Helen J Mackay

University of Toronto, Toronto, Ontario, Canada

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Publications (74)394.63 Total impact

  • International journal of radiation oncology, biology, physics 09/2015; DOI:10.1016/j.ijrobp.2015.09.009 · 4.26 Impact Factor
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    ABSTRACT: Adjuvant therapy increases disease-free survival in endometrial cancer (EC), but has no impact on overall survival and negatively influences the quality of life. We investigated the discriminatory power of classical and immunological predictors of recurrence in a cohort of EC patients and confirmed the findings in an independent validation cohort. We reanalysed the data from 355 EC patients and tested our findings in an independent validation cohort of 72 patients with EC. Predictors were selected and Harrell's C-index for concordance was used to determine discriminatory power for disease-free survival in the total group and stratified for histological subtype. Predictors for recurrence were FIGO stage, lymphovascular space invasion and numbers of cytotoxic and memory T-cells. For high risk cancer, cytotoxic or memory T-cells predicted recurrence as well as a combination of FIGO stage and lymphovascular space invasion (C-index 0.67 and 0.71 vs 0.70). Recurrence was best predicted when FIGO stage, lymphovascular space invasion and numbers of cytotoxic cells were used in combination (C-index 0.82). Findings were confirmed in the validation cohort. In high-risk EC, clinicopathological or immunological variables can predict regional or distant recurrence with equal accuracy, but the use of these variables in combination is more powerful.British Journal of Cancer advance online publication, 28 July 2015; doi:10.1038/bjc.2015.268 www.bjcancer.com.
    British Journal of Cancer 07/2015; 113(5). DOI:10.1038/bjc.2015.268 · 4.84 Impact Factor
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    ABSTRACT: Background: In lung cancer, the MAPK pathway is activated mainly by KRAS and EGFR1 mutations in smokers and non-smokers, respectively. It is relatively unknown how smoking affects MAPK and PI3K pathways across multiple cancers. Methods: Mutation and smoking status were available from 854 solid tumor patients whose tumors were profiled by NGS with Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons) in the Princess Margaret Cancer Centre Integrated Molecular Profiling in Advanced Cancer Trial (IMPACT). The panel included hotspot exons of EGFR1, EGFR2, KRAS, NRAS, BRAF, PIK3CA, PTEN and AKT1. Mutation frequencies between smokers and non-smokers (never smoker + former light smoker [<5pack year]) were compared using Chi-Square test or Fisher’s exact test. Results: Lung cancers (N=101) from smokers contained more KRAS mutations (38% vs.12%, P=0.004) while those from non-smokers had more EGFR1 mutations (34% vs. 10%, P=0.003). In contrast, non-lung cancers (N=753) had no difference in KRAS mutation frequencies between smokers and non-smokers (19% vs.17%, P=0.47). Too few EGFR1 and NRAS mutations were found in this cohort for meaningful analysis. Across the cohorts, there was no difference in BRAF, PIK3CA, or PTEN mutation frequency between smokers and non-smokers (BRAF, 5% vs. 4.5%, P=0.6; PIK3CA, 14% vs.15%, P=0.8; PTEN, 4.5% vs. 3.6%, P=0.6). Five non-lung cancers (4 non-smokers, 1 smoker) had AKT1 mutations. All nine cases with EGFR2 mutations (2 lung and 7 non-lung cancers) were non-smokers. No difference in KRAS, BRAF, PIK3CA and PTEN mutation frequencies between smokers and non-smokers was observed within specific cancers; breast, cervix, colorectal, endometrium, ovarian, pancreatobiliary and upper aerodigestive (P values>0.05, N= 107, 36, 126, 55, 167, 70, 81 respectively). Conclusions: Our data suggest that, with the exception of lung cancer, there is no difference in frequencies of hotspot mutations in critical genes encoding MAPK and PI3K pathways members between smokers and non-smokers across multiple cancers analysed. EGFR2 hotspot mutations (N=9) were exclusively found in non-smokers.
    AACR Precision Medicine Series Integrating Clinical Genomics and Cancer Therapy, Salt Lake City, UT; 06/2015
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    ABSTRACT: Polymorphisms in the VEGF/angiogenesis pathway have been previously implicated in cancer risk, prognosis, and response to therapy including in esophageal adenocarcinoma. Prior esophageal adenocarcinoma studies focused on using candidate polymorphisms, limiting the discovery of novel polymorphisms. Here, we applied the tagSNP approach to identify new VEGF-pathway polymorphisms associated with esophageal adenocarcinoma prognosis and validated them in an independent cohort of esophageal adenocarcinoma patients. In 231 esophageal adenocarcinoma patients of all stages/treatment plans, 58 genetic polymorphisms (18 KDR, 7 VEGFA, 33 FLT1), selected through tagging and assessment of predicted function were genotyped. Cox-proportional hazard models adjusted for important socio-demographic and clinico-pathological factors were applied to assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then validated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis, and median OS and PFS were 20 and 12 months respectively. KDR rs17709898 was found significantly associated with PFS (adjusted hazard ratio,aHR=0.69, 95%CI:0.53-0.90;P=5.2E-3). FLT1 rs3794405 and rs678714 were significantly associated with OS (aHR=1.44, 95%CI:1.04-1.99;P=0.03 and aHR=1.50, 95%CI:1.01- 2.24;P=0.04, respectively). No VEGFA polymorphisms were found significantly associated with either outcome. Upon validation, FLT1 rs3794405 remained strongly associated with OS (aHR=1.59, 95%CI:1.04-2.44;P=0.03). FLT1 rs3794405 is significantly associated with OS in esophageal adenocarcinoma; whereby each variant allele confers a 45-60% increased risk in mortality. Validation and evaluation of this association in other cancer sites is warranted.
    Carcinogenesis 05/2015; 36(9). DOI:10.1093/carcin/bgv073 · 5.33 Impact Factor
  • Helen J Mackay · Lari Wenzel · Linda Mileshkin
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    ABSTRACT: Despite the declining incidence of cervical cancer as a result of the introduction of screening programs, globally it remains a leading cause of cancer-related death in women. Outcomes for patients who are diagnosed with anything but early-stage disease remain poor. Here we examine emerging strategies to improve the treatment of locally advanced disease. We discuss emerging biologic data, which are informing our investigation of new therapeutic interventions in persistent, recurrent, and metastatic cervical cancer. We recognize the importance of interventions to improve quality of life and to prevent long-term sequelae in women undergoing treatment. Finally, and perhaps most importantly, we recognize the need for global collaboration and advocacy to improve the outcome for all women at risk of and diagnosed with this disease.
    05/2015; 35:e299-309. DOI:10.14694/EdBook_AM.2015.35.e299
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    ABSTRACT: Optimal management of women with early stage GCT presents a management conundrum - they have excellent prognosis but a third will relapse. Advances uncovering the molecular characteristics of GCTs have not been matched by improvements in our understanding and treatment. Stage I GCT patients referred to Auckland City Hospital (1955-2012) and Princess Margaret Cancer Centre (1992-2012) were identified. Baseline characteristics, histopathology and outcomes were recorded retrospectively. One hundred and sixty stage I GCT patients were identified with median age of 49 years. Median follow-up was 7.0 years (range 0.1-44.2 years). Fifty-one patients (32%) relapsed with a median time to relapse (TTR) of 12.0 years (1.3-17.7 years) - 20 initial relapses occurred 10 years post-diagnosis. Higher relapse rates (43% vs. 24% p=0.02) and shorter TTR (10.2 vs. 16.2 years p=0.007) were seen with stage Ic versus stage Ia disease. Cyst rupture was associated with increased relapse (p=0.03). Surgery was the main therapeutic modality at relapse. Eighty six percent of patients received non-surgical management at least once post-relapse. Clinical benefit rate was 43% with chemotherapy, 61% with hormonal therapy and 86% with radiation. Five- and 10-year overall survival (OS) were 98.5 and 91.6%, respectively. Median OS was similar in patients with (24.3 years) and without relapse (22.3 years). Surgery remains fundamental at diagnosis and relapse. Caution should be exercised in recommending adjuvant chemotherapy at initial diagnosis given OS was greater than 20 years even with relapse. Hormonal therapy at relapse appears encouraging but needs further assessment. Novel treatment strategies need exploration with international collaboration essential for this. Copyright © 2015. Published by Elsevier Inc.
    Gynecologic Oncology 05/2015; 138(2). DOI:10.1016/j.ygyno.2015.05.011 · 3.77 Impact Factor
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    ABSTRACT: A phase II study was performed to evaluate the efficacy and safety of single-agent RO4929097 (a gamma-secretase inhibitor) in patients with recurrent platinum-resistant ovarian cancer. Women with progressive platinum-resistant ovarian cancer treated with ≤ 2 chemotherapy regimens for recurrent disease were enrolled in this trial. Patients received oral RO4929097 at 20 mg once daily, 3 days on/4 days off each week of a three week cycle. The primary endpoint was progression-free survival (PFS) rate at the end of 4 cycles. Secondary objectives included assessment of the safety of RO4929097 and exploration of molecular correlates of outcome in archival tumour tissue and serum. Of 45 patients enrolled, 40 were evaluable for response. Thirty-seven (82%) patients had high-grade ovarian cancer. No objective responses were observed. Fifteen patients (33%) had stable disease as their best response,with a median duration of 3.1 months. Median PFS for the whole group was 1.3 months (1.2-2.5). Treatment was generally well tolerated with 10% of patients discontinuing treatment due to an adverse event. In high grade serous ovarian cancer patients, the median PFS trended higher when the expression of intracellular Notch (NICD) protein by immunohistochemistry was high versus low (3.3 versus 1.3 months p=0.09). No clear relationship between circulating angiogenic factors and PFS was found despite a suggestion of an improved outcome with higher baseline VEGFA levels. RO4929097 has insufficient activity as a single-agent in platinum-resistant ovarian cancer to warrant further study as monotherapy. Future studies are needed to explore the potential for cohort enrichment using NICD expression. Copyright © 2015. Published by Elsevier Inc.
    Gynecologic Oncology 03/2015; 137(2). DOI:10.1016/j.ygyno.2015.03.005 · 3.77 Impact Factor
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    ABSTRACT: Objectives Surgery remains the primary therapy for locally advanced gastric cancer, but locoregional recurrence (LRR) has been documented in up to 68.6 % of patients with surgery alone. Peri- or post-operative adjuvant treatment improves survival. The objective of this study is to examine rates and patterns of recurrence following resection and adjuvant chemoradiation. Methods We reviewed consecutive patients undergoing adjuvant chemoradiation (45 Gy/25 with 5-FU-based chemotherapy) for resected gastric adenocarcinoma (Stages Ib-IV) at the Princess Margaret Cancer Centre between January 1, 2000, and November 30, 2009. Site of first disease recurrence, overall survival (OS) and relapse-free rates (RFR) was determined. Results Among 197 patients identified, median age was 58.4 (range 21.6-79.5) years and median follow-up 28.7 (range 4.0-99.4) months. The majority were male (62.9 %), with stage II (33.0 %) or III (39.6 %) disease. Three-year OS and RFR were 66.7 and 57.7 % respectively; 71 patients relapsed. Isolated LRR was seen in 14 (7.1 %), while 48 (24.4 %) had isolated distant and 9 (4.6 %) had both LRR and distant relapses. In multivariate analysis, only T-category is a significant predictor for RFR (p = 0.009), whilst age (p = 0.03), T-category (p = 0.001), N-category (p = 0.02) and type of surgery (p = 0.046) were significant predictors for OS. Conclusions Isolated LRR in this study was uncommon. The predominant pattern was distant failure. This is in keeping with other studies that have observed lower rates of LRR with adjuvant chemoradiation after curative resection of gastric cancer.
    03/2015; 4(1):79-85. DOI:10.1007/s13566-015-0183-x
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    ABSTRACT: This study aimed to investigate whether molecular analysis can be used to refine risk assessment, direct adjuvant therapy, and identify actionable alterations in high-risk endometrial cancer. TransPORTEC, an international consortium related to the PORTEC3 trial, was established for translational research in high-risk endometrial cancer. In this explorative study, routine molecular analyses were used to detect prognostic subgroups: p53 immunohistochemistry, microsatellite instability and POLE proofreading mutation. Furthermore, DNA was analyzed for hotspot mutations in 13 additional genes (BRAF, CDKNA2, CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, and PTEN) and protein expression of ER, PR, PTEN, and ARID1a was analyzed. Rates of distant metastasis, recurrence-free, and overall survival were calculated using the Kaplan-Meier method and log-rank test. In total, samples of 116 high-risk endometrial cancer patients were included: 86 endometrioid; 12 serous; and 18 clear cell. For endometrioid, serous, and clear cell cancers, 5-year recurrence-free survival rates were 68%, 27%, and 50% (P=0.014) and distant metastasis rates 23%, 64%, and 50% (P=0.001), respectively. Four prognostic subgroups were identified: (1) a group of p53-mutant tumors; (2) microsatellite instable tumors; (3) POLE proofreading-mutant tumors; and (4) a group with no specific molecular profile (NSMP). In group 3 (POLE-mutant; n=14) and group 2 (microsatellite instable; n=19) patients, no distant metastasis occurred, compared with 50% distant metastasis rate in group 1 (p53-mutant; n=36) and 39% in group 4 (NSMP; P<0.001). Five-year recurrence-free survival was 93% and 95% for group 3 (POLE-mutant) and group 2 (microsatellite instable) vs 42% (group 1, p53-mutant) and 52% (group 4, NSMP; P<0.001). Targetable FBXW7 and FGFR2 mutations (6%), alterations in the PI3K-AKT pathway (60%) and hormone receptor positivity (45%) were frequently found. In conclusion, molecular analysis of high-risk endometrial cancer identifies four distinct prognostic subgroups, with potential therapeutic implications. High frequencies of targetable alterations were identified and may serve as targets for individualized treatment.Modern Pathology advance online publication, 27 February 2015; doi:10.1038/modpathol.2015.43.
    Modern Pathology 02/2015; 28(6). DOI:10.1038/modpathol.2015.43 · 6.19 Impact Factor
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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. DOI:10.1186/1471-2407-14-982 · 3.36 Impact Factor
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    ABSTRACT: The Brief Family History Questionnaire (bFHQ) was developed to identify endometrial cancer patients whose family histories suggest Lynch syndrome (LS). We compared the bFHQ, Extended Family History Questionnaire (eFHQ) and dictated medical records (DMR) to determine which family history screening strategy is superior in identifying LS in unselected women with newly diagnosed endometrial cancer that have undergone universal germline testing. Prospective cohort study recruiting women with newly diagnosed endometrial cancer to evaluate screening strategies to identify LS. Participants completed bFHQ and eFHQ, had tumor assessed with immunohistochemistry (IHC) for mismatch repair proteins (MMR) and micro-satellite instability testing and underwent universal germline testing for LS. The sensitivity, specificity, positive and negative predictive values (PPV, NPV) were compared between the family history screening strategies as well as IHC. 118 of 182 eligible patients (65%) consented; 87 patients (74%) were evaluable with both family history and germline mutation status. Median age was 61years (range 26 - 91). All 7 patients with confirmed LS were correctly identified by bFHQ, compared to 5 and 4 by eFHQ and DMR, respectively. The sensitivity, specificity, PPV and NPV values of bFHQ were 100%, 76.5%, 25.9% and 100%, respectively, performing similar to IHC testing. While eFHQ was more specific than bFHQ (86.7% vs. 76.5%, p=0.007), 2 cases of LS were missed. The patient-administered bFHQ effectively identified women with confirmed LS and is a good screening tool to triage women with endometrial cancer for further genetic assessment. Copyright © 2014. Published by Elsevier Inc.
    Gynecologic Oncology 12/2014; 136(2). DOI:10.1016/j.ygyno.2014.12.023 · 3.77 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; 16(1). DOI:10.1016/S1470-2045(14)71135-0 · 24.69 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; 135(2). DOI:10.1016/j.ygyno.2014.06.033 · 3.77 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 10/2014; 111(12). DOI:10.1038/bjc.2014.567 · 4.84 Impact Factor
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    ABSTRACT: Purpose/Objective(s): Angiogenesis is up-regulated in many solid tumors including cervical cancer and may contribute to radioresistance. Pre-clinical studies have shown that sorafenib, an oral multi-targeted kinase inhibitor with antiangiogenic effects, can improve response to radiation therapy (RT). The purpose of this study was to examine the efficacy and toxicity of sorafenib in patients with cervix cancer receiving RT and cisplatin chemotherapy (RTCT). Materials/Methods: This was a prospective phase 1/2 study of sorafenib in patients with locally advanced cervix cancer receiving standard RTCT. There were 6 FIGO IB/IIA, 3 IIB/IIIA and 4 IIIB tumors. Sorafenib 400 mg or 800 mg was administered daily for 1 week prior to the start of RTCT in all patients, as well as during RTCT in 3 patients with high-risk disease. Needle-based measurements of hypoxia and interstitial fluid pressure (IFP), DCEMR and tumor biopsies were obtained before treatment and after 1 week of sorafenib. Biopsy-based markers of proliferation, vascularity, and hypoxia were evaluated by IHC separately in tumor and stroma excluding necrosis. Median follow-up was 4.1 years. Results: At last follow-up, 1 patient had died without achieving disease control and 4 recurred after an initial complete response 2 in pelvis and 2 at distant metastatic sites. Acute toxicity was similar to RTCT alone. Grade 3-4 late toxicity was identified in 5 patients, 1 with pelvic fistulae, 3 with rectal bleeding and 1 with an anal fissure.MR tumor volume increased during treatment with sorafenib alone (mean 78 to 86 cm3, p < 0.01). The ktrans from DCE MR decreased (mean 0.016 to 0.008s-1, p = 0.02) in keeping with a reduction in tumor perfusion and/or vascular permeability. The tumors also became more hypoxic (mean pO2 14 to 3 mm Hg, p = 0.01; and mean hypoxic proportion 51 to 67%, p = 0.06). At baseline, the mean tumor, stromal, and necrotic percentages were 23%, 29%, and 48%, respectively, and remained unchanged after 1 week of sorafenib. Tumor expression of the HIF-dependent genes GLUT1 (p < 0.04) and CXCR4 (p < 0.03) increased with sorafenib, consistent with increased hypoxia. There was a reduction in stromal infiltration by CD11b+ (p = 0.001) and CD66b+ (p = 0.01) myeloid cells, implicated in pre-clinical studies as contributing to disease progression following antiangiogenic treatment or RT. Conclusions: Sorafenib reduces tumor perfusion/permeability and increases hypoxia in cervical cancer suggesting that it is unlikely to improve clinical outcomes when used prior to RT. However, sorafenib also reduces tumor infiltration by myeloid cells that can contribute to vascular persistence and new vessel formation during RT. Further study of the interaction between the angiogenic and chemokine pathways involved in vascular response to RT is warranted, particularly in relation to the potential for combined inhibition during and after treatment.
    International Journal of Radiation OncologyBiologyPhysics 09/2014; 90(1):S187–S188. DOI:10.1016/j.ijrobp.2014.05.717 · 4.26 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 08/2014; 120(15). DOI:10.1002/cncr.28722 · 4.89 Impact Factor
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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. Methods: A 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. Results: A 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 07/2014; 120(24). DOI:10.1002/cncr.28933 · 4.89 Impact Factor
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    ABSTRACT: Objective: 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. Methods: We performed a multicenter, single arm, two-stage phase II study of sunitinib, 50mg daily administered on a 4 weeks on-2 weeks off schedule. Eligibility criteria included recurrent/metastatic EC or carcinosarcoma with no more than one prior line of chemotherapy. The primary endpoint was objective response rate. Results: 34 women were enrolled; 33 received at least one dose of sunitinib and were included in the analyses. Six women (18.1%) had a partial response and six additional women (18.1%) stable disease. In total, ten patients (30.3%) had disease control for at least 6 months and of these, seven were controlled for more than one year. Median progression free and overall survival times were 3 months and 19.4 months, respectively. Adverse events related to treatment were frequent. At least one grade 3 toxicity occurred in 30 patients and dose reductions were required in 17 patients (52%). The most common grade 3 toxicities were fatigue, hypertension, palmar-plantar erythrodysesthesia, diarrhea and hematologic. Conclusion: Sunitinib therapy showed promising activity in women with recurrent EC. Toxicity was seen frequently but was manageable. Anti-angiogenic agents warrant further investigation in EC to define which patients will derive the greatest benefit.
    Gynecologic Oncology 05/2014; 134(2). DOI:10.1016/j.ygyno.2014.05.016 · 3.77 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.
    05/2014; 34:e258-66. DOI:10.14694/EdBook_AM.2014.34.e258

Publication Stats

1k Citations
394.63 Total Impact Points


  • 2008–2015
    • University of Toronto
      • Department of Obstetrics and Gynaecology
      Toronto, Ontario, Canada
  • 2007–2014
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2012–2013
    • University Health Network
      • • Princess Margaret Hospital
      • • Radiation Medicine Program
      Toronto, Ontario, Canada
  • 2010
    • National Cancer Institute
      Μπογκοτά, Bogota D.C., Colombia
  • 2005
    • University of Washington Seattle
      Seattle, Washington, United States