Jolijn Boer Alison H. Brand Amit M Oza Jennifer O’Donnell

Findings from clinical trials have led to advancement of care for patients with gynecologic malignancies. However, restrictive inclusion of patients into trials has been widely criticized for inadequate representation of the real-world population. Ideally, patients enrolled in clinical trials should represent a broader population to enhance external validity and facilitate translation of outcomes across all relevant groups. Specifically, there has been a systematic lack of data for underrepresented groups, with many studies failing to report or differentiate study participants based on sociodemographic domains, such as race and ethnicity. As such, the impact of treatment in these underrepresented groups is poorly understood, and clinical outcomes according to various sociodemographic factors are infrequently assessed. Inclusion of diverse trial participants, with different racial and ethnic background, is essential for the understanding of factors that may impact clinical outcomes. Therefore, we conducted a multi-national meeting of clinical trial groups and industry with the goal of increasing equity, diversity, and inclusion in gynecologic cancer clinical trials and to address barriers to recruitment, participation, and harmonization of data collection and reporting. These Gynecologic Cancer Intergroup (GCIG) statements present recommendations and strategies for the gynecologic cancer research community to improve equity, diversity, and inclusion in gynecologic cancer clinical trials.

Gynecologic cancer

10.1136/ijgc-2024-005982

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Author Financial Conflicts of Interest, Industry Funding, and Clinical Practice Guidelines for Anticancer Drugs

Journal of Clinical Oncology (2014)

Ariadna Tibau Philippe L. Bédard Amirrtha Srikanthan Josée-Lyne Ethier Francisco Vera-Badillo

Purpose Clinical practice guidelines (CPGs) and consensus statements (CSs) are used to apply evidence-based medicine or expert recommendations to clinical practice. Here we explore author financial conflicts of interest (FCOIs), sources of guideline funding, and their relationship with endorsement of specific drugs. Methods An electronic search of MEDLINE was conducted to identify CPGs and CSs for common solid cancers published between January 2003 and October 2013. The search was restricted to articles evaluating systemic therapy. We extracted data on self-reported author FCOIs, funding sources, use of manuscript writers, and endorsement of specific drugs in the abstract of the article. Results Of 142 articles evaluated, 64% were CPGs, and 36% were CSs. The proportion of articles reporting FCOIs improved from 11% in 2003 to 93% in 2013 (P for trend < .001). Only 45% of articles explicitly reported funding sources. Of these, 65% disclosed partial or full industry sponsorship. Use of manuscript writers was declared in 13%, but many articles did not explicitly report the role of authors in the writing of the manuscript. Endorsement of specific drugs was significantly associated with author FCOIs (odds ratio [OR], 7.29; P = .001), but not with industry funding (OR, 0.95; P = .37). Conclusion Reporting of FCOIs in CPGs and CSs has improved over time. Despite prevalent funding of guideline development by industry, such funding is not associated with endorsement of specific drugs. Author FCOIs are prevalent, and endorsement of a specific drug seems to be more common when authors have FCOIs with the pharmaceutical company marketing that drug.

Guideline

Clinical Practice

Odds

10.1200/jco.2014.57.8898

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Citations (53)

Influence of companion diagnostics on efficacy and safety of targeted anti-cancer drugs: systematic review and meta-analyses

Oncotarget (2015)

Alberto Ocaña Josée-Lyne Ethier Laura Díez-González Verónica Corrales‐Sánchez Amirrtha Srikanthan

// Alberto Ocana 1 , Josee-Lyne Ethier 2 , Laura Díez-González 1 , Verónica Corrales-Sánchez 1 , Amirrtha Srikanthan 2 , María J. Gascón-Escribano 1 , Arnoud J. Templeton 3 , Francisco Vera-Badillo 2 , Bostjan Seruga 4 , Saroj Niraula 5 , Atanasio Pandiella 6 and Eitan Amir 2 ¹ Medical Oncology Department, Albacete University Hospital and Translational Research Unit, Albacete, Spain ² Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre and the Department of Medicine, University of Toronto, Toronto, Canada 3 Department of Medical Oncology and Hematology, Kantonsspital St. Gallen, Switzerland 4 Department of Medical Oncology, Institute of Oncology, Ljubljana, Slovenia 5 Department of Medical Oncology and Hematology, CancerCare Manitoba and University of Manitoba, Winnipeg, Canada 6 Centro de Investigación del Cáncer CIC-CSIC, Universidad de Salamanca, Salamanca, Spain Correspondence to: Alberto Ocana, email: // Keywords : cancer drugs, companion diagnostics, efficacy, trial design Received : August 01, 2015 Accepted : September 06, 2015 Published : October 04, 2015 Abstract Background: Companion diagnostics aim to identify patients that will respond to targeted therapies, therefore increasing the clinical efficacy of such drugs. Less is known about their influence on safety and tolerability of targeted anti-cancer agents. Methods and findings: Randomized trials evaluating targeted agents for solid tumors approved by the US Food and Drug Administration since year 2000 were assessed. Odds ratios (OR) and and 95% confidence intervals (CI) were computed for treatment-related death, treatment-discontinuation related to toxicity and occurrence of any grade 3/4 adverse events (AEs). The 12 most commonly reported individual AEs were also explored. ORs were pooled in a meta-analysis. Analysis comprised 41 trials evaluating 28 targeted agents. Seventeen trials (41%) utilized companion diagnostics. Compared to control groups, targeted drugs in experimental arms were associated with increased odds of treatment discontinuation, grade 3/4 AEs, and toxic death irrespective of whether they utilized companion diagnostics or not. Compared to drugs without available companion diagnostics, agents with companion diagnostics had a lower magnitude of increased odds of treatment discontinuation (OR = 1.12 versus 1.65, p < 0.001) and grade 3/4 AEs (OR = 1.09 versus 2.10, p < 0.001), but no difference in risk of toxic death (OR = 1.40 versus 1.27, p = 0.69). Differences between agents with and without companion diagnostics were greatest for diarrhea (OR = 1.29 vs . 2.43, p < 0.001), vomiting (OR = 0.86 vs . 1.44, p = 0.005), cutaneous toxicity (OR = 1.82 vs . 3.88, p < 0.001) and neuropathy (OR = 0.64 vs . 1.60, p < 0.001). Conclusions: Targeted drugs with companion diagnostics are associated with improved safety, and tolerability. Differences were most marked for gastrointestinal, cutaneous and neurological toxicity.

10.18632/oncotarget.5946

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Citations (29)

Hyperglycemia and survival in solid tumors: A systematic review and meta-analysis.

Journal of Clinical Oncology (2017)

Reeta Barua Arnoud J. Templeton Boštjan Šeruga Alberto Ocaña Eitan Amir

e18158 Background: Diabetes is associated with adverse cancer outcomes. However, the effect of hyperglycemia independent of diabetes is unclear. Here we report on a meta-analysis exploring the effect of hyperglycemia on outcomes of solid tumors, and the influence of clinical factors on this association. Methods: A systematic search of electronic databases identified publications exploring the effect of hyperglycemia on overall (OS), disease-free (DFS) or progression-free survival (PFS). Definitions of hyperglycemia (fasting blood glucose, random blood glucose or HbA1c) and cut-offs varied between studies. Data from studies reporting a hazard ratio (HR) and 95% confidence interval (CI) or a p -value were pooled in a meta-analysis using generic inverse-variance and random effects modeling. Subgroup analyses were conducted based on method of hyperglycemia measurement (HbA1c, other) and tumor stage (early, advanced, mixed). Meta-regression was performed to evaluate the influence of clinical characteristics including baseline diabetes status on the HR for OS. All statistical tests were two-sided. Results: Eight studies comprising a total of 4342 patients were included. All studies reported HRs for OS. Two studies reported DFS outcomes, and two reported PFS. Hyperglycemia was associated with worse OS (HR 2.07, 95% CI = 1.70 - 2.52; P < 0.001) and DFS (HR 1.61, 95% CI = 1.04 - 2.49; P < 0.001), but did not decrease PFS (HR 1.08, 95% CI = 0.72 - 1.62; P = 0.71). The association with worse OS maintained in subgroups based on method of hyperglycemia measurement (subgroup difference P = 0.65) and tumor stage ( P= 0.47). Meta-regression analyses did not identify any factors significantly altering the magnitude of association between hyperglycemia and OS (see Table). Conclusions: Hyperglycemia is associated with adverse OS and DFS in patients with cancer, and the therapeutic role of optimal glycemic control warrants further investigation. [Table: see text]

Subgroup analysis

10.1200/jco.2017.35.15_suppl.e18158

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A systematic review and quality appraisal of international guidelines for early breast cancer systemic therapy: Are recommendations sensitive to different global resources?

The Breast (2015)

Sonal Gandhi Sunil Verma Josée-Lyne Ethier Christine Simmons Heather Burnett

The breast cancer incidence in low and middle income countries (LMCs) is increasing globally, and patient outcomes are generally worse in these nations compared to high income countries (HICs). This is partly due to resource constraints associated with implementing recommended breast cancer therapies. Clinical practice guideline (CPG) adherence can improve breast cancer outcomes, however, many CPGs are created in HICs, and include costly recommendations that may not be feasible in LMCs. In addition, the quality of CPGs can be variable. The aim of this study was to perform a systematic review of CPGs on early breast cancer systemic therapy with potential international impact, to evaluate their content, quality, and resource sensitivity. A MEDLINE and gray literature search was completed for English language CPGs published between 2005 and 2010, and then updated to July 2014. Extracted guidelines were evaluated using the AGREE 2 instrument. Guidelines were specifically analyzed for resource sensitivity. Most of the extracted CPGs had similar recommendations with regards to systemic therapy. However, only one, the Breast Health Global Initiative, made recommendations with consideration of different global resources. Overall, the CPGs were of variable quality, and most scored poorly in the quality domain evaluating implementation barriers such as resources. Published CPGs for early breast cancer are created in HICs, have similar recommendations, and are generally resource-insensitive. Given the visibility and influence of these CPGs on LMCs, efforts to create higher quality, resource-sensitive guidelines with less redundancy are needed.

Guideline

Critical appraisal

10.1016/j.breast.2014.12.005

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Citations (7)