Amit M Oza

University Health Network, Toronto, Ontario, Canada

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Publications (131)914.19 Total impact

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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: Purpose: Randomized ovarian cancer trials, including ICON7, have reported improved progression-free survival (PFS) when bevacizumab was added to conventional cytotoxic therapy. The improvement was modest prompting the search for predictive biomarkers for bevacizumab. Experimental Design: Pre-treatment training (n = 91) and validation (n = 114) blood samples were provided by ICON7 patients. Plasma concentrations of 15 angio-associated factors were determined using validated multiplex ELISAs. Results: The combined values of circulating Ang1 and Tie2 concentrations predicted improved PFS in bevacizumab-treated patients in the training set. Using median concentrations as cut-offs, high Ang1/low Tie2 values were associated with significantly improved PFS for bevacizumab-treated patients (median: 23.0 months versus 16.2, log rank test, p=0.006). High Ang1/high Tie2 values were associated with a poor outcome for bevacizumab-treated patients (median: 12.8 months versus 28.5 months, log rank test p=0.007). Ang1 and Tie2 jointly interacted with the effect of bevacizumab on PFS (pinteraction=0.003). The prognostic indices derived from the training set differentiated classes of high and low probability for progression in the validation set (p = 0.008). Conclusions: The combined values of Ang1 and Tie2 are predictive biomarkers for improved PFS in bevacizumab-treated patients with ovarian cancer.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 06/2014;
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    ABSTRACT: Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival.
    The Lancet Oncology 06/2014; · 25.12 Impact Factor
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    ABSTRACT: The aim of this study was to determine the optimal patient-reported outcome measure (PROM) for assessing symptom benefit in trials of palliative chemotherapy for women with symptomatic ovarian cancer.
    International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 06/2014; 24(5):865-73.
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    ABSTRACT: Background: Low-grade serous (LGS) carcinomas of the ovary, fallopian tube and primary peritoneum are rare and unique tumors for which current therapies (chemotherapy, hormonal) have demonstrated limited efficacy. As LGS carcinoma is characterized by mutations in genes of the RAS/RAF/MEK/ERK signaling pathway, such as BRAF and KRAS, evaluating therapies that target this pathway is warranted. This study will evaluate the efficacy of the MEK1/2 inhibitor binimetinib (MEK162) vs physician’s choice chemotherapy in patients with LGS carcinoma. This study will enroll patients regardless of RAS/RAF mutational status; however, tumor tissue will be retrospectively analyzed for mutations in RAS/RAF and other genes (NCT01849874 ). Methods: This is a 2-arm, open-label, 2:1 randomized Phase 3 study of binimetinib vs physician’s choice chemotherapy (pegylated liposomal doxorubicin, paclitaxel or topotecan). Eligible patients must have LGS carcinoma that is recurrent or persistent following at least 1 prior platinum-based chemotherapy and no more than 3 prior lines of chemotherapy, and must have RECIST v1.1-defined measurable disease confirmed by independent central review. Prior to randomization, independent central review of a patient’s tumor specimen is required to confirm LGS diagnosis. Prior treatment with a MEK or BRAF inhibitor is prohibited. Randomization is stratified by last platinum-free interval and number of prior systemic therapy regimens. The primary endpoint is progression-free survival as determined by blinded independent central review; secondary endpoints include overall survival, overall response, duration of response, disease control rate, safety, quality of life and pharmacokinetics of binimetinib. Binimetinib is administered 45 mg BID orally. Patients receive therapy until disease progression or unacceptable toxicity. This study will enroll 300 patients worldwide. Clinical trial information: NCT01849874.
    Journal of Clinical Oncology 05/2014; Vol 32, No 15_suppl (May 20 Supplement),. · 18.04 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;
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    ABSTRACT: Early prediction of the expected benefit of treatment in recurrent ovarian cancer (ROC) patients may help in drug development decisions. The actual value of 50% CA-125 decrease is being reconsidered. The main objective of the present study was to quantify the links between longitudinal assessments of CA-125 kinetics and progression-free survival (PFS) in treated recurrent ovarian cancer (ROC) patients. The CALYPSO randomized phase III trial database comparing two platinum-based regimens in ROC patients was randomly split into a "learning dataset" and a "validation dataset". A parametric survival model was developed to associate longitudinal modeled CA-125 changes (ΔCA125), predictive factors, and PFS. The predictive performance of the model was evaluated with simulations. The PFS of 534 ROC patients were properly characterized by a parametric mathematical model. The modeled ΔCA125 from baseline to week 6 was a better predictor of PFS than the modeled fractional change in tumor size. Simulations confirmed the model's predictive performance. We present the first parametric survival model quantifying the relationship between PFS and longitudinal CA-125 kinetics in treated ROC patients. The model enabled calculation of the increase in ΔCA125 required to observe a predetermined benefit in PFS to compare therapeutic strategies in populations. Therefore, ΔCA125 may be a predictive marker of the expected gain in PFS and an early predictive tool in drug development decisions.
    Gynecologic Oncology 04/2014; · 3.93 Impact Factor
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    ABSTRACT: The Ovarian Task Force of the Gynecologic Cancer Steering Committee convened a clinical trials planning meeting on October 28-29, 2011, with the goals to identify key tumor types, associated molecular pathways, and biomarkers for targeted drug intervention; review strategies to improve early-phase screening, therapeutic evaluation, and comparison of new agents; and optimize design of randomized trials in response to an evolving landscape of scientific, regulatory, and funding priorities. The meeting was attended by international clinical and translational investigators, pharmaceutical industry representatives, government regulators, and patient advocates. Panel discussions focused on disease types, early-phase trials, and randomized trials. A manuscript team summarized the discussions and assisted with formulating key recommendations. A more integrated and efficient approach for screening new agents using smaller selective randomized trials in specific disease-type settings was endorsed, together with collaborative funding models between industry and the evolving national clinical trials network, as well as efforts to enhance public awareness and study enrollment through advocacy.
    CancerSpectrum Knowledge Environment 03/2014; · 14.07 Impact Factor
  • Leukemia & lymphoma 03/2014; · 2.61 Impact Factor
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    ABSTRACT: Patients with advanced cancer have reduced quality of life, which tends to worsen towards the end of life. We assessed the effect of early palliative care in patients with advanced cancer on several aspects of quality of life. The study took place at the Princess Margaret Cancer Centre (Toronto, ON, Canada), between Dec 1, 2006, and Feb 28, 2011. 24 medical oncology clinics were cluster randomised (in a 1:1 ratio, using a computer-generated sequence, stratified by clinic size and tumour site [four lung, eight gastrointestinal, four genitourinary, six breast, two gynaecological]), to consultation and follow-up (at least monthly) by a palliative care team or to standard cancer care. Complete masking of interventions was not possible; however, patients provided written informed consent to participate in their own study group, without being informed of the existence of another group. Eligible patients had advanced cancer, European Cooperative Oncology Group performance status of 0-2, and a clinical prognosis of 6-24 months. Quality of life (Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being [FACIT-Sp] scale and Quality of Life at the End of Life [QUAL-E] scale), symptom severity (Edmonton Symptom Assessment System [ESAS]), satisfaction with care (FAMCARE-P16), and problems with medical interactions (Cancer Rehabilitation Evaluation System Medical Interaction Subscale [CARES-MIS]) were measured at baseline and monthly for 4 months. The primary outcome was change score for FACIT-Sp at 3 months. Secondary endpoints included change score for FACIT-Sp at 4 months and change scores for other scales at 3 and 4 months. This trial is registered with, number NCT01248624. 461 patients completed baseline measures (228 intervention, 233 control); 393 completed at least one follow-up assessment. At 3-months, there was a non-significant difference in change score for FACIT-Sp between intervention and control groups (3·56 points [95% CI -0·27 to 7·40], p=0·07), a significant difference in QUAL-E (2·25 [0·01 to 4·49], p=0·05) and FAMCARE-P16 (3·79 [1·74 to 5·85], p=0·0003), and no difference in ESAS (-1·70 [-5·26 to 1·87], p=0·33) or CARES-MIS (-0·66 [-2·25 to 0·94], p=0·40). At 4 months, there were significant differences in change scores for all outcomes except CARES-MIS. All differences favoured the intervention group. Although the difference in quality of life was non-significant at the primary endpoint, this trial shows promising findings that support early palliative care for patients with advanced cancer. Canadian Cancer Society, Ontario Ministry of Health and Long Term Care.
    The Lancet 02/2014; · 39.06 Impact Factor
  • Stephanie Lheureux, Amit M Oza
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    ABSTRACT: Introduction: Epithelial ovarian cancer (OC) remains the most lethal gynecologic malignancy. Germline mutations in either breast cancer gene 1(BRCA1) or BRCA2 genes are responsible for 15% of all OC, including those in women without a family history of cancer. Despite an initial response to the first line of treatment based on surgery and chemotherapy, most patients will relapse, highlighting the urgent need to develop smarter treatment options. The family of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors is one of the most promising targeted agents. Areas covered: This report reviews the interest to target DNA repair defects with a focus on olaparib, the most investigated PARP inhibitor (PARPi) in OC. The results of the completed Phase I and II studies are analyzed and discussed with an update on translational research presented at major international congresses. Expert opinion: With five disparate histological subtypes, and a complex genomic landscape, OC remains a therapeutic challenge as evidenced by poor overall survival. Maturing data on olaparib provide evidence of efficacy and safety in the specific subgroup of women with high grade serous OC and BRCA mutations, and it seems likely that PARPi will represent an important step in the personalization of OC treatment.
    Expert Opinion on Orphan Drugs. 01/2014; 2(5).
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    ABSTRACT: The src family of kinases may play a role in the malignant phenotype through effects on migration, motility, adhesion and proliferation. The activity of saracatinib, an orally available inhibitor of src kinases, was evaluated in patients with advanced, platinum-pretreated NSCLC. Eligible patients with advanced NSCLC of any histologic subtype and who had obtained a best response to prior platinum-based chemotherapy of at least stable disease received saracatanib 175 mg orally daily in a 28 day cycle. The primary end point was the proportion of patients progression-free after 4 cycles (16 weeks) of therapy; 8 such patients of 32 evaluable were required to deem the therapy active. Immunohistochemistry for src expression was performed on archival tissue from enrolled patients. Thirty-seven patients received a median of 2 cycles (range, 1-14) each. Six of 31 evaluable patients were progression-free at 16 weeks. Two partial responses were observed, lasting 3.7 and 14.6 months; 1 responder had an EGFR exon 19 deletion. An additional 4 patients had stable disease for at least 4 cycles. The median progression-free and overall survival times were 1.8 and 7.6 months. No correlation between src protein expression and outcome was observed. There may be a subset of saracatinib-responsive NSCLC that is currently molecularly undefined. Further studies of this agent in a population preselected for target mutations that potentially relevant to src pathways, such as EGFR, should be considered.
    Clinical Lung Cancer 10/2013; · 2.04 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: To evaluate the use and objectives of expansion cohorts in phase I cancer trials and to explore trial characteristics associated with their use. We performed a systematic review of MEDLINE and EMBASE, limiting studies to single-agent phase I trials recruiting adults and published after 2006. Eligibility assessment and data extraction were performed by two reviewers. Data were assessed descriptively, and associations were tested by univariable and multivariable logistic regression. We identified 611 unique phase I cancer trials, of which 149 (24%) included an expansion cohort. The trials were significantly more likely to use an expansion cohort if they were published more recently, were multicenter, or evaluated a noncytotoxic agent. Objectives of the expansion cohort were reported in 74% of trials. In these trials, safety (80%), efficacy (45%), pharmacokinetics (28%), pharmacodynamics (23%), and patient enrichment (14%) were cited as objectives. Among expansion cohorts with safety objectives, the recommended phase II dose was modified in 13% and new toxicities were described in 54% of trials. Among trials aimed at assessing efficacy, only 11% demonstrated antitumor activity assessed by response criteria that was not previously observed during dose escalation. The utilization of expansion cohorts has increased with time. Safety and efficacy are common objectives, but 26% fail to report explicit aims. Expansion cohorts may provide useful supplementary data for phase I trials, particularly with regard to toxicity and definition of recommended dose for phase II studies.
    Journal of Clinical Oncology 10/2013; · 18.04 Impact Factor
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    ABSTRACT: In this randomized phase 2 study, the authors assessed the efficacy and safety of intravenous aflibercept at 2 different doses (2 mg/kg or 4 mg/kg) in patients with recurrent, platinum-resistant ovarian, peritoneal, or fallopian tube cancer who developed disease progression after receiving topotecan and/or pegylated liposomal doxorubicin. Patients were randomized to receive intravenous aflibercept at a dose of either 2 mg/kg or 4 mg/kg every 2 weeks until they developed disease progression or significant toxicity. The primary endpoint was to evaluate Response Evaluation Criteria in Solid Tumor response rates (overall response rate [ORR] = complete responses plus partial responses) and to test the null hypothesis (ORR, >5%). Secondary endpoints included time to tumor progression, safety, progression-free survival/overall survival, drug pharmacokinetics, and immunogenicity. In total, 67 evaluable patients per cohort were planned based on a Simon 2-stage design, and, if those patients responded, then enrollment could extend to 200 patients. Tumor radiographic response was assessed by investigators and by an independent review committee. After the first 84 evaluable patients, 8 unconfirmed partial responders were noted (ORR, 10%) across both arms; the Independent Data Monitoring Committee recommended continuing blinded accrual. At study completion, 215 evaluable patients were accrued, including 1 responder of 106 patients (0.9%) in the 2-mg/kg cohort and 5 responders of 109 patients (4.6%) in the 4-mg/kg cohort according to the independent review committee. The clinical benefit rate (ORR plus stable disease >6 months) was 12.3% and 11% in the 2-mg/kg and 4-mg/kg cohorts, respectively. Treatment-related grade 3 and 4 adverse events included hypertension (25.5% and 27.5% in the 2-mg/kg and 4-mg/kg cohorts, respectively), proteinuria (9.4% and 7.3%, respectively), and fatigue (5.7% and 3.7%, respectively). The gastrointestinal perforation rate was low (3 patients; 1.4%). Aflibercept at a dose of either 2 mg/kg or 4 mg/kg was generally well tolerated but did not meet the primary endpoint for response. Cancer 2013. © 2013 American Cancer Society.
    Cancer 10/2013; · 5.20 Impact Factor
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    ABSTRACT: Chemotherapy for platinum-resistant/refractory ovarian cancer is motivated by the hope of benefit. We sought to determine the relationships between: (a) trait hope, expectation of symptom benefit from chemotherapy, and anxiety and depression; (b) hope and perceived efficacy of chemotherapy; and (c) unfulfilled hope (where expectations for benefit are not fulfilled) and depression. Adult patients enrolled within stage 1 of the Gynecologic Cancer Intergroup Symptom Benefit Study were included. Reported outcomes were collected from 126 women with predominantly platinum-resistant ovarian cancer at baseline, prior to the first four treatment cycles (12-16 weeks), and four weeks after completing chemotherapy or at disease progression, whichever came first. Associations were assessed with Spearman rank correlation coefficient (r) and odds ratio. Trait hope and expectation of symptom benefit from chemotherapy were weakly correlated with each other (r = 0.25). Trait hope, but not expectation of symptom benefit, was negatively correlated with anxiety (r = -0.43) and depression (r = -0.50). The smaller the discrepancy between perceived and expected symptom benefit, the less likely the patient was to have scores indicative of depression (odds ratio: 0.68; 95% confidence interval: 0.49-0.96; p = .026). Trait hope and expectation of symptom benefit from chemotherapy appear to be distinct and independent of the aspects of quality of life and scores for depression. Hope did not appear to affect perceived efficacy of chemotherapy in alleviating symptoms, but women whose expectation of symptom benefit from chemotherapy was not fulfilled were more likely to have scores indicative of depression. It may be preferable to encourage hope toward achievable goals rather than toward benefits from chemotherapy.
    The Oncologist 10/2013; · 4.10 Impact Factor
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    ABSTRACT: Temsirolimus (TEM) has recently shown activity (NCIC CTG phase II trial) in endometrial cancer (EC). Despite EC having a high rate of PTEN mutation, in this trial activity was independent of PTEN and other molecular markers. We explored whether treatment related toxicity occurring in cycle one was predictive of outcomes. Patients were those enrolled on two sequential phase II studies of the NCIC CTG that evaluated single agent TEM in women with recurrent or metastatic chemotherapy naïve or treated EC. An exploratory landmark analysis examined the relationship between early treatment related toxicities as well as prior chemotherapy and efficacy outcomes (response, progression, and tumour size shrinkage) in univariate and multivariate analyses. The relationship between molecular markers and outcomes were also reexamined in patients. Mucositis, diarrhea, decrease absolute neutrophil count, as well as elevated glucose, or cholesterol were not independent predictors of response or progression. Highest fasting triglyceride predicted for a 3.5% tumour shrinkage from baseline. Women previously treated with chemotherapy were at 7.37 times greater risk of progression and experienced 20.9% increased tumour growth compared to chemotherapy naïve women. Molecular markers were not predictors of response or progression. Except for elevation in fasting triglyceride being associated with minimal tumour shrinkage, no other relationship between efficacy and TEM induced adverse events were found. mTOR inhibition activity in EC seems greatest in chemo-naive patients. Future studies of mTOR inhibitors in EC should focus on women without prior chemotherapy while continuing to explore molecular mechanisms of benefit.
    Gynecologic Oncology 08/2013; · 3.93 Impact Factor
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    ABSTRACT: Preclinical data suggest that exposure to poly(ADP-ribose) polymerase inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated. We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200mg twice-daily for ≥1 month. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing. Data were collected from 89 patients who received a median of 3 (range 1-11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by RECIST and 45% (35/78) by RECIST and/or GCIG-CA125 criteria with median progression-free (PFS) and overall survival (OS) of 17 weeks (95%-CI: 13-21) and 34 weeks (95%-CI: 26-42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19/48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95%-CI: 15-29) and OS of 45 weeks (95%-CI: 15-75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of 6 PARPi-resistant patients (estimated frequency of such mutations adjusted for sample size: 0.125 [95%-CI: 0-0.375]). Heavily pre-treated, PARPi-resistant PBMCOC retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC.
    Clinical Cancer Research 08/2013; · 7.84 Impact Factor
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    ABSTRACT: Radiotherapy with concurrent cisplatin (CRT) is standard treatment for locally advanced cervical cancer. However, not all patients benefit from the addition of cisplatin to RT alone. This study explored the value of pre-treatment tumor interstitial fluid pressure (IFP) and hypoxia measurements as predictors of cisplatin response in 291 patients who were treated with RT (1994-1998) or RT plus concurrent cisplatin (1999-2009). Clinical characteristics were similar between the two groups, apart from a greater proportion of patients with pelvic lymph node metastases and hypoxic tumors in the CRT cohort. Patients were followed for a median duration of 5.6 years. Information about recurrence and survival was recorded prospectively. The addition of cisplatin to RT improved survival compared to treatment with RT alone (HR 0.61, p=0.0097). This improvement was confined to patients with high-IFP tumors at diagnosis (HR 0.40, p=0.00091). There was no benefit of adding cisplatin in those with low-IFP tumors (HR 1.05, p=0.87). There was no difference in the effectiveness of cisplatin in patients with more or less hypoxic tumors. In conclusion, patients with locally advanced cervical cancer and high tumor IFP at diagnosis have greater benefit from the addition of cisplatin to RT than those with low IFP. This may reflect high tumor cell proliferation, which is known to influence IFP, local tumor control and patient survival.
    International Journal of Cancer 07/2013; · 6.20 Impact Factor
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    ABSTRACT: Background:The Notch signalling pathway has been implicated in tumour initiation, progression, angiogenesis and development of resistance to vascular endothelial growth factor (VEGF) targeting, providing a rationale for the combination of RO4929097, a γ-secretase inhibitor, and cediranib, a VEGF receptor tyrosine kinase inhibitor.Methods:Patients received escalating doses of RO4929097 (on a 3 days-on and 4 days-off schedule) in combination with cediranib (once daily). Cycle 1 was 42 days long with RO4929097 given alone for the first 3 weeks followed by the co-administration of both RO4929097 and cediranib starting from day 22. Cycle 2 and onwards were 21 days long. Soluble markers of angiogenesis were measured in plasma samples. Archival tumour specimens were assessed for expression of three different components of Notch signalling pathway and genotyping.Results:In total, 20 patients were treated in three dose levels (DLs). The recommended phase II dose was defined as 20 mg for RO4929097 on 3 days-on and 4 days-off schedule and 30 mg daily for cediranib. The most frequent treatment-related adverse events (AEs) were diarrhoea, hypertension, fatigue and nausea. Eleven patients had a best response of stable disease and one patient achieved partial response. We did not detect any correlation between tested biomarkers of angiogenesis or the Notch pathway and treatment effect. There was no correlation between mutational status and time to treatment failure.Conclusion:RO4929097 in combination with cediranib is generally well tolerated at the DLs tested. Preliminary evidence of antitumour efficacy with prolonged disease stabilisation in some patients with progressive malignancies warrants further clinical investigation of this treatment strategy.British Journal of Cancer advance online publication, 18 July 2013; doi:10.1038/bjc.2013.380
    British Journal of Cancer 07/2013; · 5.08 Impact Factor

Publication Stats

3k Citations
914.19 Total Impact Points


  • 2005–2014
    • University Health Network
      Toronto, Ontario, Canada
  • 2003–2014
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 1997–2014
    • University of Toronto
      • • Department of Medicine
      • • Department of Radiation Oncology
      Toronto, Ontario, Canada
  • 2013
    • Hospices Civils de Lyon
      Lyons, Rhône-Alpes, France
    • New York Presbyterian Hospital
      New York City, New York, United States
  • 2012
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2011
    • Vancouver Prostate Centre
      Vancouver, British Columbia, Canada
    • BC Cancer Agency
      Vancouver, British Columbia, Canada
  • 2010
    • Peter MacCallum Cancer Centre
      • Department of Medical Oncology
      Melbourne, Victoria, Australia
  • 2008
    • University of Southern California
      Los Angeles, California, United States
    • Hamilton Health Sciences
      Hamilton, Ontario, Canada
  • 2007
    • Regional Integration Cancer Center
      Мендоса, Mendoza, Argentina
  • 2002
    • Ottawa Regional Cancer Foundation
      Ottawa, Ontario, Canada
  • 2000
    • Ontario Institute for Cancer Research
      Toronto, Ontario, Canada