Helen J Mackay

University of Toronto, Toronto, Ontario, Canada

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Publications (54)294.5 Total impact

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    ABSTRACT: Ovarian low-grade serous carcinoma (LGSC) has fewer mutations than ovarian high-grade serous carcinoma (HGSC) and a less aggressive clinical course. However, an overwhelming majority of LGSC patients do not respond to conventional chemotherapy resulting in a poor long-term prognosis comparable to women diagnosed with HGSC. KRAS and BRAF mutations are common in LGSC, leading to clinical trials targeting the MAPK pathway. We assessed the stability of targetable somatic mutations over space and/or time in LGSC, with a view to inform stratified treatment strategies and clinical trial design. Eleven LGSC cases with primary and recurrent paired samples were identified (stage IIB-IV). Tumor DNA was isolated from 1-4 formalin-fixed paraffin-embedded tumor blocks from both the primary and recurrence (n = 37 tumor and n = 7 normal samples). Mutational analysis was performed using the Ion Torrent AmpliSeqTM Cancer Panel, with targeted validation using Fluidigm-MiSeq, Sanger sequencing and/or Raindance Raindrop digital PCR. KRAS (3/11), BRAF (2/11) and/or NRAS (1/11) mutations were identified in five unique cases. A novel, non-synonymous mutation in SMAD4 was observed in one case. No somatic mutations were detected in the remaining six cases. In two cases with a single matched primary and recurrent sample, two KRAS hotspot mutations (G12V, G12R) were both stable over time. In three cases with multiple samplings from both the primary and recurrent surgery some mutations (NRAS Q61R, BRAF V600E, SMAD4 R361G) were stable across all samples, while others (KRAS G12V, BRAF G469V) were unstable. Overall, the majority of cases with detectable somatic mutations showed mutational stability over space and time while one of five cases showed both temporal and spatial mutational instability in presumed drivers of disease. Investigation of additional cases is required to confirm whether mutational heterogeneity in a minority of LGSC is a general phenomenon that should be factored into the design of clinical trials and stratified treatment for this patient population.
    BMC Cancer 12/2014; 14(1):982. · 3.32 Impact Factor
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    ABSTRACT: The poly(ADP-ribose) polymerase inhibitor olaparib has shown antitumour activity in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with or without BRCA1 or BRCA2 mutations. The aim of this study was to assess the efficacy and tolerability of olaparib in combination with chemotherapy, followed by olaparib maintenance monotherapy, versus chemotherapy alone in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer. In this randomised, open-label, phase 2 study, adult patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer who had received up to three previous courses of platinum-based chemotherapy and who were progression free for at least 6 months before randomisation received either olaparib (200 mg capsules twice daily, administered orally on days 1-10 of each 21-day cycle) plus paclitaxel (175 mg/m(2), administered intravenously on day 1) and carboplatin (area under the curve [AUC] 4 mg/mL per min, according to the Calvert formula, administered intravenously on day 1), then olaparib monotherapy (400 mg capsules twice daily, given continuously) until progression (the olaparib plus chemotherapy group), or paclitaxel (175 mg/m(2) on day 1) and carboplatin (AUC 6 mg/mL per min on day 1) then no further treatment (the chemotherapy alone group). Randomisation was done by an interactive voice response system, stratified by number of previous platinum-containing regimens received and time to disease progression after the previous platinum regimen. The primary endpoint was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1, analysed by intention to treat. Prespecified exploratory analyses included efficacy by BRCA mutation status, assessed retrospectively. This study is registered with ClinicalTrials.gov, number NCT01081951, and has been completed. Between Feb 12 and July 30, 2010, 173 patients at 43 investigational sites in 12 countries were enrolled into the study, of whom 162 were eligible and were randomly assigned to the two treatment groups (81 to the olaparib plus chemotherapy group and 81 to the chemotherapy alone group). Of these randomised patients, 156 were treated in the combination phase (81 in the olaparib plus chemotherapy group and 75 in the chemotherapy alone group) and 121 continued to the maintenance or no further treatment phase (66 in the olaparib plus chemotherapy group and 55 in the chemotherapy alone group). BRCA mutation status was known for 107 patients (either at baseline or determined retrospectively): 41 (38%) of 107 had a BRCA mutation (20 in the olaparib plus chemotherapy group and 21 in the chemotherapy alone group). Progression-free survival was significantly longer in the olaparib plus chemotherapy group (median 12·2 months [95% CI 9·7-15·0]) than in the chemotherapy alone group (median 9·6 months [95% CI 9·1-9·7) (HR 0·51 [95% CI 0·34-0·77]; p=0·0012), especially in patients with BRCA mutations (HR 0·21 [0·08-0·55]; p=0·0015). In the combination phase, adverse events that were reported at least 10% more frequently with olaparib plus chemotherapy than with chemotherapy alone were alopecia (60 [74%] of 81 vs 44 [59%] of 75), nausea (56 [69%] vs 43 [57%]), neutropenia (40 [49%] vs 29 [39%]), diarrhoea (34 [42%] vs 20 [27%]), headache (27 [33%] vs seven [9%]), peripheral neuropathy (25 [31%] vs 14 [19%]), and dyspepsia (21 [26%] vs 9 [12%]); most were of mild-to-moderate intensity. The most common grade 3 or higher adverse events during the combination phase were neutropenia (in 35 [43%] of 81 patients in the olaparib plus chemotherapy group vs 26 [35%] of 75 in the chemotherapy alone group) and anaemia (seven [9%] vs five [7%]). Serious adverse events were reported in 12 (15%) of 81 patients in the olaparib plus chemotherapy group and 16 of 75 (21%) patients in the chemotherapy alone group. Olaparib plus paclitaxel or carboplatin followed by maintenance monotherapy significantly improved progression-free survival versus paclitaxel plus carboplatin alone, with the greatest clinical benefit in BRCA-mutated patients, and had an acceptable and manageable tolerability profile. AstraZeneca. Copyright © 2014 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 12/2014; · 25.12 Impact Factor
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    ABSTRACT: Objective The phosphatidylinositol-3 kinase/serine-threonine kinase PI3K/AKT pathway is postulated to be central to cancer cell development. Activation of this pathway is believed to promote angiogenesis, protein translation and cell cycle progression. A large percentage of endometrial carcinomas have demonstrated mutations within this regulation pathway which result in constitutional activation. The downstream effector protein mammalian target of rapamycin (mTOR) acts as a critical checkpoint in cancer cell cycling and is a logical target for drug development. The efficacy and tolerability of the oral mTOR inhibitor Ridaforolimus was evaluated in this study. Methods This phase II study evaluated the single agent tolerability and activity of oral ridaforolimus administered at a dose of 40 mg for 5 consecutive days followed by a 2 day break, in women with recurrent or metastatic endometrial carcinoma who had received no chemotherapy in the metastatic setting. Results 31 of 34 patients were evaluable. Three partial responses (8.8%) were observed with response duration ranging between 7.9-26.5 months. An additional 18 patients showed disease stabilisation (52.9%) for a median duration of 6.6 months. Response rates were not affected by previous chemotherapy exposure. No correlation was found between response and mutation status. Conclusion Oral Ridaforolimus was reasonably tolerated and demonstrated modest activity in women with recurrent or metastatic endometrial cancers. Potential synergy between mTOR inhibition, angiogenesis and hormonal pathways warrants ongoing evaluation.
    Gynecologic Oncology 11/2014; · 3.69 Impact Factor
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    ABSTRACT: Background:Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa.Methods:Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival.Results:FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94).Conclusions:FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.British Journal of Cancer advance online publication, 30 October 2014; doi:10.1038/bjc.2014.567 www.bjcancer.com.
    British journal of cancer. 10/2014;
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    ABSTRACT: BACKGROUND Immunohistochemistry (IHC) for mismatch repair protein expression, microsatellite instability (MSI) testing, tumor morphology, and family history were compared to determine which screening strategy is superior in identifying Lynch syndrome (LS) in unselected women with newly diagnosed endometrial cancer (EC) who have undergone universal germline mutation testing.METHODSA prospective cohort study was performed that recruited women with newly diagnosed EC. Participants completed a family history assessment with molecular characterization of EC with IHC and MSI testing and EC assessment for LS-associated morphologic features and underwent universal germline mutation testing for mutations in the mismatch repair pathway. The sensitivity, specificity, and positive and negative predictive values were compared between the screening strategies.RESULTSA total of 118 (65%) of 182 consecutive women with EC participated. Of these, 34 women (29%) had tumors that were IHC deficient and 27 women (23%; N = 117) had tumors that were positive for MSI. Twenty women (17%) met IHC criteria and 16 women (15.2%, N = 105) met family history criteria based on Ontario Ministry of Health Criteria for the genetic assessment for LS. Seven women (5.9%) had a germline mutation: 4 had MLH1 (mutL homolog 1), 2 had MSH6 (mutS homolog 6), and 1 had MSH2 (mutS homolog 2). IHC in women aged <60 years had the best performance characteristics, with a sensitivity of 100%, a specificity of 86.1%, a positive predictive value of 58.3%, and a negative predictive value of 100%. Family history and tumor morphology both had the lowest sensitivity at 71.4%. Overall tumor morphology had the poorest performance, with a specificity of 42.1%.CONCLUSIONS The mutation rate of 5.9% was higher than expected in this unselected cohort of women with EC. The superior screening strategy to identify women presenting with EC is universal IHC screening in women aged <60 years. Cancer 2014. © 2014 American Cancer Society.
    Cancer 07/2014; · 5.20 Impact Factor
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    ABSTRACT: Treatment options remain limited for women with relapsed/metastatic endometrial cancer (EC). Angiogenesis is one of the major components of tumor progression and thus an attractive target. The aim of this phase II trial was to assess the efficacy and tolerability of sunitinib, an oral multitargeted receptor tyrosine-kinase inhibitor with antiangiogenic and antitumor activity in the treatment of recurrent EC.
    Gynecologic Oncology 05/2014; · 3.69 Impact Factor
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    ABSTRACT: Introduction: Endometrial cancer (EC) is the most common gynecological cancer in the developed world. For women with advanced or high-risk disease, survival has remained unchanged over the last 20 years highlighting the need for better therapies. Phase II trials are critical to ascertain an estimate of benefit and determine which new agents undergo further development. Areas covered: Based on a literature search of MEDLINE and ASCO over the last 5 years, the authors present Phase II clinical trial data in the context of EC management. They highlight ongoing clinical trials from the National Cancer Institute website and suggest future directions to address ongoing questions. Expert opinion: A better understanding of EC biology and high-quality preclinical studies will inform the future design of EC Phase II studies. Inclusion of correlative studies and continued longitudinal profiling in future trials is essential to elucidate mechanisms of drug resistance and response. Targeting the phosphoinisotol-3-kinase, angiogenesis, DNA repair and metabolic pathways appear promising strategies for subsets of patients with recurrent or advanced disease. Further, investigation of maintenance strategies and radio-sensitizing agents in the frontline setting should be explored. Given the patient demographic, and frequency of co-morbidities, tolerability and quality of life are key be considerations when designing future studies.
    Expert Opinion on Investigational Drugs 04/2014; · 4.74 Impact Factor
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    ABSTRACT: Invasive cervical cancer remains an important global cause of death, despite the declining prevalence within the United States. Definitive therapies, including surgical resection of early-stage disease and chemoradiation for locally advanced disease, can be curative. For women who experience local or distant recurrences, the prognosis remains poor and better treatments are required. On July 18, 2013, The Gynecologic Oncology Group sponsored a State of the Science in Cervical Cancer Symposium with experts, researchers, clinicians, and interested stakeholders. This article summarize the progress that has been made, questions that require further investigation, and contemporary genomic findings and innovative treatments that may help inform the next generation of clinical trials for patients with cervical cancer. Cancer 2014. © 2014 American Cancer Society.
    Cancer 04/2014; · 5.20 Impact Factor
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    ABSTRACT: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.
    Nature Genetics 03/2014; · 29.65 Impact Factor
  • Clare L Scott, Helen J Mackay, Paul Haluska
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    ABSTRACT: In the era of targeted therapies, patients with gynecologic malignancies have not yet been major beneficiaries of this new class of agents. This may reflect the fact that the main tumor types-ovarian, uterine, and cervical-are a highly heterogeneous group of cancers with variable response to standard chemotherapies and the lack of models in which to study the diversity of these cancers. Cancer-derived cell lines fail to adequately recapitulate molecular hallmarks of specific cancer subsets and complex microenvironments, which may be critical for sensitivity to targeted therapies. Patient-derived xenografts (PDX) generated from fresh human tumor without prior in vitro culture, combined with whole genome expression, gene copy number, and sequencing analyses, could dramatically aid the development of novel therapies for gynecologic malignancies. Gynecologic tumors can be engrafted in immunodeficient mice with a high rate of success and within a reasonable time frame. The resulting PDX accurately recapitulates the patient's tumor with respect to histologic, molecular, and in vivo treatment response characteristics. Orthotopic PDX develop complications relevant to the clinic, such as ascites and bowel obstruction, providing opportunities to understand the biology of these clinical problems. Thus, PDX have great promise for improved understanding of gynecologic malignancies, serve as better models for designing novel therapies and clinical trials, and could underpin individualized, directed therapy for patients from whom such models have been established.
    American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting. 01/2014; 34:e258-66.
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    ABSTRACT: The advances achieved in the surgical management of vulvar squamous cell carcinoma (SCC) have not been mirrored in systemic therapy options. The objective of this paper is to summarize current evidence regarding systemic therapy in vulvar cancer, review the latest research on the biology of this disease, and identify future strategies to improve patient management. MEDLINE and EMBASE were searched for all relevant English-language articles from inception to December 10, 2012. Existing evidence regarding systemic therapy in vulvar SCC was synthesized descriptively, with an emphasis on prospective studies when available. Single-patient case-reports were excluded. We identified 12 studies of neoadjuvant chemoradiation, 8 studies of neoadjuvant chemotherapy alone, 18 studies of chemoradiation as primary therapy, 4 studies of chemotherapy in the adjuvant setting, and 8 studies of chemotherapy for recurrent or metastatic disease. Review of the biology of vulvar cancer was performed, and promising targets for the future were identified based on the two biologic pathways of disease development. New therapeutic strategies such as immune-therapy and targeted agents hold promise for the future. Advances in systemic therapy for vulvar SCC are urgently needed, especially in the setting of recurrent and metastatic disease. A focus on the investigation of new targeted agents is encouraged and consideration of quality of life and sexual health issues is essential. International cooperation and adaptive trial designs are required to improve outcomes for this group of traditionally under-served women.
    Gynecologic Oncology 11/2013; · 3.69 Impact Factor
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    ABSTRACT: Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is of increasing interest as a therapeutic strategy in many tumors. The aim of this study was to identify molecular markers associated with mTOR inhibitor activity in women with metastatic endometrial cancer. Archival tumor samples were collected from 94 women with recurrent or metastatic endometrial cancer who participated in 3 National Cancer Insitute of Canada Clinical Trials Group phase 2 trials investigating single-agent mTOR inhibitors: IND160A and IND160B (temsirolimus) and IND192 (ridaforolimus). Analyses included mutational profiling using the OncoCarta Panel version 1.0 and immunohistochemical expression of the tumor suppressor gene PTEN (phosphatase and tensin homologue) and stathmin, a marker of PI3K activation. Associations between biomarker results and clinical outcomes were assessed. Mutations were found in 32 of 73 analyzed tumors, PIK3CA (21 patients) was the most common mutated gene. Co-mutations were seen in 8 tumors, most frequently KRAS and PIK3CA (4 cases). PTEN loss was observed in 46 of 85 samples analyzed and increased stathmin expression was observed in 15 of 65 analyzed samples. No correlation was observed between biomarkers and response or progression. In patients taking concurrent metformin, there was a trend toward lower progression, of 11.8% versus 32.5% (P = .14). No predictive biomarker or combination of biomarkers for mTOR inhibitor activity were identified in this study. Restriction and enrichment of study entry, especially based on archival tumor tissue, should be undertaken with caution in trials using these agents. Cancer 2013. © 2013 American Cancer Society.
    Cancer 10/2013; · 5.20 Impact Factor
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    ABSTRACT: Uterine adenosarcomas (AS) are rare tumors thought to have a favorable prognosis. The aim of this study was to evaluate clinicopathological characteristics and treatment outcome in women with uterine AS. Patients with uterine AS were identified from the institutional databases at two regional cancer centers, Princess Margaret Hospital, Toronto and Vancouver General Hospital. All cases underwent specialist pathological review and were re-staged according to FIGO criteria (2009). Patient demographics, treatment data and outcomes were evaluated. Between 1984 and 2010, 64 patients with confirmed AS were identified: 30 exhibited sarcomatous overgrowth (AS+SO). 47 patients presented with stage I disease: 27 IA and 18 IB. 57 of the 58 patients with known surgical management underwent hysterectomy: 55 having bilateral salpingo-oophorectomy, 12 having lymph node dissection. 14 patients received adjuvant treatment: 10 radiotherapy, 3 chemotherapy and 1 both. Sixteen of the 45 patients (35.6%) with follow-up recurred; median time to recurrence 21.2months, range 2.1-87.8months. Recurrence was associated with myometrial invasion (p=0.05). Two of the 10 women (20%) with AS+SO receiving adjuvant treatment recurred compared to 9 of the 14 (64%) who did not. One of the 5 women (20%) with stage 1B disease who received adjuvant treatment recurred (20%) compared to 6 of the 7 (85.6%) who did not. Long term surveillance is required given the variable time to recurrence. For those with AS+SO and myometrial invasion adjuvant treatment should be considered and further investigation of adjuvant strategies is warranted.
    Gynecologic Oncology 10/2013; · 3.69 Impact Factor
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    ABSTRACT: Does chemotherapy-that is, gemcitabine, gemcitabine plus docetaxel, doxorubicin, or trabectedin-improve clinical outcomes in women with inoperable, locally advanced, recurrent, or metastatic uterine leiomyosarcoma (lms)? Is there a difference in the tumour response rate to chemotherapy between recurrent pelvic disease and extrapelvic metastases in the target patients? This guideline was developed by Cancer Care Ontario's Program in Evidence-Based Care, the Sarcoma Disease Site Group (dsg), and the Gynecologic Cancer dsg. The core methodology was the systematic review. The medline and embase databases (2004 to June 2011), the Cochrane Library, main guideline Web sites, and relevant annual meeting abstracts (2005-2010) were searched. Internal and external reviews were conducted, with final approval by the dsgs and the Program in Evidence-Based Care. Based on currently available evidence from the medical literature (four single-arm phase ii studies, one arm of a randomized controlled trial, and one abstract), doxorubicin alone, gemcitabine alone, or gemcitabine plus docetaxel may be treatment options in first- or second-line therapy (or both) for women with inoperable, locally advanced, recurrent, or metastatic uterine lms. Hematologic toxicity is common and should be monitored, and granulocyte colony-stimulating factor should be considered when gemcitabine plus docetaxel is used. Other toxicities, such as neurotoxicity, pulmonary toxicity, and cardiovascular toxicity should be monitored. No recommendation is made for or against the use of trabectedin in the targeted patients. No data were available concerning differences in response in recurrent pelvic disease or extrapelvic metastases, or concerning quality of life.
    Current Oncology 10/2013; 20(5):e448-54. · 1.64 Impact Factor
  • Anna Spreafico, Helen J Mackay
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    ABSTRACT: Introduction: The PI3K/AKT/mammalian target of rapamycin (mTOR) pathway plays a critical role in controlling cellular metabolism, proliferation and cell cycle regulation. Constitutive activation of this pathway has been demonstrated in many tumor types. Targeting the PI3K/AKT/mTOR pathway is of increasing therapeutic interest. Areas covered: Ridaforolimus belongs to a class of agents known as the rapalogs, first-generation mTOR inhibitors, which inhibit mTORC1, a part of the mTOR complex. Both oral and intravenous formulations of this agent have been tested in Phase II clinical trials for the treatment of solid tumors and hematologic malignancies. Promising results have been seen in endometrial cancer and soft tissue and bone sarcomas. Expert opinion: This article summarizes the current clinical and biological data on the use of ridaforolimus emerging from these Phase II studies, and provides potential advantages and drawbacks of the mTOR inhibitors in the current clinical practice.
    Expert Opinion on Investigational Drugs 08/2013; · 4.74 Impact Factor
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    ABSTRACT: Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival. 12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed. 2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74). PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer. Carraresi Foundation and others.
    The Lancet Oncology 07/2013; · 25.12 Impact Factor
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    ABSTRACT: OBJECTIVE: HPV infection has been associated with deregulation of the PI3K-Akt-mTOR pathway in invasive cervical carcinomas. This 2-stage phase II study assessed the activity of the mTOR inhibitor, temsirolimus, in patients with measurable metastatic and/or locally advanced, recurrent carcinoma of the cervix. METHODS: Temsirolimus 25 mg i.v. was administered weekly in 4 week cycles. One response amongst the first 18 patients was required to proceed to the second stage of accrual. Correlative molecular studies were performed on archival tumour tissue. RESULTS: Thirty-eight patients were enrolled. Thirty-seven patients were evaluable for toxicity and 33 for response. One patient experienced a partial response (3.0%). Nineteen patients had stable disease (57.6%) [median duration 6.5 months (range 2.4-12.0 mo)]. The 6-month progression free survival rate was 28% (95% CI: 14-43%). The median progression free survival was 3.52 months [95% CI (1.81-4.70)]. Adverse effects were mild-moderate in most cases and similar to other temsirolimus studies. No toxicity > grade 3 was observed. Assessment of PTEN and PIK3CA by IHC, copy number analyses and PTEN promoter methylation status did not reveal subsets associated with disease stability. CONCLUSION: Single agent temsirolimus has modest activity in cervical carcinoma with about two-thirds of patients exhibiting stable disease. Molecular markers for treatment benefit remain to be identified.
    Gynecologic Oncology 05/2013; · 3.69 Impact Factor
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    ABSTRACT: Very late recurrence of gastric cancer is rare. Here, we report a dramatic recurrence of gastric cancer, with isolated skeletal metastasis and bone marrow carcinomatosis, 22 years after the patient's initial presentation. Gastric cancer recurrence involving bone or bone marrow is also uncommon and associated with poor prognosis. Pathology from a bone marrow biopsy showed signet ring cell morphology. The patient in this case demonstrated a surprising response-lasting 11 months-to palliative chemotherapy with cisplatin and capecitabine. This case report and literature review describes the characteristics of late gastric cancer recurrence and an approach to the diagnosis and management of patients with bone metastasis or bone marrow carcinomatosis.
    Current Oncology 04/2013; 20(2):e161-4. · 1.64 Impact Factor
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    ABSTRACT: The goal of this systematic review was to investigate and compare the treatment effects of systemic chemotherapy (i.e. doxorubicin, gemcitabine, gemcitabine plus docetaxel, or trabectedin) in women with inoperable, locally advanced, recurrent, or metastatic uterine leiomyosarcoma. A 2005 systematic review (searching the literature from 1980 to June 2004) on systemic therapy in advanced uterine sarcoma was used as the basis for this updated review. MEDLINE and EMBASE (from January 2004 to June 2011), the Cochrane Library, some main guideline websites and the American Society of Clinical Oncology and the Connective Tissue Oncology Society annual meeting abstracts were searched. One arm from a randomised controlled trial (RCT), four single-arm phase II trials and one abstract were included in this systematic review. The studies of gemcitabine plus docetaxel have reported numerically longer median overall survival (14.7-17.9 months versus 12.1 months) and numerically higher objective response rates (27-53% versus 25%) than those reported in the study of doxorubicin alone. The combination of gemcitabine plus docetaxel resulted in more toxicity than doxorubicin alone. The available study for single-agent gemcitabine reported a tumour response rate of 21%, which is not superior to the 25% response rate with doxorubicin alone. One abstract (pooling data from two RCTs) failed to show the superiority of gemcitabine plus docetaxel over gemcitabine alone for tumour response rate (23% versus 18%) and progression-free survival (6 versus 4.9 months). To date, there is insufficient evidence to support or refute the use of trabectedin in the target patients. Doxorubicin, gemcitabine, and gemcitabine plus docetaxel are treatment options in women with inoperable, locally advanced, recurrent, or metastatic uterine leiomyosarcoma as first- or second-line therapy. Well-designed and good-quality RCTs are required to investigate the efficacy of chemotherapy and quality of life in target patients with uterine leiomyosarcoma.
    Clinical Oncology 01/2013; · 2.83 Impact Factor
  • European journal of cancer (Oxford, England: 1990) 12/2012; · 4.12 Impact Factor

Publication Stats

709 Citations
294.50 Total Impact Points


  • 2008–2014
    • University of Toronto
      • Department of Obstetrics and Gynaecology
      Toronto, Ontario, Canada
  • 2005–2014
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2013
    • BC Cancer Agency
      Vancouver, British Columbia, Canada
  • 2011–2013
    • University Health Network
      • • Princess Margaret Hospital
      • • Radiation Medicine Program
      Toronto, Ontario, Canada
  • 2012
    • Harvard Medical School
      Boston, Massachusetts, United States