Jo Ballot

St. Vincents University Hospital, Dublin, Leinster, Ireland

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Publications (20)79.51 Total impact

  • [Show abstract] [Hide abstract] ABSTRACT: Background H+ breast cancer (BC) is an aggressive variant of BC with earlier and more frequent metastatic relapse than HER2 normal disease. Following the reports in 2005 of several large random assignment trials, which showed that the anti-HER2 monoclonal antibody T improved the outcome of pts with H+ESBC receiving cytotoxic chemotherapy, we introduced T as a routine component of standard adjuvant therapy for all pts with H+ESBC at our institution. Others had received it investigationally from 2000-2004. We report our 14 year experience with adjuvant (AdjT) and neo-Adjuvant (NAdjT) therapy with T. Methods We compiled a comprehensive database of all pts ever treated at our institution with AdjT or NAdjT for H+ESBC. All pts were cross-checked through the pathology, pharmacy and medical oncology datasets, and all cases were individually reviewed. Results Out of 764 pts included in the H+BC medical oncology database, we identified 518 pts (AdjT=373, NAdjT=145) with stage I-III disease treated with T between August 2000 and October 2014. Pts characteristics are median age: 54-yrs (range 26-86); hormone-receptor (HR) status: HR positive (HR+) 64%/HR negative (HR-) 35%/HR unknown 1%; lymph node positive (LN+) 52% (AdjT: 44%/NAdjT 72%); and T-containing systemic therapy: TCH (docetaxel/carboplatin/trastuzumab) 306 (59%), anthracycline and taxane regimens-85 (16%), single-agent taxane 48 (9%), other regimens or T without chemotherapy 79 (15%). The database lock out date was May 31st 2015. The median follow-up time is 50.6-months (range 1.4-156.6). The overall relapse rate (RR) in the whole population is 8.9% (AdjT 9.4%/NAdjT 7.6%) and distant RR is 8.3% (AdjT 9.1%/NAdjT 6.2%). Overall survival (OS) rate in the whole study population is 93.4% (AdjT 92.5%/NAdjT 95.9%). RR was lower in pts with HR+ [7.2% (AdjT 7.1%/NAdjT 7.8%)] than in those with HR- [10.6% (AdjT 11.9%/NAdjT 7.4%)] disease. Among all the subgroups analyzed the lowest RR was observed in the HR+/LN- subgroup (2.7%) whilst the highest was in the HR-/LN+ subgroup (15.5%). Pts treated in the NAdjT cohort had a pathological complete response (pCR) rate of 38.6%. In the whole study population the median time to relapse was 31.8-months (range 7.9-97.6) with no difference between the AdjT and NAdjT cohorts. 87% of all relapses happened within 60-months of first T. Out of 6 delayed relapses (observed after 60-months) 4 were HR+, 1 was HR unknown and 1 was HR- in the form of a contralateral axillary recurrence, possibly from a second occult breast primary. Among pts treated prior to March 2010 (N=267), who have a minimum follow-up of 5-yrs, the RFS is 86.5% and the OS rate of 89.1%. Conclusions The prognosis of pts with H+ESBC in the T era is excellent. Despite the large proportion of pts with LN+ disease in our database, over 90% are alive at almost 5-yrs. HR+ confers a better prognosis than HR- in both LN+ and LN- disease. Long term outcome data show that nearly 90% of all relapses occur within 5-yrs from initiation of anti-HER2 therapy especially in the HR- subgroup. Late relapse is rare in ER- pts. Adjuvant hormonal therapy is likely to contribute meaningfully to the favourable outcome of HR+/H+ ESBC and may explain the discordance between the improved survival of ER+ Adjuvant pts and the improved pCR reported for NAdjT in ER+ pts.
    No preview · Poster · Dec 2015
  • No preview · Article · Sep 2015
  • [Show abstract] [Hide abstract] ABSTRACT: Doxorubicin (Dox), a mainstay of adjuvant breast cancer treatment, is associated with cardiac toxicity in the form of left ventricular dysfunction (LVD), LV diastolic dysfunction, or LV systolic dysfunction. Study objectives were to evaluate the prevalence of LVD in long-term breast cancer survivors treated with Dox and determine if brain-type natriuretic peptide (BNP) may help identify patients at risk for LVD. Patients who participated in prospective clinical trials of adjuvant Dox-based chemotherapy for breast cancer with a baseline left ventricular (LV) ejection fraction evaluation from 1999 to 2006 were retrospectively identified from the St Vincent's University Hospital database. Patients were invited to undergo transthoracic echocardiography, BNP analysis, and cardiovascular (CV) risk factor assessment. LVDD was defined as left atrial volume index >34 mL/m(2) and/or lateral wall E prime <10 m/s, and LVSD as LVEF <50 %. Of 212 patients identified, 154 participated, 19 patients had died (no cardiac deaths), and 39 declined. Mean age was 60.7 [55:67] years. A majority of the patients (128, 83 %) had low CV risk (0/1 risk factors), 21 (13.6 %) had 2 RFs, and 5 (3.2 %) ≥3 RFs. BMI was 27.2 ± 4.9 kg/m(2). Median Dox dose was 240 mg/m(2) [225-298]; 92 patients (59.7 %) received ≤240 mg/m(2) and 62 (40.3 %) > 240 mg/m(2). Baseline LVEF was 68.2 ± 8 %. At follow-up of 10.8 ± 2.2 years, LVEF was 64.4 ± 6 %. Three (1.9 %) subjects had LVEF <50 % and one (0.7 %) had LVDD. Dox >240 mg/m2 was associated with any LVEF drop. BNP levels at follow-up were 20.3 pg/ml [9.9-36.5] and 21.1 pg/ml [9.8-37.7] in those without LVD and 61.5 pg/ml [50-68.4] in those with LVD (p = 0.04). Long-term prospective data describing the impact of Dox on cardiotoxicity are sparse. At over 10 years of follow-up, decreases in LVEF are common, and dose related, but LVD as defined is infrequent (2.6 %). Monitoring with BNP for subclinical LVD needs further evaluation.
    No preview · Article · Sep 2015 · Breast Cancer Research and Treatment
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    [Show abstract] [Hide abstract] ABSTRACT: Lung cancer is the second most common type of cancer in the world and is the most common cause of cancer-related death in both men and women. Research into causes, prevention and treatment of lung cancer is ongoing and much progress has been made recently in these areas, however survival rates have not significantly improved. Therefore, it is essential to develop biomarkers for early diagnosis of lung cancer, prediction of metastasis and evaluation of treatment efficiency, as well as using these molecules to provide some understanding about tumour biology and translate highly promising findings in basic science research to clinical application. In this investigation, two-dimensional difference gel electrophoresis and mass spectrometry were initially used to analyse conditioned media from a panel of lung cancer and normal bronchial epithelial cell lines. Significant proteins were identified with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1), pyruvate kinase M2 isoform (PKM2), Hsc-70 interacting protein and lactate dehydrogenase A (LDHA) selected for analysis in serum from healthy individuals and lung cancer patients. hnRNPA2B1, PKM2 and LDHA were found to be statistically significant in all comparisons. Tissue analysis and knockdown of hnRNPA2B1 using siRNA subsequently demonstrated both the overexpression and potential role for this molecule in lung tumorigenesis. The data presented highlights a number of in vitro derived candidate biomarkers subsequently verified in patient samples and also provides some insight into their roles in the complex intracellular mechanisms associated with tumour progression.
    Full-text · Article · Dec 2014 · Molecular BioSystems
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    [Show abstract] [Hide abstract] ABSTRACT: Background Serum profiling using mass spectrometry-based proteomic techniques has great potential to detect biomarkers that might improve the management for advanced breast cancer patients. The albuminome has previously been investigated as a tool in biomarker discovery, however other high abundant blood proteins are also likely to sequester potentially interesting molecules. Methods Affinity resin purified and isolated Transferrin and associated bound proteins from normal control and breast cancer patient serum samples were analysed by label-free mass spectrometry during the discovery phase. Results 21 significant proteins were identified with Fibrinogen and Fibronectin selected for further analysis in an independent sample set, with significant difference found when comparing the controls groups (normal healthy control, inflammatory bowel disease and benign breast disease) to stage IV breast cancer. Conclusions The area under the curve value for Fibrinogen compared favourably with cancer antigen 15-3, an established breast cancer tumour marker. A combination of all three biomarkers improved accuracy when comparing control/benign to stage V breast cancer patient groups. General Significance Mass spectrometry profiling of Transferrin-bound proteins has revealed serum proteins that can distinguish between serum from advanced breast cancer patients and healthy control subjects with high confidence.
    Full-text · Article · Dec 2014 · Biochimica et Biophysica Acta - Clinical
  • [Show abstract] [Hide abstract] ABSTRACT: Evaluation of protein and metabolite expression patterns in blood using mass spectrometry and high-throughput antibody-based screening platforms has potential for the discovery of new biomarkers for managing breast cancer patient treatment. Previously identified blood-based breast cancer biomarkers, including cancer antigen 15.3 (CA15-3) are useful in combination with imaging (computed tomography scans, magnetic resonance imaging, X-rays) and physical examination for monitoring tumour burden in advanced breast cancer patients. However, these biomarkers suffer from insufficient levels of accuracy and with new therapies available for the treatment of breast cancer, there is an urgent need for reliable, non-invasive biomarkers that measure tumour burden with high sensitivity and specificity so as to provide early warning of the need to switch to an alternative treatment. The aim of this study was to identify a biomarker signature of tumour burden using cancer and non-cancer (healthy controls/non-malignant breast disease) patient samples. Results demonstrate that combinations of three candidate biomarkers from Glutamate, 12-Hydroxyeicosatetraenoic acid, Beta-hydroxybutyrate, Factor V and Matrix metalloproteinase-1 with CA15-3, an established biomarker for breast cancer, were found to mirror tumour burden, with AUC values ranging from 0.71 to 0.98 when comparing non-malignant breast disease to the different stages of breast cancer. Further validation of these biomarker panels could potentially facilitate the management of breast cancer patients, especially to assess changes in tumour burden in combination with imaging and physical examination.
    No preview · Article · Jun 2014 · Metabolomics
  • No preview · Article · Dec 2012 · Cancer Research
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    [Show abstract] [Hide abstract] ABSTRACT: Insulin-like growth factor-1 receptor (IGF1R) signalling is implicated in resistance to trastuzumab. However, the benefit of co-targeting HER2 and IGF1R has not been extensively studied, and the relationship between activated IGF1R and clinical response to trastuzumab has not been reported. This study aimed to evaluate the combination of trastuzumab with IGF1R tyrosine kinase inhibitors (TKIs) in a panel of HER2-positive breast cancer cell lines, and to examine the relationship between IGF1R expression and activation and response to trastuzumab in HER2-positive breast cancer patients. The anti-proliferative effects of trastuzumab combined with IGF1R TKIs BMS-536924 or NVP-AEW541 were measured in nine HER2-positive cell lines. IGF1R and phosphorylated IGF1R/insulin receptor (pIGF1R/IR) were measured by immunohistochemistry in 160 tumour samples from trastuzumab-treated patients (ICORG 06-22). The HER2-positive cell lines displayed varying sensitivity to IGF1R TKIs alone (IC(50)s: 0.7 to >10 μM). However, when combined with trastuzumab, a significantly enhanced effect was observed in five cell lines treated with BMS-536924, and three with NVP-AEW541. While IGF1R levels correlated with reduced response to NVP-AEW541 alone, neither IGF1R nor pIGF1R were predictive of response to BMS-536924 or NVP-AEW541 in combination with trastuzumab. Low HER2 levels correlated with response to BMS-536924 in combination with trastuzumab. Akt levels correlated with improved response to trastuzumab and NVP-AEW541 (P = 0.039). Cytoplasmic IGF1R staining was observed in all tumours, membrane IGF1R was detected in 13.8 %, and pIGF1R/IR was detected in 48.8 %. Although membrane IGF1R staining was associated with larger tumour size (P = 0.041), and lower tumour grade (P = 0.024), no association between IGF1R or pIGF1R/IR and patient survival was observed. In conclusion, while neither IGF1R expression nor activation was predictive of response to trastuzumab, these pre-clinical data provide evidence that co-targeting HER2 and IGF1R may be beneficial in some HER2-amplified breast cancers.
    Preview · Article · Nov 2012 · Breast Cancer Research and Treatment
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    [Show abstract] [Hide abstract] ABSTRACT: Early detection, clinical management and disease recurrence monitoring are critical areas in cancer treatment in which specific biomarker panels are likely to be very important in each of these key areas. We have previously demonstrated that levels of alpha-2-heremans-schmid-glycoprotein (AHSG), complement component C3 (C3), clusterin (CLI), haptoglobin (HP) and serum amyloid A (SAA) are significantly altered in serum from patients with squamous cell carcinoma of the lung. Here, we report the abundance levels for these proteins in serum samples from patients with advanced breast cancer, colorectal cancer (CRC) and lung cancer compared to healthy controls (age and gender matched) using commercially available enzyme-linked immunosorbent assay kits. Logistic regression (LR) models were fitted to the resulting data, and the classification ability of the proteins was evaluated using receiver-operating characteristic curve and leave-one-out cross-validation (LOOCV). The most accurate individual candidate biomarkers were C3 for breast cancer [area under the curve (AUC) = 0.89, LOOCV = 73%], CLI for CRC (AUC = 0.98, LOOCV = 90%), HP for small cell lung carcinoma (AUC = 0.97, LOOCV = 88%), C3 for lung adenocarcinoma (AUC = 0.94, LOOCV = 89%) and HP for squamous cell carcinoma of the lung (AUC = 0.94, LOOCV = 87%). The best dual combination of biomarkers using LR analysis were found to be AHSG + C3 (AUC = 0.91, LOOCV = 83%) for breast cancer, CLI + HP (AUC = 0.98, LOOCV = 92%) for CRC, C3 + SAA (AUC = 0.97, LOOCV = 91%) for small cell lung carcinoma and HP + SAA for both adenocarcinoma (AUC = 0.98, LOOCV = 96%) and squamous cell carcinoma of the lung (AUC = 0.98, LOOCV = 84%). The high AUC values reported here indicated that these candidate biomarkers have the potential to discriminate accurately between control and cancer groups both individually and in combination with other proteins.
    Full-text · Article · Aug 2012 · International Journal of Cancer
  • [Show abstract] [Hide abstract] ABSTRACT: Early detection, clinical management and disease recurrence monitoring are critical areas in cancer treatment in which specific biomarker panels are likely to be very important in each of these key areas. We have previously demonstrated that levels of AHSG, C3, CLI, HP and SAA are significantly altered in serum from patients with squamous cell carcinoma of the lung. Here, we report the abundance levels for these proteins in serum samples from advanced breast, CRC (colorectal cancer) and lung cancer patients compared to healthy controls (age and gender matched) using commercially available ELISA kits. Logistic regression models were fitted to the resulting data and the classification ability of the proteins was evaluated using receiver operating characteristic (ROC) curve and leave-one-out cross validation (LOOCV). The most accurate individual candidate biomarkers were C3 for breast cancer (AUC=0.89, LOOCV=73%), CLI for CRC (AUC=0.98, LOOCV=90%), HP for small cell lung carcinoma (AUC=0.97, LOOCV=88%), C3 for lung adenocarcinoma (AUC=0.94, LOOCV=89%) and HP for squamous cell carcinoma of the lung (AUC=0.94, LOOCV=87%). The best dual combination of biomarkers using logistic regression analysis were found to be AHSG+C3 (AUC=0.91, LOOCV=83%) for breast cancer, CLI+HP (AUC=0.98, LOOCV=92%) for CRC, C3+SAA (AUC=0.97, LOOCV=91%) for small cell lung carcinoma and HP+SAA for both lung adenocarcinoma (AUC=0.98, LOOCV=96%) and squamous cell carcinoma of the lung (AUC=0.98, LOOCV=84%). The high AUC values reported here indicated that these candidate biomarkers have the potential to discriminate accurately between control and cancer groups both individually and in combination with other proteins. (c) 2011 Wiley-Liss, Inc.
    No preview · Article · Jan 2012
  • No preview · Article · May 2011 · Journal of Clinical Oncology
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    [Show abstract] [Hide abstract] ABSTRACT: Malignant melanoma, generally described as incurable, is notoriously refractory to chemotherapy. The mechanisms contributing to this have not yet been defined and the contributions of drug efflux pumps, implicated in chemo-resistance of many other cancer types, have not been extensively investigated in melanoma. In this study, expression of multi-drug resistant (MDR1/P-gp and MRP-1) proteins was examined, by immunohistochemistry, in archival specimens from 134 melanoma patients. This included 92 primary tumours and 42 metastases. On assessing all specimens, MRP-1 and MDR1/P-gp expression was found to be common, with the majority (81%) of melanomas expressing at least one of these efflux pumps. Although there is significant association between expression of these pumps (P=0.007), MRP-1 was found to be the predominant (67% of cases) form detected. chi(2) analysis showed significant associations between expression of MRP-1 and/or MDR1/P-gp and the aggressive nature of this disease specifically increased Breslow's depth, Clark's level and spread to lymph nodes. This association with aggressiveness and spread is further supported by the observation that a significantly higher percentage of metastases, than primary tumours, express MRP-1 (91% vs 57%; P<0.0001) and MDR1/P-gp (74% vs 50%; P=0.010). The predominant expression of these pumps and, in particular, MRP-1 suggests that they may be important contributors to the inherent aggressive and resistant nature of malignant melanoma.
    Full-text · Article · Mar 2010 · British Journal of Cancer
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    [Show abstract] [Hide abstract] ABSTRACT: Background Renal cell carcinoma patients respond poorly to conventional chemotherapy, this unresponsiveness may be attributable to multidrug resistance (MDR). The mechanisms of MDR in renal cancer are not fully understood and the specific contribution of ABC transporter proteins which have been implicated in the chemoresistance of various cancers has not been fully defined in this disease. Methods In this retrospective study the expression of two of these transporter efflux pumps, namely MDR-1 P-gp (ABCB1) and MRP-1 (ABCC1) were studied by immunohistochemistry in archival material from 95 renal cell carcinoma patients. Results In the first study investigating MDR-1 P-gp and MRP-1 protein expression patterns in renal cell carcinoma patients, high levels of expression of both efflux pumps are observed with 100% of tumours studied showing MDR-1 P-gp and MRP-1 positivity. Conclusion Although these findings do not prove a causal role, the high frequency of tumours expressing these efflux pumps suggests that they may be important contributors to the chemoresistance of this tumour type.
    Full-text · Article · Jul 2009 · BMC Urology
  • [Show abstract] [Hide abstract] ABSTRACT: Most lung cancers are diagnosed too late for curative treatment to be possible, therefore early detection is crucial. Serum proteins are a rich source of biomarkers and have the potential to be used as diagnostic and prognostic indicators for lung cancer. In order to examine differences in serum levels of specific proteins associated with human lung squamous carcinoma, immunodepletion of albumin and five other high-abundant serum proteins followed by 2-D difference gel electrophoresis (DIGE) analysis and subsequent MS was used to generate a panel of proteins found to be differentially expressed between the cancer and normal samples. Proteins found to have increased abundance levels in squamous cell carcinoma sera compared to normal sera included apolipoprotein A-IV precursor, chain F; human complement component C3c, haptoglobin, serum amyloid A protein precursor and Ras-related protein Rab-7b. Proteins found to have lower abundance levels in squamous cell carcinoma sera compared to normal sera included alpha-2-HS glycoprotein, hemopexin precursor, proapolipoprotein, antithrombin III and SP40; 40. The data presented here demonstrate that high-abundant protein removal combined with 2-D DIGE is a powerful strategy for the discovery of potential biomarkers. The identification of lung cancer-specific biomarkers is crucial to early detection, which in turn could lead to a dramatic increase in survival rates.
    No preview · Article · Dec 2007 · Electrophoresis
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    [Show abstract] [Hide abstract] ABSTRACT: Pancreatic cancer is one of the most challenging solid organ malignancies. This is due to its aggressiveness, frequent late presentation as advanced disease and chemoresistance. A better understanding of the molecular basis of its drug resistance is needed. In this study, the first of its kind, the expression of both MDR1 P-gp and MRP-1 protein in pancreatic tumour specimens was examined by immunohistochemistry. Expression of these drug efflux pumps was examined using semi-quantitative immunohistochemistry according to the percentage of cells within the tumour, demonstrating another staining intencity. Overall, 93.3% of pancreatic carcinomas expressed MDR1 P-gp, approximately 31% co-expressed MRP-1 with MDR1 P-gp, while 6.7% expressed neither of these proteins. Our results show that drug efflux pumps, in particular that of MDR1 P-gp, are frequently expressed in pancreatic cancer. While a causative role for these efflux pumps in pancreatic cancer chemoresistance cannot necessarily be concluded, the information presented here should be considered when selecting chemotherapy/drug efflux pump inhibitors for future therapies.
    Full-text · Article · Jul 2007 · Anticancer research
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    [Show abstract] [Hide abstract] ABSTRACT: Multiple drug resistance (MDR), both inherent and acquired, is a serious problem in non-small cell lung carcinomas (NSCLC). The purpose of this study was to investigate the prevalence of expression of genes encoding drug efflux pumps, MDR1 and MRP-1, at both the mRNA and protein levels, in this type of cancer. Tumour specimens (38 cases) were analysed using immunohistochemistry and, where possible (30 cases), also using reverse-transcriptase polymerase chain reaction. The results from this analysis indicated that either, or both, drug efflux pumps were frequently expressed in NSCLC. Expression of mrp1 was found to be predominant over mdr1 at the mRNA level, while MDR1 P-gp was more frequently detected than MRP-1 protein. In some cases, proteins encoding pumps were detected without corresponding mRNAs--possibly due to differing sensitivities of the analysis techniques. Future studies of mdr1 and mrp1 using increased-sensitivity qPCR techniques, in parallel with protein analysis, in larger cohorts of cases may help to elucidate the role of drug efflux pumps in NSCLC multiple drug resistance.
    Full-text · Article · May 2007 · Anticancer research
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    [Show abstract] [Hide abstract] ABSTRACT: Multi-drug resistance mediated by ATP-binding cassette trans-membrane protein pumps is an important cause of cancer treatment failure. Sulindac has been shown to be a competitive substrate for the clinically important resistance protein, multi-drug resistance protein-1 (MRP-1), and thus might enhance the anti-cancer activity of substrate chemotherapeutic agents, e.g. anthracyclines. We conducted a dose-escalating, single arm, prospective, open label, non-randomised phase I trial of epirubicin (75 mg/m(2)) in combination with escalating oral doses of sulindac (0-800 mg) in patients with advanced cancer to identify an appropriate dose of sulindac to use in future resistance studies. Anthracycline and sulindac pharmacokinetics were studied in cycles 1 and 3. Seventeen patients (8 breast, 3 lung, 2 bowel, 1 melanoma, 1 renal, 1 ovarian and 1 of unknown primary origin, 16/17 having had prior chemotherapy) were enrolled. Eight patients received a full six cycles of treatment; 14 patients received three or more cycles. Dose-limiting toxicity was observed in two patients at 800 mg sulindac (1 renal impairment, 1 fatal haemoptysis in a patient with advanced lung cancer), and sulindac 600 mg was deemed to be the maximum tolerated dose. Sulindac had no effect on epirubicin pharmacokinetics. Among 15 patients with evaluable tumour, two partial responses were seen (malignant melanoma and breast cancer). Four others had prolonged stable disease. Epirubicin 75 mg/m(2) and sulindac 600 mg are the recommended doses for phase II studies for these agents in combination.
    Full-text · Article · Feb 2007 · Cancer Chemotherapy and Pharmacology
  • No preview · Conference Paper · Jan 2006
  • No preview · Conference Paper · Mar 2005
  • No preview · Article · Sep 1999 · European Journal of Cancer